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Overview of Genetic Concepts.

by Bill Tillier

• TABLE OF CONTENTS
• Introduction
• Part 1. Basic Overview of Genetics.
  1A). Basic Chemistry
  1B). Basic Genetics Overview
  1C). Protein Synthesis
  1D). Summary from Matt Ridley
  1E). A Newer View of How Genes Work by Gary Marcus.
  1F). Overall Summary
• .
• Power Point Overview of Basic Genetics.
• .
• 2). Mendelian model of inheritance
• .
• 3A). Alleles
  3B). Heterozygous, homozygous and hemizygous genes
  3C). Genetic Relatedness
• .
• 4A). Autosomal Chromosomes
  4B). Inheritance of Genetic Diseases - Overview
  4C). Autosomal Recessive Disorders
  4D). Autosomal Dominant Disorders
• .
• 5A). Sex Chromosomes
  5B). Y chromosomes
  5C). Y-linked
  5D). X chromosomes
  5E). X-linked dominant inheritance
  5F). X-linked recessive inheritance
  5G). Other Sex Chromosomal Abnormalities
  5H). Inheritance of sex chromosomes
• .
• 6A). Inheritance - Sexual reproduction and sex determination
  6B). Sexual reproduction - chromosome numbers
  6C). Mitosis, the Process of Cell Reproduction
  6D). Meiosis, the Process of Chromosome Reduction
  6E). Multi-gene (polygenic) diseases with complex segregation patterns:
• .
• 7A). Genetic Variation
  7B). Mutations
  7C). Spontaneous Mutations
• .
• 8A). Non-Mendelian forms of inheritance
  8B). Mosaicism
  8C). Telomeres
  8D). Penetrance and Expressivity
  8E). Parental imprinting
  8F). Genetic anticipation
  8G). Mitochondrial DNA Abnormalities
• .
• 9). Common genetic misunderstandings
• .
• 10). RNA Primer
• .
• Part 2. Genetics of Neuromuscular Disorders
• .
• 10A). Terminology and synopsis of the neuromuscular disorders
  10B). Major types of muscle disease and some common examples
• .
• 11A). Pathology and Inheritance of the Major Muscular Disorders
  11B). Summary of the genetics of neuromuscular disorders (some other major disease types also listed)
  11C). Websites on Neuromuscular diseases.
• .
• 12). X Chromosome Inactivation and Skewed X Chromosome Inactivation: Manifesting carriers in X-linked neuromuscular disorders
• .
• 13). U. S. Department of Energy Human Genome Primer.

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Introduction:

This essay outlines the genetic processes involved in human reproduction with a focus on mechanisms related to neuromuscular disorders. Neuromuscular disorders is an umbrella term encompassing over 100 different specific diseases. Each form of muscle disease follows one of three basic patterns of inheritance: autosomal recessive, autosomal dominant or X-linked. This paper describes these different genetic patterns and their relation to common neuromuscular diseases. The paper begins with a "crash course" in basic genetics but is written in language designed to make the ideas easy to understand for the average reader. The reader's knowledge of the ideas needed to understand basic neuromuscular genetics develops as the paper unfolds.

The material is cobbled together from various sources and while I reference, I have not followed a rigorous academic format.
Science and medicine is full of jargon. For a basic glossary and a list of a few (there are hundreds) on-line medical glossaries, please see: glosrevbea.html

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Part 1. Basic Overview of Genetics.

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1A). Basic Chemistry:

The earth's basic elements are made up of atoms. An ounce of perfectly pure gold consists only of gold atoms. There are 92 natural elements found on Earth - the ingredients used to make everything we find on Earth (there are also some man made elements as well). The properties of the elements are described in the periodic table or at periodic table. The most common elements in biology are: hydrogen, carbon, nitrogen, oxygen - these comprise more than 95% of all living matter.

Each type of atom has unique properties that determine how it will behave, especially how it will interact with other atoms. Let's look at an example, two hydrogen atoms (H) can combine with one Oxygen atom (O) to yield one water molecule (H₂O).

Each hydrogen atom (silver here) forms a connection (a bond - shown as a line) with the single oxygen atom (red) creating a stable molecule. A pail of pure water is 100% H₂O molecules. In life's hierarchy, molecules join together and interact to make larger and larger units that then do different jobs.

Let's think of a chemical as like a chain, each individual link of the chain is an atom and together, one chain is a molecule. Links are held together by small, but strong, electrical forces called bonds. Atoms of different kinds have different electrical properties and can only link up with certain other atoms. Not just any link can join with another and in this way, some atoms are naturally drawn toward each other (like hydrogen and oxygen are drawn together to form water) and some are repulsed away from each other (oil and water don't mix).

Molecules often have an interesting property - they have "new" characteristics that the individual atoms did not have. Molecules will display 'new' and different properties after they form:
Sodium (Na) atoms make up a very reactive (nearly explosive) metal.
Chlorine (Cl) atoms exist as a toxic gas.
Sodium (Na) and chlorine (Cl) join together (bond) to form sodium chloride (NaCl), a molecule with the characteristic properties we know as table salt.

Based upon their unique properties, molecules also link together and interact with each other to form even larger, more complex chemical compounds. In turn, chemical compounds join or interact to form very complex networks of chemical reactions and substances, e. g., to make a DNA molecule or, on a larger scale, to form a single cell. All matter as we know it and all life forms are composed of complex chemical structures interacting with each other, governed by the laws of basic chemistry.

The different chemical parts of the body are made up of different combinations of atoms forming different molecules. These molecules then join together to form different and increasingly complex chemical structures, eventually forming proteins, cells, and the other tissues, organs and large structures in the body.

How does life arise from molecules?

One of the hardest questions in biology is what is life? This question has two aspects, one, what is life? and secondly, how does life arise? One of the most amazing aspects of life is how life arises from a collection of inanimate parts. At some point, a conglomeration of lifeless chemicals becomes a series of interrelated structures that come to life. The raw chemical atoms and molecules on the laboratory bench are not alive, but somehow, a complex web of interacting molecules springs to life and becomes a living organism. One of the key features of life is the utilization of energy to create complex self organized structures. Understanding how molecules are able to organize and become an energy consuming and energy producing organism is surely going to be one of the long term goals of biology.

1B). Basic Genetics Overview:

DNA

Our genetic information is carried as two long strands of chemicals they join together like a long zipper. DNA: deoxyribonucleic acid [dee-OX-see-rye-bow-noo-Clay-ick].

DNA is basically a long molecule that contains sequences of coded instructions. DNA stores an organism's genetic information and controls the production of proteins and is thus responsible for the biochemistry of an organism.

The body has over 220 different, major cell types and various subtypes. Everything the cells do is coded somehow in DNA - how cells should divide, which cells should grow and when, which cells should die and when, which cells should create products and what they should look like. Every cell contains every bit of code needed to become any type of body cell and to produce any product. One of the more complex aspects is how cells differentiate, for example, how liver cells "know" to become and stay liver cells (and not get "entangled" with other types of cells).

The genetic message is the sequence (order) of the chemicals in the zipper. Each link of DNA is called a base. They are called bases (also called nucleotides) because of how they react with acids. There are only four "letters" in this chemical alphabet, the four bases are: A = adenine, T = thymine, C = cytosine, and G = guanine.

Just like a zipper, the DNA is in two strands, each strand has a backbone and a row of teeth (the bases). The DNA backbone is mostly made out of sugar (deoxyribose) and phosphate molecules. The two strands come together and "zip" together - the bases on one strand bond to the bases on the other forming what we call base pairs. Because of the chemical properties involved, the two strands wrap together into a helix shape:

Again, because of their chemical properties, certain bases always pair up with (bond to) certain others: A always forms a pair with T and C always pairs with G. So, we see a zipper with a complimentary sequence - the bases on one strand compliment the bases on the other, for example:

A sequence of bases A C T G on one strand MUST pair up with the bases T G A C on the other strand.

This pairing makes it easy: once researchers or doctors know the chemicals on one side of the zipper, they will know exactly what is on the opposite side of the zipper.

Part of the complexity comes from the sheer sizes involved: One piece of DNA can have millions of bases (chemical teeth) in the zipper. The largest single message yet found, the gene involved in causing Duchenne MD, has 2,220,223 bases on each side.

The 4 letters in the DNA code A T C and G make up 3 letter words (called codons) that spell out the genetic messages.
Examples: G G G     G G C     A G T
There are 64 different combinations possible. The entire genetic code is made up of series of these 64 codons, presented in different combinations to form 'sentences' these are what we commonly refer to when we talk about genes. Each gene is a 'sentence' of code spelling out the formula for one or more proteins in the body.

Another outstanding site on DNA and genetics, with lots of information and "hands on" illustrations, is at: http://gslc.genetics.utah.edu/

In summary, these sequences of base pairs are attached to each other, one after the other, to form a long DNA chain. However, these long sequences are not random, they are ordered - the base pairs are found in thousands of three letter "words" called codons. A total of 64 different three letter words are possible using combinations of the 4 letters. Each codon presents a chemical profile (made up of its three parts) that corresponds to one amino acid. Together, codons form sequences of code or message that form many subsections of the DNA, usually called genes. Each gene is a 'sentence' of code spelling out the formula for one or more proteins in the body.

DNA Summary
DNA is made up of a two long strings of sugar (deoxyribose) and phosphate links (molecules) that form the outside backbone of each strand.
DNA never leaves the relative safety of the center of the cell (the nucleus).
The four base chemicals (also called nucleotides) attach along the inside of the backbone strands.
Bases on opposite strands bond to each other in the middle, zipping the strands together into a helix.
Sequences of bases form our 25 to 30,000 genes.
DNA forms chromosomes: we get 23 from each parent, these are then copied for the rest of our lives.
Chemicals in the cell can unzip and re-zip the helix as the genetic messages are needed by the cells.
DNA is ultra stable, long term information storage.

Basic RNA
RNA stands for ribonucleic acid.
[rye-bow-noo-Clay-ick]
RNA is similar to DNA, except: RNA has the same bases as DNA, except one ' instead of T = thymine there is a U = uracil. In RNA, the chemical backbone of the strand has a different type of sugar it has a ribose instead of deoxyribose.
RNA is usually found as just a single strand it usually does not form into a two stranded helix.
Many kinds of RNA have been identified, some are well understood, others, not at all.
RNA is a temporary intermediary between DNA in the center of the cell and the protein making factories, the ribosomes in the body of the cell.
RNA is an unstable, short term information transfer vehicle and soon after it delivers its message in the cell's body (in th ecytoplasm), it is broken down into its parts and recycled.

The genetic message has to be copied:

The sequences on the DNA are not directly used to make proteins.
DNA is in the center of the cell (the nucleus) and it never leaves.
Proteins are made in the body of the cell.
RNA acts as a messenger, making a copy of the sequence needed from the DNA and carrying it out of the cell's center into the body of the cell where it is used to make protein.

Here is an overall summary:
DNA - transcription--> RNA - translation-->Protein.

From: http://folding.stanford.edu/education/protfold.html

DNA to RNA transcription has four basic steps:
Step 1: The 2 strands of DNA unwind and unzip.
Step 2: Primary RNA 'sees' a start sign ('promoter') on the DNA strand and it joins on, copying the sequence of the four bases the reading frame until it hits a stop signal.
Step 3: This primary RNA carries a complete copy of the base sequence of the DNA it is now edited into messenger RNA (mRNA).
Step 4: The final mRNA moves into the body of the cell and acts as a template for protein synthesis.

The two unwrapped DNA strands are shown in the illustration below as blue. The top blue strip called 'sense' (coding) DNA is not used in the copying ('transcription') process. The second blue strip (middle) is the template strand of DNA used to make the copy (this is the opposite side of the sense DNA strip, so it is called 'antisense' (non-coding) DNA).

The bottom, yellow strip is the newly formed RNA strand. Notice it comes out as an exact copy of the top DNA strip (but with U for T).

Sections of base sequence are read as 3 letter words codons, to form 'sentences' the gene's message.

I am going to cheat a bit and use some common 3 letter English words to illustrate how the triplet genetic code makes sense and how mutations create problems.

Remember, in 'real life' there are just 4 letters in the genetic alphabet A T G and C and the three letter codons they form don't make much sense to us (but they do make sense to the protein factory in the cell).

The DNA sequence of bases contains the messages needed by the cell but not all of the DNA is used.

It is estimated that only about 3 percent of the DNA consists of coding sequences used to make proteins it is not clear what the rest does. The whole DNA sequence in the gene is initially transcribed into primary RNA. The RNA is then edited, some parts are kept (the actual coding sequences called exons) and the other parts (untranslated regions called introns) are removed from the final mRNA message.

An illustration:
Code sequence:
dek|THEdkeOLDuteCATyjiWASkhyFAT|ert
the exons are shown in RED, introns shown in small letters
The sequence is now edited the exons are kept and the introns are removed to yield the final mRNA message:
|THE OLD CAT WAS FAT|
In the illustration above, the start and the end of the reading frame is shown as | |
The sequence of exons between these bookends is the critical message used to make a protein.
This message is now translated into a protein.

Summary: to put a genetic message into action
The DNA helix unzips into one sense strand (not used) and one template, antisense strand.
An RNA strand forms by moving along the template DNA strand and adding new bases corresponding to the sequence it finds.
When done, the 2 DNA strands zip back together.
The RNA is now edited before it moves out of the cell's center into the body of the cell. Differences in editing allow one gene to make several different mRNAs and thus make several different proteins.
Proteins are made according to the sequences of code carried by the mRNAs that move into the cell.

Genes:

It is critical to realize that our everyday usage of the word gene may differ from the way that biologists use it. There is a lot of discussion in biology about just how a gene ought to be defined and what aspects make a section of DNA a gene. Also, genes do not (cannot) act alone to do or create anything. All genes act in concert with one another and their final impacts (products) are always determined collectively with the environment. So when we hear the news talking about discovery of a "gene for breast cancer," this is really a misunderstanding. It is very unlikely that one gene determines (causes) breast cancer. It would be more correct to say that researchers have discovered the defective allele, the defective version of a gene - likely one of several - that increases the odds that a given individual will get breast cancer.

For our purposes, let us say that each subsection of code that holds a given message is called a gene. A gene is often defined as a sequence of codons that specify a sequence of two or more amino acids (called a polypeptide). Some genes are short and simple sequences, others are long and complex.

Interspersed with the genetic code that apparently makes up a gene, there are also many sequences of genetic code in the DNA molecule that traditionally have been viewed as non-functional and at this point their purpose is unknown (this material was often called "junk DNA)." There are many contradictory findings about this DNA, on one hand, in experiments that delete much of this DNA, mice go on to develop, apparently normally. On the other hand, it appears that mutations in this type of DNA are implicated in causing several diseases.

One of the most complex questions about genes is how genes are controlled. At any given time, most genes are turned off and are not producing protein. If all genes operated all the time, the body would be flooded with protein products. Genes must turn on and off just when proteins are needed. Also, genes must turn on and off at different times in the life cycle and in response to environmental demands. There must be an elaborate chemical control system to control and interact with genes. I have seen estimates that about 10% of the genes are turned on at any given time in a cell (about 3500).

These coding genes comprise only about 2 - 3% of the human genome; the remainder consists of noncoding regions and repeated sequences.

Science is learning about genes in leaps and bounds, but this knowledge is creating a lot of confusion. The more we see, the more we realize that it is not as "simple" as once thought. Today, major questions are being reexamined, for example: What is a gene? What does a gene do? How do genes work together? What controls genes, for example, what controls when they turn on and off? Does "junk" DNA play a role - yes definitely but exactly what is it?

Chromosomes are long threads of DNA that carry the genes (like beads on a string). One DNA helix is tightly wrapped to form one chromosome. The location of a gene on a chromosome is called its locus.

From: http://www.microscopix.co.uk/chromosomes/16286.gif

From: http://www.epilepsyfoundation.org/research/genediscovery/humangenome.cfm

The genes are depicted as colored bands.

Humans have 46 different chromosomes that contain an estimated 25 to 35,000 protein-coding genes. Together, the 46 chromosomes hold about 6 billion individual chemical links, (about 3 billion base pairs [exactly 3164.7 million], or about one billion codons of information per set of 23). If printed out as letters on a page, it is said the genetic code can fill 1,000 Manhattan telephone directories, or some 75,000 pages of a newspaper filled with text.

From: http://www.ncbi.nlm.nih.gov/Class/MLACourse/Modules/MolBioReview/chromosome.html

From: http://www.accessexcellence.org/AE/AEPC/NIH/gene03.html

There are two types of chromosomes, one type are called autosomes, the other type are called sex chromosomes. All chromosomes are found in pairs. There are 22 pairs of autosomes and one pair of sex chromosomes (either an XX or an XY). One chromosome in each pair is inherited from the mother and one from the father, but both are normally the same size and carry the same genes. The pairs of chromosomes in autosomes consist of well matched partners, as alike as matching pairs of candlesticks.

The sex chromosomes, the X and the Y also function as a pair, although they are not alike. The sex chromosomes determine the sex of the child.

Chromosomes are said to be homologous if they contain the same linear sequence of genes. The chromosomes in the cells of humans exist as homologous pairs, each one is called a homologue of the other, one member of each pair being inherited from each parent. Although they carry the same sequence of genes, they may not carry identical information since the genes on each chromosome may exist as slightly different variations called alleles.

Each human cell (except eggs and sperm cells) contains 22 pairs of autosomes (44 single chromosomes) plus one pair of sex chromosomes for a total of 23 pairs of 46 chromosomes. This is called a diploid cell. Germ cells (eggs or sperm) each contain only 23 single chromosomes and are thus called haploid cells.

For a great summary see: http://fig.cox.miami.edu/~cmallery/150/gene/mol_gen.htm

1C). How is Protein Made and What is Its Function?

The central dogma of genetics was coined by Francis Crick. In its original version it stated that the flow of genetic information is one directional: DNA to RNA to protein. The central dogma is certainly valid in that it defines what proteins are possible to make, but in recent years it has become evident that much more genetic information exists in the genome, namely the information used in controlling the timing and rates of the protein manufacturing processes. Part of the story are intron sections of DNA code that are not used to create protein. Far from being 'junk' DNA (ie an evolutionary lefover or relic) some nonprotein coding transcripts may in fact play a critical role in regulating gene expression and so organizing the development and maintenance of complex life. "Modern" views must extend beyond the central dogma.

Another well established "old idea" was that ONE gene = ONE protein. It is now know that this does not hold and that the ratio is more like one gene = three proteins.

Genetic information is put into use through the production of proteins. The old textbook view was that genetic "blueprints" tell the cell's machinery how to string sequences of amino acids together to form proteins. The old view was that the code was a blueprint for making a protein or a cell or a person etc. Each gene would give the instructions for a given piece (a protein).

The view today: Today we see the genetic code as the sequence of nucleotides, coded in triplets (codons) along the mRNA that determines the sequence of amino acids in protein synthesis. The DNA sequence of a gene can be used to predict the mRNA sequence, and the genetic code can in turn be used to predict the amino acid sequence. The old blueprint view has now been rejected, it is now seen that genes work together in a more flexible way to create an end product. Richard Dawkins makes the analogy that the genetic code is like a cooking recipe. It gives a list of ingredients and a sequence to follow and at the end we get a cake. But we can not take a cake and look at a piece and say, this crumb was made by the second word in the recipe. All of the genes contribute together to the recipe like all of the ingredients go into the cake.

If anything about the protein (its size, shape, sequence, how it interacts with other proteins, etc.) is even slightly wrong, we usually have trouble. Mutations (defects) in the genetic sequence that lead to protein defects are the most common type of problem in muscle diseases.

There are fewer genes than proteins. It appears that a single gene can code for (manufacture) a number of different proteins, the average is an estimated 3 proteins per gene. This complicates matters as there are a number of different mechanisms that create and control this multiple protein manufacture, and each has to be discovered and understood.

The recent breakthroughs in discovering the genetic code are not enough in themselves to unravel all of the problems in genetic diseases. In order to understand the actual biology of an organism, researchers must move beyond the analysis of gene sequences (called the genome) and understand the proteins in the body (called the proteome).

Proteins often function in clumps called protein complexes and often complexes interact with each other. Progress in understanding proteins, protein-protein interactions within complexes and interactions among complexes will need to be made before many diagnostic and therapeutic advances take place.

In summary, there are still many mysteries about how genes work and communicate with each other. The metaphor of a complex cookbook full of recipes or an instruction manual of some type will probably turn out to be a bad one because a lot more is going on that has not yet been appreciated or discovered yet (a recipe alone cannot make a cake). So, at this stage, I think it is fair to say that most of the scenarios described here are still at a very preliminary stage. We know more than ever about how genetics and biology works, but with each step forward, it seems that we discover there is a lot farther to go than we first thought before we can really understand how it all works and develop treatments for diseases.

Overview of the process:
When a protein is made and works correctly, it is said to be 'expressed' normal protein expression is critical to the function of every system in the body.
Estimates are there are >100,000 proteins in humans.
Each final edited mRNA sequence spells out a protein.
In the cell there are 'factories' (called ribosomes) that 'read' the sequence of bases on the mRNA.
The ribosomes take chemicals called amino acids (AA) and assemble them into a long string corresponding to the final mRNA sequence.
Recall, there are 64 different 3 letter words codons: 61 code for amino acids, 3 code for stop signals.
There is some overlap as the 61 codons specify just 20 different amino acids. Here is the code breakdown (the amino acid abbreviations are spelled out below). For example the codon UUU stands for a Phe animo acid - phenylalanine. UUC also stands for phenylalanine.

From: http://iusd.k12.ca.us/uhs/cs2/codon_chart.htm

As the mRNA is read, the codons tell the factory what amino acid to add next in the new protein chain: this process is called translation.
Proteins can contain from tens to a few thousand amino acids.

From: http://library.thinkquest.org/C004535/media/translation.gif

Post-translational Processing.
More flexibility (and more complexity) is added after the protein chain of amino acids is assembled:
Several modifications can be made here that alter the final protein and how it functions. This is extremely important for medical research. It is not enough to know the genetic code, how it is edited, and the final code of a protein, we also need to know how proteins are modified and assembled after their amino acid sequence is put together.

Post-translational processing is also another way that the cell can make several proteins from a single gene. The sequence of amino acids in the strips defines the protein (along with any other strips that are added and the final shape it forms). One or more strands of AAs are twisted together to form a protein. In a complex series of steps, the cell gathers the strand(s) into a final folded, 3-D shape. This shape is critical to the protein's ability to function. The amino acid side chains are really meaningless on the long strip of chemicals, but once folded, they make a "pocket" that has a chemical signature - the binding site shown in a) below. This creates a receptor for other chemicals to be attracted to and to interact with - sort of like a lock and a key. The pocket is the lock and only certain keys will fit. Picture b) below shows how a chemical comes into the binding site and is "locked in" with chemical (hydrogen) bonds.

From: http://folding.stanford.edu/education/protfold.html

It does not take much of a mistake or change in one of the amino acids to cause trouble. Mutations in DNA leading to altered protein function are the usual culprit in most genetic disorders.

Code to Protein Diagram.

From: http://folding.stanford.edu/education/protfold.html

Here is a simpler diagram:

From: http://cnx.rice.edu/content/m11415/latest/

Summary From Code To Protein.
DNA carries the genetic code in sequences of chemicals that form genetic 'messages.'
A message is read by RNA and used as a template to make a unique sequence of amino acids.
Chains of amino acid sequences form into proteins.
Proteins then interact and form into complex structures that are the basis of all living matter.
The code is not always final, some modifications can be made along the way that alter the final protein product and how it will function.
To devise genetic treatments, Doctors will have to understand this whole process in great detail.

Amino Acids.

All 20 different amino acids have the same basic structure, but their side chain groups (the R group) may vary in size, shape, charge, hydrophobicity (how much they don't like water and try to avoid it), and their reactivity. The amino acids could be considered as the alphabet in which the proteins are written.

Here is a basic chemical diagram of what one looks like: Click

1F). Overall Summary:

• The principles of natural selection
  • Heritability
    • Offspring inherit traits from their parents in some fashion and to some degree
  • Variation
    • Every species is composed of a great variety of individuals, some having greater adaptive abilities than others based on their interaction with the environment they find themselves in
      • Without this adaptive variety, one kind of individual could not be favored over another
  • Differential reproductive success
    • Chances are that individuals with greater adaptive abilities will produce more offspring than others, thus, the frequency of adaptive traits gradually increases in following generations in the population
• Necessities of Life
  • Reproduction is required so that life can continue generation after generation
    • Facilitated by molecules from the chemical family of Nucleic Acids (DNA and RNAs)
  • Maintenance of essential physiological functions of life (metabolism)
    • Facilitated by molecules from the chemical family known as Proteins
• Cellular structure
  • DNA
    • Deoxyribonucleic acid is the chemical substance that controls heredity and takes the form of a double-helix
    • The human genome project will attempt to assemble a complete genetic map for humans - detail all of the basic code that DNA carries
  • RNA
    • One type of ribonucleic acid (messenger RNA) moves outside the cell nucleus to direct the formation of proteins
  • Proteins
    • Serve many functions and are considered to be responsible for most of the characteristics of an organism
• Alleles and Genes
  • Allele: alternative forms of a gene
    • Pairs of genes for each trait are inherited
    • If the two genes for a given trait are the same (A-A), then the organism is "homozygous" for that trait
    • If the two genes for a given trait are different (AA), then the organism is "heterozygous" for that trait
  • Genes are located on rope-like bodies called chromosomes found within the nucleus of every one of the organism's cells
    • In humans, there are 46 chromosomes (23 pairs)
• Dominant or Recessive Traits
  • Alleles are dominant or recessive depending upon whether they are phenotypically expressed (dominant) or hidden (recessive) in heterozygotes
    • For example, in the human blood type system, A and B alleles are dominant over O, co-dominant with each other (blood type AB) and O is recessive to both A and B.
• Genotype and Phenotype
  • Genotype: the actual genetic makeup (specific DNA code) of the individual
    • The genotype refers to the genetic information (the pairs of chromosomes with their gene alleles) that the individual received from his or her mother and father
      • For example, an individual may have a genotype for blood type made up of an A allele (from father) and an O allele (from mother)
  • Phenotype: the observable expression of the genes
    • In this example, the individual's blood type genotype (AO) would produce a phenotype of blood type A - what a blood test would show - because A is dominant over O.
• Chain of Protein Production
  • DNA carries the code
    • RNA acts as an intermediary, carries on the code
      • Ribosomes create a string of amino acids that correspond to (that are specified by) the code carried in the RNA
        • The amino acids fold into a unique protein structure
• Gene control
  • Genes are turned on and off as their products are needed
  • A complex control system must control this process
• Sources of variability
  • There are two main sources for the origin of genetic differences between individuals
    • Genetic recombination (shuffling)
      • Crossing-over or exchange of sections of chromosomes during meiosis (egg and sperm formation)
    • Mutation or a change in the DNA sequence that produces an altered gene
      • Mismatching of DNA bases that can take place when DNA duplicates itself
      • Some mutations are extremely serious and many are fatal
        • Example, Sickle cell anemia results from a single mutation and can lead to illness and early death
• Reasons humans vary
  • Mating patterns
    • The ways that people choose mates can affect the distribution of characteristics
    • We often mate with others who are like us, thus increasing the rate of homozygotes in the population
  • Genetic drift
    • Random processes that impact gene frequencies in small, isolated populations
    • Significant for human evolution since we spent most of the past 5 million years in small (less than 50) isolated sub-populations
  • Gene flow
    • Genes pass from one sub-population to another through mating and reproduction
    • Maintains the overall genetic unity of the species across many sub-populations
• Variation has an important role
  • Changes in genotype frequencies and allele frequencies from one generation to the next lead to natural selection
    • Differential reproduction
      • An individual must survive to sexual maturity in order to be able to reproduce
      • Some variations have higher fertility and a higher production of offspring
    • Natural selection is a two-step process
      • Production of variation (mutation)
      • Differential reproduction (selection)

To see much of this introduction presented in a visual format, please see the terrific site at: http://gslc.genetics.utah.edu/units/basics/tour/

Here is another overview presented as a hierarchy from the top down:
-species: homo sapiens (all humans)
-individual human
-organ systems (digestive, circulatory, etc.)
-organs (heart, kidney, lung, etc.)
-specialized cells (heart cell, liver cell, skin cell, etc.)
-proteins (hundreds of thousands in a human)
-amino acids (20)
-genome (total overall genetic code that specifies a human being)
-chromosomes (46 in humans) carry the DNA, one long DNA helix per chromosome
-DNA strands contain genes
-genes (thought to be about 25,000 to 35,000 in humans)
-codons (three letter words)
-four chemical bases (A = adenine, T = thymine, C = cytosine, and G = guanine)

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2). Mendelian model of inheritance:

The Mendelian model of inheritance, is based on several key ideas;
-acquired characteristics are not inherited (for example the ability to play bridge is acquired)
-inheritance is controlled by discrete factors (the genes)
-each parent carries two factors but only passes down one factor to its offspring through its eggs/sperm.
-each gene displays (at least) two alternate forms (called alleles) and that in a given pair of alleles, one allele will be dominant (and will be expressed) and one will be recessive (and will be "cancelled out").
-Mendelian patterns of inheritance are thus divided into two general types:
   =dominant, in which expression of the trait requires that only one allele for that trait be present
   =recessive, in which two copies of the same allele at that locus are required for obvious expression.

Mendel's theories are used to create mathematical probabilities of offspring, if we know the characteristics of the parents, we can predict the probable outcomes of the offspring based on Mendel's ideas.

Mendelian inheritance (often called simple inheritance) has been considered the standard case of transmission in sexually reproducing organisms. Mendel's laws were initially found to be applicable to humans, but from the beginning they were fraught with problems. Sex-linked traits and linked genes defied Mendel's rules. Later, other exceptions were found, special cases where the expected probabilities are not found, a situation called non-Mendelian inheritance.

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3A). Alleles:

Alleles can be thought of as various forms of a single gene, one gene may have several alleles. Different alleles produce variation in inherited characteristics, examples include hair color and blood type.

In a diploid cell there are usually two alleles of any one gene (one from each parent), which occupy the same relative position (locus) on homologous chromosomes. One allele is usually dominant to the other one (the latter is called recessive), the dominant allele determines which aspects of a particular characteristic the organism will display. [In "everyday language" we refer to genes as dominant or recessive but strictly speaking, this property refers to the expression of the gene - whether a gene is phenotypically expressed (dominant) or not (recessive).] Within a population there may be many alleles of a gene; each with a unique nucleotide sequence.

If we look at populations of animals and plants we find that there are multiple alleles at 10-20% of the gene loci. In other words, if we look at a given gene locus in all the members of a population about 10-20% of the time we will find more than one gene sequence at that locus.

3B). Heterozygous, homozygous and hemizygous genes:

Heterozygous: (hetero meaning different). When there are two different versions of a given gene present in a cell. For example, a person with one abnormal gene allele and one normal allele in a chromosome pair is called heterozygous for that gene. Whether this characteristic will be expressed or not depends upon which gene is dominant and which is recessive in the pair. If a child receives an abnormal recessive disease gene from both parents, the child will show the disease and will be homozygous for that gene.

Homozygous: (homo meaning the same). When the two versions of a gene present are the same.

Hemizygous: Genes present in only one copy are called hemizygous. For example, human males are hemizygous for most of the genes on the X chromosome. Genes on the Y chromosome are also hemizygous.

3C). Genetic Relatedness:

Degrees of genetic relatedness: proportion of alleles shared in common due to inheritance from a common ancestor.

Identical twins- 1.00 (barring mutations in one twin, conventional wisdom is that theoretically, the gene code is identical in each twin)
First order relatives- 0.5 (one half) Parent/offspring (exactly), siblings (on average)
Second order relatives- 0.25 (one quarter) Grandparent/grandchild, aunt-uncle/niece/nephew, half-siblings
Third order relatives- 0.125 (one eight) First cousins

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4A). Autosomal chromosomes:

The pairs of autosomal chromosomes (one from mom and one from dad) carry basically the same information. Each has the same pattern of genes along the chromosome, (hence they are called homologous chromosomes) but there are often slight variations in the DNA sequence of nucleotide bases in each gene. These slight variations occur in less than 1% of the DNA sequence and produce different variants of a particular gene - the different versions are called alleles.

For convenience, the autosomal chromosomes are numbered by size, The largest is number 1 with 2968 genes, the smallest is number 22 (although overall, the Y is the smallest human chromosome with 231 genes). The X chromosome is large, about half way between the size of chromosome 7 and 8. Chromosomes range in size from 50 million to 250 million bases.

Genes of a similar function and type do not necessarily cluster on the same chromosome, therefore there is no one chromosome for health, no chromosome for personality, etc. Individual traits are found on different chromosomes.

Linked genes: Genes that are close to each other on a chromosome tend to stay together over time. Thus, when the genetic code is shuffled in each generation, genes that are close to each other tend to stay close (like shuffling a deck of cards - two cards next to each other may stay next to each other for many shufflings). This is a phenomenon called gene linkage. If two genes are right next to each other on a chromosome, a major gene shuffle involving these genes will be a rare event. This explains why multiple diseases are sometimes inherited together, if two defective genes, coding for two diseases, are right next to each other on a chromosome, they will tend to be inherited together. Linkage is an exception to Mendel's laws.

See: http://www.ndsu.nodak.edu/instruct/mcclean/plsc431/linkage/linkage2.htm

4B). Inheritance of Genetic Diseases: Overview

There are two basic ways that genetic diseases are acquired, through inheritance and through new mutations. In the way we traditionally think about genetic inheritance, genes in germ cells (in an egg or in a sperm cell) carry a mutation and it is passed on to offspring when sexual union introduces the mutated DNA into the genetic mix that creates the new "embryo." This inherited gene mutation is then replicated as the cells in the embryo divide (replicate) and differentiate. The mutation is passed on from generation to generation.

There are several general types of genetic disorders falling into this category:

-Mendelian, or single-gene ("simple inheritance"): mutations are inherited in recognizable patterns.

-Multifactorial conditions that involve interactions between two or more genes and environmental factors (example: some types of cancer). When more than one gene has a major influence over a trait it is called epistasis.

-Chromosomal abnormalities: include structural and numerical defects (too many or too few chromosomes) (example: Down Syndrome, Trisomy 21- an extra whole chromosome 21)

-Others: Recently, mitochondrial and other nontraditional patterns of disease inheritance have also been recognized.

Errors in the genetic code are responsible for an estimated 3,000 - 4,000 hereditary diseases, including Huntington's disease, cystic fibrosis, and Duchenne muscular dystrophy. What's more, altered genes are now known to play a part in cancer, heart disease, diabetes and many other common diseases. Genetic flaws increase a person's risk of developing these more common and complex disorders. The diseases themselves stem from interactions of such genetic predispositions and environmental factors, including diet and lifestyle. Some experts estimate that half of all people will develop a disease that has a genetic component.
From: http://www.beyonddiscovery.org/content/view.page.asp?I=241

The inheritance (and classification) of inherited disorders reflects two major factors: where the defect is found (either it is on an autosome or on a sex chromosome) and second, whether the gene itself is dominant or recessive.

-Autosomally inherited diseases are inherited through a defect on a gene on an autosome (the non-sex chromosomes). There are two patterns of inheritance that involve genes on the autosomes: autosomal dominant or autosomal recessive.

-All known sex-linked diseases are inherited through the X sex chromosome, part of chromosome pair number 23, and are thus said to have X-linked inheritance. X-linked disorders can also be dominant or recessive.

Genetic mutations are not always inherited from a parent (through an egg or sperm cell), some may occur spontaneously as a new mutation after conception and during the early days of embryonic development. This is covered in section 7C, below.

4C). Autosomal Recessive Disorders:

Autosomal recessive means that it is necessary to have two copies of a defective gene to have the disorder. Each parent contributes one defective copy of the gene to the child who has the disorder. The parents are called carriers of the disorder because they usually have one normal copy of the gene and one defective copy of the gene, but they do not show symptoms of the disorder. When both parents are carriers of the defective gene, each of their children has a 25% chance of carrying both defective genes and thus having the disorder, a 50% chance of being a carrier of the disorder (like their parents), and a 25% chance of neither being a carrier nor having the disorder. These risks are the same for each pregnancy. When there is more than one person in a family who has the disease, these people are often in the same generation.

If the disease is caused by a defect of a specific protein (e.g., an enzyme), a non-manifesting carrier sometimes has a reduced amount of that protein. If the mutation is known, molecular genetic techniques may be able to detect these carriers.

Consanguinity (e.g., mating of related persons) may be important in some autosomal recessive diseases. Related persons are more likely to share the same mutant allele.

In the case of a recessive disease, if one abnormal gene is inherited, the child will not show clinical disease, but they will carry the defect and pass the abnormal gene to 50% (on average) of their offspring.

Statistical chances of inheriting an autosomal recessive trait:
When both parents are carriers (a high risk couple) of an autosomal recessive trait, there is a 25% chance of a child inheriting abnormal genes from both parents, and therefore of developing the disease. There is a 50% chance of each child inheriting one abnormal gene (being a carrier).
In other words, if it is assumed that 4 children are produced, and both parents are carriers (neither exhibits any disease), the STATISTICAL expectation is for:
-1 child with 2 normal chromosomes (normal)
-2 children with 1 normal and 1 abnormal chromosome (carriers, without disease)
-1 child with 2 abnormal chromosomes (has the disease)
This means that EACH child has a one in four chance of inheriting the disorder and a 50:50 chance of being a carrier per pregnancy.

Remember, these are the average odds, you could be lucky and have four normal children in a row, or you could be unlucky and have four children with the disease.

If only one parent is a carrier, there is no chance of producing a baby with a recessive disease but there is a 50% chance in each pregnancy that the child will also be a carrier.
See: http://www.nlm.nih.gov/medlineplus/ency/article/002052.htm

Also see: http://www.merck.com/pubs/mmanual/section21/chapter286/286b.htm

Blue = mutated /affected, brown = normal /not affected
Blue/brown = not affected but carrier

From: http://www.atcp.org/Clinical/Chap3.pdf

Transmission autosomal recessive ( http://www.wutsamada.com/alma/medethic/mappes9.htm )

* if both parents are carriers:
o 25% chance the child will be homozygous for the disease gene and hence afflicted by the disease
o 50% chance the child will be heterozygous for the gene and hence a carrier
o 25% chance the child will be homozygous for the normal gene: not afflicted & not a carrier

* if one parent is a carrier and the other normal:
o 50% chance the child will be a carrier
o 50% chance the child will be normal

* if both parents are afflicted:
o 100% chance the child will be afflicted
o though many of these afflictions are so severe that the afflicted do not survive well enough to have any chance to reproduce

* if one is afflicted and one normal: 100% of offspring will be carriers

* if one is afflicted and the other a carrier:
o 50% afflicted
o 50% carriers

* if both parents are normal: 100% of the offspring will be normal

Autosomal recessive examples:

* Tay-Sachs disease
o most commonly affects those of Jewish and Eastern European heritage
o results in progressive neurological degeneration and death in early childhood

* sickle-cell anemia
o most commonly affecting blacks in this country: 10-12% of African-Americans carry the gene
o characterized by acute attacks of abdominal pain, of varying degrees of severity

* cystic fibrosis
o about 1 in 20 U. S. Caucasians carry the gene
o the disease causes dysfunction of the exocrine glands
    + resulting in production of abnormal amounts of mucous
    + which can obstruct organ passages
    + and cause intense pulmonary and digestive distress
    + currently most victims die before age thirty

4D). Autosomal Dominant Disorders:

Dominant inheritance occurs when one abnormal gene from ONE parent is capable of causing disease even though the matching gene from the other parent is normal. The abnormal gene dominates the outcome of the gene pair. In other words, if one gene in a pair is dominant, the trait it carries cancels out the trait carried by the other (recessive) gene. The condition becomes apparent even though the affected person has only one abnormal gene. In the case of a dominant disorder, if one abnormal gene is inherited from either mom or dad, the child will likely show the disease.

Usually, the defective gene is inherited from a parent who also has the disorder and every generation in the family may have members with the disorder. A person who carriers a gene for an autosomal dominant disorder has a 50% chance of passing the gene to each child. In other words, each child of an affected parent has a 50% chance of being affected. Either sex can have the condition and one characteristic of autosomal dominant disorders is that males are affected equally as frequently as females.

Some examples of autosomal dominant disease include familial hypercholesterolemia, Huntington's disease, achondroplasia, and Marfan's.

Statistical chances of inheriting an autosomal dominant trait:
For an autosomal dominant disorder: If one parent has an abnormal gene and the other normal, there is a 50% chance each child will inherit the abnormal gene, and therefore the dominant trait.
In other words, if it is assumed that 4 children are produced, one parent has an abnormal gene for a dominant disease, the statistical expectation is for:
-2 normal children
-2 children with the disease This does not mean that a given child will necessarily be affected. It means that EACH child has a 50:50 chance of inheriting the disorder. Children who do not inherit the abnormal gene will not develop or pass on the disease. In the unlikely case where both parents carried the same dominant mutation, all children born would be affected.
http://www.nlm.nih.gov/medlineplus/ency/article/002049.htm

It is also possible (but rare) for a person to inherit two mutated dominant copies of a gene and have one on each chromosome (homozygous). In such cases, it usually appears that they are more severely affected than people who only have one dominant gene for that same illness. In homozygous cases, all of their children will be afflicted with the disorder, as the homozygous parent has no normal genes to contribute. In many autosomal dominant diseases the homozygous genotype is incompatible with life. Example: Huntington's disease gene was discovered by studying people who were homozygous for the mutation. Strangely, people who are homozygous for Huntington's disease do NOT appear to be more affected or to be affected earlier that those with only one mutated gene copy.

-An affected person has one affected parent.
-An affected person and an unaffected person have, on average, an equal number of affected and unaffected children.
-Unaffected children of an affected parent have unaffected children and grandchildren.
-Males and females are equally likely to be affected.
-The risk for occurrence among children of an affected person is 50%.
http://www.merck.com/pubs/mmanual/section21/chapter286/286b.htm

Transmission of autosomal dominant ( http://www.wutsamada.com/alma/medethic/mappes9.htm )

* if both parents are heterozygous
o 25% chance the child will be homozygous for the disease gene and hence afflicted by the disease
o 50% chance the child will be heterozygous for the gene and hence afflicted
o 25% chance the child will be homozygous for the normal gene: not afflicted & not a carrier

* if one parent is a heterozygous and the other normal:
o 50% chance the child will be a heterozygous and hence afflicted
o 50% chance the child will be homozygous for the normal gene: not afflicted & not a carrier

* if both parents are homozygous for the disease gene: 100% chance the child will be homozygous for it also and hence afflicted

* if one is afflicted and one normal: 100% of offspring will be carriers

* if one is homozygous for the disease gene and the other heterozygous:
o 50% homozygous and afflicted
o 50% heterozygous and afflicted

* if both parents are normal: 100% of the offspring will be normal

Autosomal dominant example:

Huntington's disease:
* symptoms typically emerge only in the prime of life: between ages 35 and 50
* characterized by mental and physical deterioration, leading to death within a few years

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5A). Sex Chromosomes:

Sex chromosomes are so named because they determine the sex (male or female) of the offspring. There are two types of sex chromosome: an X and a Y chromosome. The X and Y always pair together (XX or XY). Although the X and Y behave as a pair, they are very different and don't match each other. The Y chromosome is much smaller than the X, having no more than several dozen genes, far fewer than the number on the X. A number of the genes on the Y are unique to it and have no match on the X (and likewise, most genes on the X have no pair matching on the Y).
The sex chromosomes make up about 5% of the total genome. There is an implication that because of the differences between men and women in terms of XY versus XX, differences will be expected in the protein organization and biochemical function of male versus female cells.

5B). Y chromosomes:

The central importance of the Y chromosome is that it contains a single gene that acts as a trigger to activate male characteristics. Early in embryo development, the cells are unisex. If development proceeds without a Y chromosome, a female will develop (the default state). If the Y chromosome is present, a gene on the Y chromosome will be activated and set off a cascade of effects that transform the embryo into a male. The Y chromosome also encodes traits found only in males (e.g. testis- determining factor).

The Y contains unusually high amounts of noncoding DNA and repetitive sequences. Y chromosome linked genes fall into two categories, one, genes that are homologous to genes on the X chromosome and that are expressed everywhere in different tissues. Some of these genes are involved in basic cellular functions, creating differences between male and female cells. For example, ribosomes in male cells differ from those in female cells, creating the opportunity for large scale differences in cellular biochemistry between males and females. The other class of Y genes are expressed only in the testis (Wizemann and Pardue, 2001).

5C). Y-linked:

A gene on the Y chromosome is said to be Y-linked. Y linked genes are passed from father to son, since the Y chromosome is only transmitted by a male to his sons. So far, no Y-linked genetic diseases have been identified.

5D). X chromosomes:

Almost all of the genes on the X are unique to the X and have no counterpart on the Y chromosome. Because of this and because males have only a single X chromosome, any gene on the X (even if it is a recessive trait), will be expressed in males. The X chromosome appears to carry about 1000 to 2000 genes.
Males receive only one X (always from mom), however, females receive two copies. To ensure the "dosage" of X genes is correct, one of the two X chromosomes in each of the female's cells is inactivated. This introduces two important differences between males and females. XX cells must have mechanisms to count X chromosomes and to tag and inactivate one. Second, because different X chromosomes are inactivated in different cells (in some cells, paternal Xs are inactivated, in other cells, the maternal X is inactivated), female's are composed of a mosaic of cells, some expressing a maternal X and some a paternal X (males all express a maternal X).

5E). X-linked dominant inheritance:

In X-linked dominant inheritance, the presence of a defective gene makes itself manifest in females (XX) even if there is also a normal X chromosome present. Males who inherit a defective X will always express the defect (as it is the only X they have). Since males only pass their Y chromosome to their sons (XY), males affected with an X dominant disorder mating with normal females will not have affected sons (never passed from father to son), but all of their daughters will be affected (she receives her father's defective X). Sons or daughters of affected females and normal males will each have a 50% chance of getting the disease. X-linked dominant inheritance follows a pattern similar to autosomal dominant inheritance except, overall, more females are affected than males. X-linked dominant disorders are very rare.

5F). X-linked recessive inheritance:

X-linked recessive disorders are usually only expressed in males and they are much more common than X-linked dominant disorders. Males only have one X chromosome, so if a male inherits a defective gene on his X chromosome (always inherited from his mother), then he does not have another copy of the gene to compensate even if the trait is recessive).
Females with one copy of a defective gene on one X chromosome are carriers of the X-linked recessive disorder. In most cases, females who are carriers do not show symptoms because they have two X chromosomes, one defective and one healthy, the healthy copy of the gene compensates for the defective copy. It is also possible, but rare, for a female to have the same defective gene on both her X chromosomes, in this case, she would manifest the illness. A very small percentage of females are affected by a phenomena called skewed X inactivation and may exhibit disease symptoms (see: xinact.html).

X-linked recessive is the pattern seen in diseases such as hemophilia and Duchenne muscular dystrophy.

Statistical chances of inheriting a trait for an X-linked recessive disorder:
If only the mother carries the gene and the father is normal, all of the female children will be normal (50% with 2 normal chromosomes and 50% carriers), one half of all the male children will exhibit the disease, and one half will be normal. The recessive gene is expressed in the male because there is not another X to counteract it, only the Y (which determines for maleness).
If only the father carries the recessive gene, all of his daughters will be carriers and all of his sons will be normal.
If both the mother carries the abnormal gene and the father has the disease, then STATISTICALLY out of 4 children 1 daughter will have the disease (two recessive genes on the X chromosome), 1 daughter will be a carrier, 1 son will have the disease (one recessive gene on the X and a Y chromosome) and the other son will be normal.
In other words, 50% of the children (boys and girls) will be affected and 50% normal.
It is assumed that 4 children are produced (2 boys and 2 girls), the mother is a carrier (one abnormal X but no disease), and the father is normal, the STATISTICAL expectation is for:
-1 boy normal
-1 boy with disease
-1 girl normal
-1 girl carrier without disease
If it is assumed that 4 children are produced (2 boys and 2 girls), the father is a carrier (1 abnormal X, he has the disease), and the mother is normal, the STATISTICAL expectation is for:
-2 boys normal
-2 girls carriers without disease
If it is assumed that 4 children are produced (2 boys and 2 girls), the father is a carrier (1 abnormal X, he has the disease), and the mother is a carrier (one abnormal X but no disease), the STATISTICAL expectation is for:
-1 girl with disease
-1 girl carrier without disease
-1 boy (abnormal X) with disease
-1 boy normal
This does not mean that a given child will necessarily be affected. It means that EACH has a chance of inheriting the disorder or of being a carrier.
(Above based on: http://www.nlm.nih.gov/medlineplus/ency/article/002051.htm )

5G). Other Sex Chromosomal Abnormalities:

Note:
Euplod (ic) describes the number of chromosomes: haploid (n), diploid (2n), triploid 3n. A normal euploid human cell has a chromosome number of 46 (2n).
Polyploid cells have extra chromosome sets. Polyploids result from the fertilization of an oocyte by two sperm or after fertilization involving a diploid gamete. A complete extra set of chromosomes raises the total number to 69 (triploidy).A triploid fetus (which usually miscarries) would be 69,XXY (most common), 69,XXX or 69,XYY depending on the origin of the extra set of chromosomes.
Aneuploid (Aneuploidy) refers to chromosomal abnormalities where there are n + or -1, 2n + or -1, etc., chromosomes present. An aneuploid cell lacks a chromosome or has an extra one and can result from meiotic nondisjunction. In this section, XXX is an example.
A cell with an extra copy of a chromosome is a trisomy, a cell with a missing copy of that chromosome is an example of monosomy.

While SCA can include a variety of abnormalities of the sex chromosomes, by far the most commonly occurring SCA involve the deletion (45:X or partial X monosomy) or addition (47:XXY, 47:XYY, 47:XXX) of an X or Y chromosome. [Recall normal is 46 with an XX or 46 with an XY]. Of these conditions, only Turner syndrome, caused by the loss of all or part of an X chromosome, results in an easily identifiable physical phenotype. Subtle language, neuromotor, and learning difficulties have been identified in most forms of SCA, however. The neurodevelopmental effects of the 47XXY (Klinefelter Syndrome) and 47XXX karyotypes are also investigated in light of these phenotypic features.

Most cases of simple aneuploidy (having too few or too many chromosomes) - monosomy or trisomy - are likely due to meiotic non-disjunctions. These are mistakes made in chromosome segregation during meiosis. If pairs of homologous chromosomes fail to separate during the first meiotic division or if the centromere joining sister chromatids fails to separate during the second meiotic division, gametes, and hence offspring, will be produced that have too many and too few chromosomes.

Brief review of sex determination in fruit flies and humans:

Nature has helped soften the blow of having extra X chromosomes. The process of X inactivation operates in both males and females. If the counting mechanism detects more that one X (however many) in males or females, the extras are tagged and inactivated. See the section on X inactivation.

Examples of aneuploidy involving the sex chromosomes include XYY (male with one extra Y chromosome), XXY (male with one extra X chromosome), XXXY (male with two extra X chromosomes), XXXXY (male with three extra X chromosomes), XXYY (male with one extra X and one extra Y chromosome), XXX (female with one extra X chromosome), XXXX (female with two extra X chromosomes) and XXXXX (female with three extra X chromosomes).

Turner's syndrome: females with but a single X chromosome. The phenotypic effect is mild because their cells have a single functioning X chromosome like those of normal [XX] females where one X is inactivated. Number of Barr bodies = zero.

XXX, XXXX, XXXXX: all females with mild phenotypic effects because in each cell, all the extra X chromosomes are inactivated. Number of Barr bodies = number of X chromosomes minus one.

Klinefelter's syndrome: people with XXY or XXXY karyotypes are males (because of their Y chromosome). But again, the phenotypic effects of the extra X chromosomes are mild because, just as in females, the extra Xs are inactivated and converted into Barr bodies.

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6A). Inheritance - Sexual reproduction and sex determination:

Each parent contributes one half of each chromosome pair to their child, 22 autosomes and 1 sex chromosome. A normal sperm has 22 autosomal and either an X or a Y chromosome. A normal egg has 22 autosomes always with an X chromosome, thus, females always contribute an X chromosome to the child, whereas a male may contribute an X or a Y. As the Y chromosome makes the child into a male, it is the father's contribution that determines the sex of the child:
-The mother's egg will always contribute an X. If the contribution from the father's sperm is also an X, then the fetus will be a female (XX).
-Normal sperm cells carry either one X or one Y chromosome each (about a 50-50 ratio). If a sperm contributes an X chromosome to an egg's X, the fetus is female (XX). If the sperm contributes a Y, the child is a male (XY). One X always comes from the mother and the Y, always from the father.

6B). Sexual reproduction - chromosome numbers:

In sexual reproduction, a sperm and an egg unite to form a first single cell called a zygote that then divides to eventually produce every cell needed by the body. This initial zygote cell must have 46 chromosomes. To achieve the correct mathematics, each egg and each sperm must contribute only 23 chromosomes, not the regular 46 (if they carried 46, when the egg and sperm combine, the zygote would have 92 chromosomes). Therefore, in egg and sperm formation, a process called meiosis (explained below) halves the chromosome number.

6C). Mitosis. The process of cell reproduction:

Mitosis is the process of cell reproduction - a sort of cell Xeroxing. Mitosis is a division process that divides a cell and produces two identical daughter cells.

6D). Meiosis. Egg and sperm production and chromosome number reduction:

Meiosis is a type of cell reproduction that reduces the number of chromosomes in half in egg and sperm cells. Meiosis converts a diploid cell (46 chromosomes) to a haploid (23 chromosomes) egg or sperm cell. Meiosis also causes a change in, or shuffling of, the genetic information in order to increase the genetic diversity in the offspring (otherwise we would basically all be the same).

6E). Multi-gene (polygenic) diseases with complex segregation patterns:

Many other diseases do not conform to this genetic picture. They do not segregate in a simple Mendelian pattern, they cannot be easily classified as dominant or recessive (they have complex segregation patterns) and are not single genes disorders - they are multifactorial disorders. They are also called "complex diseases." The underlying molecular pathology is different in that common functional variants of particular genes (polymorphisms or "aetiological mutations") which are neither necessary nor sufficient in themselves to account for disease, are present at increased frequency in patients. These interact epistatically [The suppression of a gene by the effect of an unrelated gene] with other genes and gene variants to predispose to disease. The word 'predispose' here allows for the likely involvement of ubiquitous environmental factors. An example are diseases of the autoimmune type.

Complex diseases have a low heritability (tendency to be inherited) compared to single gene disorders. For example, only 2-5 per cent of the close relatives of diabetics also suffer from diabetes, much lower than would be the case for a single gene disorder like cystic fibrosis. This indicates that no single genetic factor is responsible for the disease. Several to many genes may contribute, and there may be additional environmental causes such as poor diet and exposure to hazardous chemicals.

It is thought that the incidence of any complex disease is dependent on a balance of risks. There is a balance between gene variants (alleles) with positive and negative effects, and between environmental factors with positive and negative effects. Too many negative factors, both genetic and environmental, can tip the balance towards disease.

Here is an abstract that describes the situation:
Susceptibility gene discovery for common metabolic and endocrine traits
M I McCarthy
Imperial College Genetics and Genomics Research Institute and Division of Medicine, Imperial College, London, UK
Abstract
Almost all major causes of ill-health and premature death in human societies worldwide including cancer, cardiovascular disease, diabetes and many infectious diseases are, at least in part, genetically
determined. Typically, risk of succumbing to one of these illnesses is thought to depend on both the individual repertoire of variation within a number of key susceptibility genes and the history of exposure to relevant environmental factors. For many of these conditions, the molecular basis of disease pathogenesis remains obscure. This represents a major obstacle to development of improved, rational
strategies for disease treatment, prevention and eradication. It is easy therefore to appreciate the importance attached to efforts to deliver more comprehensive understanding of the molecular basis of
disease pathogenesis. Nor is it hard to understand that identification of major susceptibility genes should highlight those components of molecular machinery that are critical for the preservation of normal health. The benefits promised are great, but progress to gene identification in multifactorial traits has been rather disappointing to date. Why is this? This review aims to answer this question by describing current and future approaches to gene discovery in multifactorial traits. The examples quoted will mostly relate to type 2 diabetes, but the issues and approaches are generic, and apply equally to other multifactorial traits in the endocrine and metabolic arena type 1 diabetes; obesity; hyperlipidaemia; autoimmune thyroid disease; polycystic ovarian syndrome and beyond.
Journal of Molecular Endocrinology (2002) 28, 117

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7A). Genetic Variation:

Synopsis of variation:
-Meiosis produces genetic variation
     =A process in division called Independent assortment creates 2ⁿ possible combinations of chromosomes in daughter cells. In humans with 23 haploid chromosomes, there are 2ⁿ = 2²³ = 8,388,608 possible combinations.
     =Variation is added by crossing-over; if only one crossover occurs within each bivalent unit, 4²³ or 70,368,744,000,000 combinations are possible
-Most human genetic variation occurs in the form of different nucleotides at single base positions - called single nucleotide polymorphisms, or SNPs {snips}.
-Fertilization also contributes to genetic variation; (2²³)² = 70,368,744,000,000 possible combinations (without crossing-over factored in)
-Combining fertilization and crossing-over, (4²³)² = 4,951,760,200,000,000,000,000,000,000 combinations are possible for each offspring
From: http://arnica.csustan.edu/Biol1010/meiosis/meiosis.htm

Summary: Sexual reproduction (meiosis) is critical for evolution as this process shuffles and mixes the genetic information, creating new and different chromosomes before moving them into the sperm or egg cells. Also, crossing over creates hybrid chromosomes combining some maternal and paternal genes. Offspring receive a mixture of maternal and paternal genes.

In DNA, about 1 of every 1300 base pairs on the autosomes differs between two individuals. This means that the genomes of two people differ by about 4 to 6 million base pairs. These differences mean that the exact composition and interactions of thousands of proteins will vary between two people, and these differences will be seen in variations among individuals, for example, in susceptibility to disease.

There are four processes involved in genetic shuffling:

First, genetic variability arises through crossing over.
During meiosis, each pair of chromosome homologues align in pairs on a gene-by-gene basis and join together to exchange various homologous regions - thus, each offspring is a unique recombination of each parent's pairs of chromosomes. The rate of exchange between chromosomes drives our diversity and influences the evolution of our species.
From: http://www.nature.com/genomics/human/overview/press-releases.html

Second, is a process called independent assortment. Each homologous pair of chromosomes aligns and orients independently of the other pairs, thus, the first meiotic division results in an independent assortment of maternal and paternal chromosomes. The process begins with the cell's pairs of homologous chromosomes aligning. Each pair consists of one maternal and one paternal chromosome. When the homologous chromosomes separate in the anaphase of meiosis I, the maternal chromosomes may go to the same pole of the meiotic spindle and the paternal chromosomes to the opposite pole. Or, there may be mixture of maternal and paternal chromosomes going to each pole. The alignment of the homologous pair is random. This results in a fifty-fifty chance that a particular daughter cell will receive the maternal chromosome of a homologous pair, and a fifty-fifty chance that it will receive the paternal chromosome.

Consequently, the eggs and sperm produced by meiosis contain all possible combinations of maternal and paternal chromosomes. In humans, the possible number of combinations is 2 to the 23 power meaning that each egg and sperm cell produced by a human contains one out of 8,388,608 possible assortments of chromosomes inherited from that person's mother and father.

Fourth, different forms of a gene originate from mutations, rare changes in the DNA structure, thus, mutations are also a source of genetic variability.

Based on: http://www.runet.edu/~rsheehy/genetics/Meiosis/B245OMeiVar.html

7B). Mutations:

Mutations are changes in the genome. There are quite a number of ways in which mutations can happen. They also differ in the way that they impact individuals and evolution.

Mutations which occur when the genome is copied during reproduction are known as vertical transfer mutations. They are called vertical mutations because they are transferred from ancestor to descendent along vertical lines of descent. Vertical transfer occurs when genes are passed from father to son, mother to daughter, etc.

Horizontal transfer mutations occur when DNA is moved from one organism to another. Horizontal transfer can be a major source of evolutionary novelty. It is important because new genes can be propagated much more rapidly by horizontal transfer than by vertical transfer. For example, bacteria might copy and pass specific genes on to other bacteria which incorporate them into their genetic makeup. Horizontal gene-transfer is very rare in sexually-reproducing organisms. One human example may be seen in retroviral infection: a segment of a retrovirus' genome is added to the total genome of the host organism. Occasionally the inserted gene will mutate and become a permanent part of the host cell. Depending on where the gene is inserted, it can change the function of the cell. If the retrovirus infects a germline cell (sperm or egg), the new genes can be passed down vertically. The organisms offspring will carry the retroviral DNA, or "retrogenes," but this is rare.

Major types of mutations:

Chromosomal Mutations:

Chromosome abnormalities can involve either the sex chromosomes or the autosomes. Large sections of chromosomes can be altered or shifted, leading to changes in the way the genes on them are expressed. They can occur either as a result of a germ cell (egg or sperm) mutation in the parent, or a more remote ancestor. Chromosomal abnormalities can also result from a somatic mutation (but is not passed on). Chromosomal abnormalities are related to a wide range of disorders, for example, over 20 broad categories of cancer with hundreds of subtypes have been associated with chromosome aberrations.

Approximately 20% of all conceptions have a chromosomal disorder, but most of these fail to implant or are spontaneously aborted, so the actual birth frequency seen is about 0.6%. The frequency of chromosomal disorders in early spontaneous abortions is 60%, whereas in late spontaneous abortions and stillbirths the frequency is 5%. Generally, chromosomal abnormalities that cause early spontaneous abortion tend to be those with the most severe effects on the fetus.

Generally, autosomal abnormalities tend to be more severe than sex chromosomal abnormalities and deletions more severe than duplications. Sex chromosome abnormalities (almost always the X) occur once in every 300-400 births. In mothers over 35 this frequency is even greater, about 1 in 250.

Genes vary a great deal with respect to how much they can be changed without the changes harming the organism. Some genes, such as those that encode the basic metabolism and the components of the replication, transcription, and translation machinery, are hard to change without harm. We see very little variation in them from one organism to another. Such genes are said to be conserved.

-Chromosomal Duplication: Sometimes one or more whole chromosomes are duplicated during reproduction; the offspring get extra copies of those chromosomes. Effects of chromosomal duplication: Duplicating only one chromosome is generally disadvantageous; an example is Down's syndrome. A chromosome number which is not an exact multiple is called aneuploidy. Aneuploidy is the gain or loss of individual chromosomes from the normal set of 46. The loss of one chromosome, monosomy, is rarely seen in live births, for the vast majority of monosomic embryos and fetuses are probably lost to spontaneous abortion at very early stages of pregnancy. An exception is the loss of an X chromosome that produces Turner syndrome. Trisomies, the gain of a single chromosome, are more common and have been associated with various disorders. A chromosome number which is an exact multiple of the haploid number (23) and exceeds the diploid number is called polyploidy, for example, a complete extra set of chromosomes raises the total number to 69 (triploidy).

-Chromosomal breakage and realignment: During reproduction a chromosome may break into two pieces or two chromosomes may be joined together. A section may be moved from one part of the chromosome to another or may be flipped in orientation (inverted). This is the mechanism by which deletions, duplications and transpositions my occur. Effects of chromosomal breakage and realignment: Quite often these types of changes do not affect the viability of the organism (the genes are still there; they're just in different places) but, in sexually reproducing species, they may make it less likely for the organism to produce viable, fertile offspring.

-Chromosomal nondisjunction: An important problem with chromosomal rearrangements, is that when large regions of a chromosome are altered, it may lose the ability to segregate properly during cell division, they "lose track" of where they are supposed to go in cell division, causing a chromosomal nondisjunction. One of the daughter cells will end up with more or less than its share of DNA. When a new cell gets less or more than its share of DNA, it will have problems with gene dosage, too many or too few genes operating. Expression of genes is specifically tailored to the exact level that a cell requires. When there are extra or too few copies of the gene, the cell runs into trouble.

-Inversions: Inversions occur when a region of DNA flips its orientation with respect to the rest of the chromosome.

-Additions and deletions: During copying a segment of DNA may be deleted or a new segment may be inserted. Typically this happens as a result of chromosome breakage or realignment.
  -Deletions remove information from the gene. A deletion could be as small as a single base or as large as the gene itself (or even whole chromosome).
  -Insertions occur when extra DNA is added into an existing gene. Effects of additions and deletions: If the length of the new or deleted segment is not a multiple of three the translation will be garbled after the point at which the insertion/deletion occurred because the frame reading is now mis-aligned This is known as a frameshift mutation. In some genes there are segments that may be duplicated as a block. This is known as tandem duplication.

-Frame shift: Frame shift mutations result from either addition or deletion of one or two nucleotide bases (recall codons are multiples of three bases). When this occurs the "reading frame" is changed so that all the codons read after the mutation are incorrect, even though the bases themselves may be still present. For example, given the coding sequence:
THE FAT CAT SAT AND ATE
Deletion of the first T would throw off the rest of the sequence and make it into gibberish:
HEF ATC ATS ATA NDA TE

The frame shift may also create a stop codon which would prematurely end and shorten the protein. Because a frameshift mutation usually garbles the message so badly, it is commonly a very devastating type of mutation with severe consequences. For example, in Duchenne muscular dystrophy, mutations of the dystrophin gene are seen. About 96% display a frameshift mutation.

Point (Base Pair) Mutations:

The most common type of copying error is the point mutation. In this form of mutation, the nucleotide at a site is replaced by a different nucleotide. When people talk about mutation rates they are usually talking about rates of point mutations.

The effects of point mutations depend upon where the mutation occurs: Point mutations in junk DNA are common but have no effect. Sometimes point mutations in regulatory regions have no effect and sometimes they alter the expression of genes.

Some types of point mutations:

-A Nonsense mutation one base is exchanged for another and a stop codon is created where none previously existed. The result is that only part of the correct message is made and, in turn, only part of the protein is made:
From our example: |THE OLD CAT WAS FAT|
The nonsense mutation product code looks like:
|THE OLD CAT|

-A splice site mutation alters the splicing of introns and exons; exon not included; reading frame is disrupted, causes incorrect amino acids and or a stop codon. Splice site mutations can also occur where the reading frame is left intact but the functional sites are disrupted.

-A Missense mutation causes an incorrect amino acid to be substituted, changes the code of the mRNA. For example, if an AGU sequence is changed to an AGA, the protein produced will have an arginine amino acid where serine was meant to go. This would likely alter the shape or properties (charge and or shape) of the protein but the effect of this type of mutation can vary in severity depending upon the protein in question.
From our example: |THE OLD CAT WAS FAT|
The missense mutation product code looks like:
|THE OLD FAT WAS FAT|

-Repeat mutation: It is normal to see triplets or quadruplets 3 or 4 bases together repeated a number of times in a row, either within a gene or in the intronic code.
When 3 chemicals are repeated, it's called a trinucleotide repeat:
Example: CTG CTG CTG CTG CTG CTG CTG
There is normally some variation between different people, re: how many repeats are present and the number is stable over generations (children have roughly the same number as their parents).
If the number of repeats is within 'normal' limits, they do not cause problems. Sometimes a mutation can occur that deletes repeats or that creates extra repeats. If a section of repeats becomes too small or too large, it leads to problems. Example: In the most common type of Myotonic Dystrophy (DM1), an untranslated repeat of CTG is 'expanded.' People normally have fewer than 50 repeats in this section of DNA. People with DM1 may have from 50 to 2000 repeats. People with the very serious Congenital Myotonic Dystrophy may have 4000 repeats.
Another type of muscular dystrophy called Facioscapulohumeral Muscular Dystrophy (FSHD) is also a repeat disorder: About 95% of people with FSHD have a mutation in a section of intronic DNA on chrm 4. This area is made up of a series of repeats. The mutation deletes repeats. The smaller the repeat left, the more severe the disease tends to be and the earlier the onset.
   -Normal repeat range: 10 to >100 copies
   -Borderline repeat range: 9 to 10 copies
   -FSHD repeat range: 1 to 8 copies.

-Silent mutation, also called synonymous mutations: Many different DNA sequences can result in the same amino acid. For example, the DNA sequences AGU and AGC both code for the amino acid serine. So if the base in the third position of AGU mutates from 'U' to 'C,' the protein produced won't change and will still have serine at the appropriate position. It is assumed these mutations will not affect the genome.

-Retrovirus based alterations: Certain viruses have the ability to insert a copy of themselves into the genome of a host. The chemical that makes this possible (reverse transcriptase) is widely used in genetic engineering. Effects of retroviruses: Usually this is a way for the virus to get the host to do the work of reproducing the virus. Sometimes, however, the inserted gene mutates and becomes a permanent part of the host organism's genome. Depending on the position of the viral DNA in the host genome, genes may be disrupted or their expression altered. When insertions occur in the germline of multicellular organisms, they can be passed on vertically.
Retroviruses are important in muscular dystrophy because they are a prime potential vehicle for gene transfer. If researchers can create a healthy gene (say to repair a faulty dystrophin gene), then they need a way to introduce the repair gene into the genome of a patient. A retrovirus may be one way to introduce (called a vector) the gene into the person's genetic material.

-Transposons: Transposons are segments of DNA (or whole genes) that can move around to different positions in the genome of a single cell. In the process, they may cause mutations or increase (or decrease) the amount of DNA in the genome. These mobile segments of DNA are sometimes called "jumping genes".
Effects of transposons: Depending on the position of insertion, transposons can disrupt or alter the expression of host genes. In some species, most mutations are due to transposon insertion, for example, in fruit flies (Drosophila), 50-85% of mutations are due to transposon insertions.

DNA Repair:

In DNA replication, a mistake is made on average about every 1000 base pairs. This error rate would be unacceptable, because too many genes would be rendered non-functional. To protect against too many mutations, organisms have developed elaborate DNA proofreading and repair mechanisms, which can recognize false base-pairing and DNA damage, and repair it. This reduces the actual error rate to more in the region of one in a million to one in a billion.

Why Are Mutations Important?

Our environment constantly changes, as the environment changes, we must change along with it, or we will become obsolete and die. One mechanism of change is at the DNA level. Mutations can often result in beneficial new genes and functions, which enable and organism to adapt to a changing environment. It is important to realize that mutations do not occur in response to the environment. They simply happen and are subsequently better in the environment (individuals have more offspring) or are less effective (individuals have fewer offspring). This is called natural selection and is part of the mechanism of evolution.

Mutations can be neutral (neither helpful nor harmful), strictly harmful, strictly helpful, or (and this is important) whether they are harmful or helpful depends on the environment. Most mutations are either neutral or their effect depends on the environment.

What is the consequence of a mutation?
Most of the time, the change either has no perceptible effect at all, or it is fatal. Mutations in critical genes are responsible for some of the early, spontaneous abortions that occur in humans, and for some of the about 40 % of the congenital malformations that develop due to unknown reasons. We do not know how frequent spontaneous abortions are, since most of them occur before the woman realizes that she is pregnant. Calculations indicate, however, that only 6 of 20 fertilized eggs result in fully developed children, less than one third of all pregnancies begun.

Muscular dystrophy and mutation:

A wide variety of types of mutations are seen in these diverse disorders, including point mutations, deletions or duplications, large chromosomal deletions, frame shift mutations, and other in-frame problems leading to protein abnormalities.

Section based on: http://www.talkorigins.org/faqs/mutations.html

7C). Spontaneous (Acquired) Mutations:

Genetic mutations are not always inherited from a parent (through an egg or sperm cell), some may occur spontaneously as a new mutation after conception and during the early days of embryonic development. In some disorders (like Duchenne MD), there is a very high rate (30%) of new mutations constantly popping up in each generation. Very early in the development of an embryo, ancestor cells that are the child's future sperm or egg cells separate from the rest of the developing cells. This batch of cells that are set aside - eggs in a female and sperm in a male - are called the germline.

Germline cells divide and multiply in the embryo and this division continues after the child's birth. For males, sperm cells don't complete their development until the child becomes an adolescent. A female's egg cells complete part of their development during fetal life and part at puberty. New mutations can occur in the genes of these cells at any stage during this process. If mutations occur early in development, they often affect many of the subsequent sperm or egg daughter cells. If they occur later, mutations may affect very few cells, or maybe even just one cell. The person will often display the disorder and will be the first in the family to show it (he or she is called the proband). Other relatives will not be at risk as this was a new mutation in the proband individual.

Whether or not a condition will affect the individual depends in part on the inheritance pattern of the disorder. If the disorder is autosomal and is recessive, the person will not be affected by having the new mutated gene copy. He or she still has a correct copy of the gene to provide the information for the cell to work normally. If the new mutation involves an autosome and a dominant disorder, the affected person will be the first in the family to display the condition.

Because the germline is segregated from the other body cells early in embryonic life, germline mutations rarely affect other cells in the body. Thus, when mutations occur after the germline has separated, there's a good chance they'll affect many sperm or egg cells but not any of the other cells in the body, such as blood or skin cells - these are the cells commonly used in genetic testing. A genetic test of these cells will not show a problem but if a child is conceived with one of the sperm or egg cells carrying a mutation, the child can inherit a disease-causing mutation (even though the genetic blood test of the parents won't show any problem). Even if a sample of sperm or egg cells is tested and shows no mutations, other egg or sperm cells could still carry the mutation. Passing on just one mutated cell is all it takes. Once a mutation has been inherited by a child, it becomes part of the DNA in everyone of his or her cells and can be passed on to future generations if he or she subsequently has children.

During a person's lifetime, new mutations are also occurring in the somatic (body) cells. These mutations cannot be passed on to future children (because they are not in sperm or egg cells), but they can cause illness in the person's lifetime. Common examples are mutations in skin cells causing skin cancer or in breast cells causing breast cancer.

In summary, these mutations may affect only some cells, leaving others healthy and leading to mosaicism in the individual. In myotonic dystrophy, it's not uncommon to find that only some of a person's egg or sperm cells (the germline cells) have the myotonic dystrophy mutation.

The recognition of somatic mutations is leading to an expanded view of how medicine defines genetics. We need to understand the traditional idea of diseases that are transmitted from generation to generation by a parent through their egg or sperm cells to their children. We also need to conceptualize genetic diseases caused by somatic mutations occurring after fertilization that are transmitted through cell reproduction from generation to generation of cells within an individual's lifetime.

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8A). Non-Mendelian forms of inheritance:

8B). Mosaicism:

Mosaicism is the term used to describe the contribution of two or more genotypes to the structure and function (i.e. the phenotype) of a multicellular organism; literally, the organism is made up of a mosaic of cells expressing two (or more) different genotypes. The term mosaicism is derived from the idea of a mosaic pattern (Think of floor made up of a checkerboard of black and white tiles to represent affected and unaffected cells.)
All women are functionally mosaic with respect to the X chromosomal genes they express. If we were able to examine each X chromosome in each cell in a female, we would see an overall "mosaic effect" or a "patchwork" of active maternal Xs in some cells and active paternal Xs in other cells (normally, about a 50 - 50 split). This patchwork pattern can sometimes be seen expressed in an organism, for example, the patchwork colored coat of a Calico Cat.

In humans a skin condition called anhidrotic ectodermal dysplasia is another example. In this condition, the person has patchy areas where they have normal sweat glands and other areas where they have none. The areas with sweat glands and without sweat glands appear in definite patterns, generally they exhibit v-stripes across the back.

The above descriptions of inheritance patterns (dominant, recessive and X-linked) assume that if there is a mutation that all of the cells will have it. This does not always happen, sometimes a few cells will have the mutation and other cells will be healthy. This complicated scenario is another example of mosaicism and the individual is referred to as a mosaic. Again, thinking of the pattern of tiles on a black and white mosaic floor - the white tiles are healthy and the black ones are mutated - this is the type of pattern seen in the cells, some are healthy and some carry the mutation.

How does this happen? As described above (see 7C), genetic mutations are not always inherited from a parent (through an egg or sperm cell), some may occur spontaneously as a new mutation after conception and during the early days of embryonic development. Very early in the development of an embryo, ancestor cells that are the child's future sperm or egg cells separate from the rest of the developing cells. This batch of cells that are set aside - eggs in a female and sperm in a male - are called the germline.
New germline mutations:
Germline cells divide and multiply in the embryo and this division continues after the child's birth. For males, sperm cells don't complete their development until the child becomes an adolescent. A female's egg cells complete part of their development during fetal life and part at puberty. New mutations can occur in the genes of these cells at any stage during this process. If mutations occur early in development, they often affect many of the subsequent sperm or egg daughter cells. If they occur later, mutations may affect very few cells, or maybe even just one cell. The condition of having some germ cells affected and some not is called germ line or germinal mosaicism or gonadal mosaicism. The person will often display the disorder and will be the first in the family to show it (he or she is called the proband). Other relatives will not be at risk as this was a new mutation in the proband individual.
Whether or not a condition will affect the individual depends in part on the inheritance pattern of the disorder. If the disorder is autosomal and is recessive, the person will not be affected by having the new mutated gene copy. He or she still has a correct copy of the gene to provide the information for the cell to work normally. If the new mutation involves an autosome and a dominant disorder, the affected person will be the first in the family to display the condition.
Because the germline is segregated from the other body cells early in embryonic life, germline mutations rarely affect other cells in the body. Thus, when mutations occur after the germline has separated, there's a good chance they'll affect many sperm or egg cells but not any of the other cells in the body, such as blood or skin cells - these are the cells commonly used in genetic testing. A genetic test of these cells will not show a problem but if a child is conceived with one of the sperm or egg cells carrying a mutation, the child can inherit a disease-causing mutation (even though the genetic blood test of the parents won't show any problem). Even if a sample of sperm or egg cells is tested and shows no mutations, other egg or sperm cells could still carry the mutation. Passing on just one mutated cell is all it takes. Once a mutation has been inherited by a child, it becomes part of the DNA in everyone of his or her cells and can be passed on to future generations if he or she subsequently has children.
Somatic Mutations:
During a person's lifetime, new mutations are also occurring in the somatic (body) cells. These mutations cannot be passed on to future children (because they are not in sperm or egg cells), but they can cause illness in the person's lifetime. Common examples are mutations in skin cells causing skin cancer or in breast cells causing breast cancer.
Summary:
In summary, these mutations may affect only some cells, leaving others healthy and leading to mosaicism in the individual. In myotonic dystrophy, it's not uncommon to find that only some of a person's egg or sperm cells (the germline cells) have the myotonic dystrophy mutation.
Mosaicism throws a wrench into things:
Mosaicism greatly complicates making predictions about inheritance or the severity of a disorder in children of mosaic parents. A parent who has the mutation in only some of his or her cells may have very mild myotonic dystrophy symptoms. But that person's child could acquire the mutation through a germline cell (an egg or a sperm) and thus have it present in all cells starting at conception. Such a child would be more severely affected than his mosaic, partially affected parent.
Example: If a parent has myotonic dystrophy diagnosed but his or her mosaic status isn't recognized, by assuming the severity of the disorder will be like that of the parent, the severity in the offspring may be underestimated.

Example: If all germline cells have the mutation, the risk of passing on a dominant disease like myotonic dystrophy is 50 percent. In mosaics, only some of the cells carry the mutation and the risk of passing on the disorder falls below 50 percent. There are two scenarios: the mosaic parent has a mixture of mutated and healthy germ cells (eggs or sperm). If a mutated egg or sperm cell from the mosaic parent becomes part of the fertilization, the child will have myotonic dystrophy (because it is a dominant disorder). In the second scenario, a healthy egg or sperm from the mosaic parent combines with a healthy egg or sperm from the other parent and the child will be myotonic dystrophy free. In summary, if a parent has myotonic dystrophy diagnosed but his or her mosaic status isn't recognized, the chances of passing on the myotonic dystrophy mutation to a child are often overestimated.

In patients who display a mild symptoms of a disorder but whose genetic testing suggests a more severe type of mutation, mosaicism should be suspected. In these cases, special genetic testing called pulsed-field gel electrophoresis analysis should be done to reveal the mosaicism.

Based on: http://www.mdausa.org/publications/Quest/q81ss.cfm and http://www.mostgene.org/gd/gdvol10a.htm
Based on: http://www.neuro.wustl.edu/neuromuscular/musdist/dmd.html

8C). Telomeres:

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8D). Penetrance and Expressivity:

Not all traits (phenotypes) are expressed 100% of the time even though the allele is present and not all that are expressed are manifested to the same degree. The penetrance of a trait or mutation is the probability that an individual carrying it will express the trait or develop the associated disease phenotype. Different diseases display different rates of penetrance. In a 100% penetrant disorder, everyone with the geneotype will eventually display symptoms. In a 50% penetrant disorder, only 50% of people with the genotype will ever show symptoms. Examples: Huntington's disease is usually 100% penetrant over the normal human lifespan while in familial breast cancer, BRCA1 mutations show both age-dependent penetrance and overall reduced penetrance, the lifetime risk for a female mutation carrier being estimated at around 70%. http://www.ich.ucl.ac.uk/cmgs/modes.htm

Expressivity: Expressivity is the range of variation that is seen in a trait (the phenotype); it refers to the degree of expression of a given trait or combination of traits that is associated with a gene. Conditions may have severe or mild symptoms; they may have symptoms that show up in one organ or combination of organs in one person but not in the same locations in other persons. Myotonic dystrophy (DM) is an autosomal dominant disorder with greatly variable expressivity.

Variable expressivity:
There are several aspects of expressivity seen, for example, Myotonic dystrophy displays several types, including age dependent onset, the extent of pleiotropy, and the extent of dysfunction. All of these vary between different individuals with myotonic dystrophy.

(Pleiotropic refers to a disease that may affect many sites including different organs, tissues, or subcellular locations. For example, in myotonic dystrophy, different sites include the eye lens, skeletal muscle, the heart, and the brain. Within muscle, problems can include myotonia, atrophy, insulin resistance, and hypotonia in affected newborns).
See: http://www.mdausa.org/experts/ask_dm.html

Age dependent expression: As an organism passes through its life cycle, the expression of its genes changes. When genes are expressed in the life cycle may vary, and some genes are not expressed until later in life. An example of this is seen in Duchenne muscular dystrophy, where expression commonly occurs at about age 2 - 5. Other examples include Huntington's disease (usually 30 or over) and male pattern baldness (usually 20 or over).

8E). Parental imprinting:

Recall that most of our genes come in pairs, one copy inherited from each parent. In many cases the maternal and paternal versions (alleles) of the gene appear equally important. However, certain chromosome mutations cause very different disease presentations depending on which chromosome - the maternal or paternal copy - is affected and passed on. This is called parental imprinting and these genes are called imprinted genes, and mutations in these genes don't obey the classical Mendelian rules

Imprinted genes violate the usual rule of inheritance - that both alleles in a heterozygote are equally expressed because imprinted genes are genes whose expression is determined by the parent that contributed them. A small number of genes in mammals (50 of them at the most recent count) have been found to be imprinted. That is, either the maternal (inherited from the mother) or the paternal (inherited from the father) allele is expressed exclusively. The process usually begins during gamete formation when a certain gene is imprinted in the sperm or in the egg. All the cells in a resulting child will have the same imprinted gene. Example, myotonic dystrophy - early onset is usually observed when the gene is inherited from the mother.

8F). Genetic anticipation (Trinucleotide repeat expansion):

8G). Mitochondrial DNA Abnormalities:

Cells also have a small amount of genetic material that is not contained in the nucleus (where the normal chromosomes are housed). Mitochondria are intracellular structures that generate energy. They contain a unique circular chromosome that codes for 13 proteins, various RNAs, and several regulating enzymes. However, most of the mitochondrial proteins are also coded by the regular nuclear genes.

Mitochondrial disease is due to mitochondrial DNA abnormalities (e.g., deletions, duplications, mutations). High-energy tissues, such as muscle, heart, and brain, are particularly at risk.
Maternal inheritance characterizes abnormalities of mitochondrial DNA. Both egg and sperm cells contain mitochondria, however, during fertilization, sperm mitochondria are selectively tagged and subsequently degraded inside the cell. Thus, the developing embryo inherits mitochondria (mitochondrial DNA) from the egg. Thus, affected females transmit the trait to all of their children, whereas affected males do not transmit the trait to any of their children.

Variability in clinical manifestations is the rule and may be due in part to variable mixtures of mutant and normal mitochondrial genomes within cells and tissues. http://www.merck.com/pubs/mmanual/section21/chapter286/286f.htm

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9). Common genetic misunderstandings:

1). Genes determine phenotype. The fact is that many environmental factors interact with genes to create diverse phenotypic expression. Even identical twins show considerable differences based on even very slight environmental differences starting within the womb. The exception is that there are a few traits that do depend heavily on genes and show a minimal (or no) environmental component, for example, genes coding for human blood groups are not influenced by the environment.

2). Genes determine capacity: People sometimes get the idea that genes are like empty buckets waiting for environment (experiences) to fill them up. If a person has "good genes," they have a big bucket. For example, looking at IQ differences, a person with good IQ genes but a poor environment will lead to low IQ, however, with a rich learning environment, the bucket will overflow as measured by high IQ scores. In reality, there is no evidence that different genotypes have different capacities while operating in "enriched" environments. The "best" environment for one genotype's maximum expression is usually different than the "best" environment for growth of an organism of another genotype. Plants that thrive at sea level will stunt at high altitude. Talking about the "best" genotype misses the point, our interest should be in the kinds of phenotypes that are developed by different genotypes in different environments. For a given genotype, there will be a particular phenotype for each environment.

3). Genes determine tendencies: People often talk about tendencies, for example, "Joe has a genetic tendency to be overweight." This implies that on some diets, Joe will be overweight, but on other diets he may be thin (we have only said he has a genetic tendency - not a certainty). But, if there is any diet on which Joe can be thin, then we can't say that he has a genetic tendency to be overweight. People may tend to be overweight on 5000 calories a day and tend to be thin on 1500 calories a day. Tendency can also be used to compare an individual with a population. So, to say Joe has a tendency to be fat might mean that eating 2000 calories a day, Joe is fat compared to the average person also eating the same diet. But, this is only correct if Joe is also fat eating 1500 calories a day compared to others on 1500 and so on. Is Joe fatter than average no matter how many calories he and other people are eating? "Genetic tendency" is only a useful concept if environments affect organisms of different genotypes in the same way.

Summary of points 1 - 3: Ideas about determination, or tendency, or capacity have little meaning for describing the relations between genotype and phenotype. The phenotype is the unique consequence of a particular genotype developing in a particular individual in a particular environment. See: Lewontin, R. (2000). The Triple Helix: Gene, Organism, and Environment. Harvard University Press.

4). We will eventually discover a gene for each trait or illness: Traits and illnesses "caused" by a single gene base pair are rare and certainly appear to be the exception. Most complex human traits and illnesses are determined by multiple genes interacting with each other and with the environment. The rare illnesses related to very specific gene mutations hold out the first hope of a medical, genetic treatment. The more common multigenic illnesses like cancer will take longer to sort out.

5). It is important to keep in mind that Mendel's experiments and a lot of our subsequent research was and is based on traits determined by single genes. Again, most traits and many disorders are determined by multiple genes and environmental factors that interact with one another.

6). It is becoming increasingly clear that in most cases, genes only provide a basic foundation and specify a set of functional parameters. The final phenotype is based upon a further development and expression within these parameters. For example, at least in some cases, the final protein conformation and function is determined by events that occur after mRNA translation. This means that the information needed to describe the final protein products seen (the phenotype) is not all contained within the genetic code. The code is really only meaningful in the overall context of its overall and final function. You cannot take DNA out of a cell and understand its total function in isolation. A complete understanding must take place in the context where DNA operates - the overall operation of the cell and all of its interacting components. In summary, a complete understanding of how organisms function will have to go beyond the simple genetic code.
This issue reflects reductionism, the idea that complex phenomena can be broken down or reduced to a number of simpler components and principles. So, there is one grand theory of everything or one formula needed to understand things. In our case, the idea was that the genetic code alone would explain the mysteries of biology. Reductionism has been a very important and productive approach for science in the study of many phenomena. However, science now recognizes many limitations to reductionism, there may be complex phenomena that simply cannot be broken down and understood in smaller parts.
In a practical example, the conventional wisdom is that a person is born with a genetically determined number of muscle fibre cells and fibre types in their body. Exercise (environment) will determine how these fibres are expressed within these initial parameters (you can enlarge the fibers you have but not increase their overall number). Your physique and performance capabilities at any given time must fall within the initial parameters you are born with. Thus, based upon your genetic makeup, even if you train hard every day, you still might not be able to make your muscles perform as well as another person's. High calibre athletes are not just made by training; they are born with higher potential based on their number and type of muscle fiber. Different types of athletes start with different innate capabilities, for example, track sprinters tend to be born with more fast twitch fibers. Marathon runners tend to be born with more slow twitch fibers. And the average person tends to have an equal distribution of both fiber types.

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Part 2. Genetics of Neuromuscular Disorders

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10A). Terminology and synopsis of the neuromuscular disorders:

What is Muscular Dystrophy?

Muscular Dystrophy is really an "old name" that at one time was used by scientists to refer to all muscle diseases. The term is still in common use today to refer to all muscle related diseases. When Doctors first looked at muscle diseases, they saw the muscles of patients shrinking and called this dystrophy (meaning "faulty nutrition") based on the belief that the muscles were not getting enough nourishment and therefore weathering away. Eventually, it became clear that there are many different types of muscle diseases, some involving just the muscle and some also related to problems involving the nerves. To better describe all of the various muscle related disorders, scientists coined the term neuromuscular disorders and this term is now commonly used by scientists.

What is a Neuromuscular Disorder?

For muscle to function, the brain must send electrical signals out along nerves (motor neurons), down the spinal cord and out to the muscle. The nerve joins the muscle at a special junction (the neuromuscular junction) and transmits its signal to the muscle, causing it to contract.

From: http://medlib.med.utah.edu/kw/mg/mml/mg_illus002.html

Muscle is made out many types of chemicals and proteins and as the muscle works, protein is used up that must later be replenished. Neuromuscular disorders generally involve a problem in one of these important mechanisms - the motor nerves, the neuromuscular junction or with the proteins in the muscle itself.

Some of the major muscle proteins and the disorders related to them:

From: http://www.novocastra.co.uk/diagrams/mddg.gif

The exact way muscles function is still largely a mystery today and research continues to try to understand the basic mechanisms in health and disease.

"Neuromuscular disorders" is a general term used to identify a large and diverse group of muscle disorders. Whether the problem originates within the motor nerve cell, the nerve, or the muscle, the most commonly experienced symptoms are varying degrees of progressive muscle weakness and wasting of the voluntary muscles that control body movement. There are over 40 major motor nerve and muscle disorders (and over 100 specific disorders) covered under the umbrella of the Muscular Dystrophy Association of Canada. These illnesses vary in their inheritance pattern, age of onset, muscles attacked and rate of progression. While all of the disorders are chronic, there is a wide range of effects, based on the exact type of problem involved. People affected have varying degrees of debilitation, from minor inconvenience getting around, to death caused by respiratory failure. These disorders are not contagious and many are caused by genetic problems.

Here are the major categories:

Motor neuron disease: Problems in the motor nerves of the brain or spinal cord that cause them to disintegrate, leading to muscle weakness. Major example in this group is Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig's Disease.
A = absence of
myo = muscle
trophic = nourishment
Lateral = side (of spine)
Sclerosis = hardening or scaring

Two kinds of motor neurons are affected in ALS the upper motor neurons, which are in the top part of the brain, and the lower motor neurons, which are in the brainstem (almost at the spinal cord) and the spinal cord.

Upper motor neurons affect all of the body's voluntary muscles by sending chemical messengers (neurotransmitters) to the lower motor neurons. They regulate the activity of the lower motor neurons, which in turn send neurotransmitters to the muscles.

Lower motor neurons in the brainstem control voluntary muscles in the face, mouth, throat and tongue. Lower motor neurons in the spinal cord control all the other voluntary muscles of the body, such as those in the limbs, trunk, head and neck, as well as the respiratory diaphragm and other muscles used in breathing.

From: http://memory.ucsf.edu/IMAGES/Education/education_als.jpg

Peripheral Nerve Disease: Peripheral means near the ends of the limbs. In these disorders, the nerves are affected and the hands and feet often lose muscle strength and sometimes sensation. The major disorder in this group is called Charcot-Marie-Tooth Disease. Charcot-Marie-Tooth disease includes a group of disorders that affect the peripheral nerves, causing muscle weakness and loss of muscle bulk. Treatment focuses on managing symptoms.

From: http://diabetes.niddk.nih.gov/dm/pubs/complications_nerves/images/peripheral.gif

Diseases of the junction between the nerve and the muscle (the neuromuscular junction) are caused by problems in chemicals that transmit the signal from the nerve to the muscle. Major example: Myasthenia Gravis. Myasthenia gravis is a disorder in which normal communication between the nerve and muscle is interrupted at the neuromuscular junction. Normally when impulses travel down the nerve, the nerve endings release a neurotransmitter substance called acetylcholine, which travels through the short neuromuscular junction and results in the activation of muscle contraction. In myasthenia gravis, the receptors for acetylcholine at the muscle surface are destroyed or modulated by antibodies that prevent the normal reaction from occurring. The antibodies are produced by the patient's own immune system, which is believed to generate an aberrant autoimmune reaction resulting in an attack on the patient's own neuromuscular junction.

Today, in its strict scientific meaning, the term muscular dystrophy refers to a group of genetic diseases that involve problems inside of the muscles. There are many types, depending on the exact problem, usually a protein that is faulty (or in some cases, another chemical defect in the way the cell works). Major example: Duchenne Muscular Dystrophy.

Another different type of muscle problem are the inflammatory myopathies. These disorders are related to major inflammation of the muscle, thought to be caused by an autoimmune problem. Major type: polymyositis.

10B). Major types of muscle disease and some common examples:

Motor Neuron Diseases (Anterior Horn Cell - spinal cord):
-Amyotrophic Lateral Sclerosis (ALS) Lou Gehrig's Disease.
-Spinal Muscular Atrophy (SMA)
-Spinal Bulbar Muscular Atrophy (SBMA) (Also known as Kennedy's Disease)

Diseases of the Peripheral Nerves:
-Charcot-Marie-Tooth Disease(CMT), also called: Peroneal muscular atrophy (PMA), also called Hereditary motor and sensory neuropathy (HMSN)
-Friedreich's Ataxia (FA)

Diseases of the Neuromuscular Junction:
-Myasthenia Gravis (MG)
-Lambert-Eaton Syndrome (LES)
-Congenital Myasthenic Syndrome (CMS)

Diseases of Skeletal Muscle (Muscular Dystrophies):
-Duchenne Muscular Dystrophy (DMD)
-Becker Muscular Dystrophy (BMD)
-Emery-Dreifuss Muscular Dystrophy (EDMD)
-Limb-Girdle Muscular Dystrophy (LGMD)
-Facioscapulohumeral Muscular Dystrophy (FSH or FSHD)
-Myotonic Dystrophy (MMD)
-Congenital Muscular Dystrophy (CMD)
-Oculopharyngeal Muscular Dystrophy (OPMD)
-Distal Muscular Dystrophy (DD) (Miyoshi)

Structural Myopathies:
-Myotonia Congenita (MC) (Two forms: Thomsen's or Becker's Disease)
-Central Core Disease (CCD)
-Nemaline Myopathy (NM)
-Myotubular Myopathy (MTM or MM)
-Periodic Paralysis (PP) (Two forms: Hypokalemic - HYPOP and Hyperkalemic - HYPP)

Inflammatory Myopathies:
-Polymyositis (PM), Dermatomyositis (DM), and Inclusion Body Myositis (IBM)

Metabolic Diseases of the Muscle:
-Mitochondrial Myopathy (MITO)
-Acid Maltase Deficiency (AMD) (Also known as Pompe's Disease)

Protein aggregate myopathies (PAM)
Protein aggregate myopathies (PAM) are an emerging group of muscle diseases characterized by structural abnormalities. Protein aggregate myopathies are marked by the aggregation of intrinsic proteins within muscle fibers and fall into four major groups or conditions:
(1) desmin-related myopathies (DRM) that include desminopathies, a-B crystallinopathies, selenoproteinopathies caused by mutations in the, a-B crystallin and selenoprotein N1 genes,
(2) hereditary inclusion body myopathies, several of which have been linked to different chromosomal gene loci, but with as yet unidentified protein product,
(3) actinopathies marked by mutations in the sarcomeric ACTA1 gene, and
(4) myosinopathy marked by a mutation in the MYH-7 gene.

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11A). Pathology and Inheritance of the Major Muscular Disorders:

Overview

Different types of muscle disorders follow different patterns of inheritance. Three patterns (recessive, dominant or X-linked) are seen, depending on the type of dystrophy involved.

This wide range of transmission is a complication in understanding inheritance. For conditions where all three modes of inheritance are observed, it can be difficult to determine the mode of inheritance, especially in small families. As an extreme example, an isolated affected male could represent (a) autosomal recessive, (b) a new autosomal dominant mutation or (c) X-linked, either a new mutation or inherited through several generations of females.

Some Example Mutations:

Gene change and example disorder:
-whole gene / adjacent genes deleted: spinal muscular atrophy
-whole gene / adjacent genes duplicated: Charcot-Marie-Tooth Disease
-contraction of tandem repeats: Facioscapulohumeral Muscular Dystrophy
-expansion of tandem repeats: Myotonic dystrophy, Friedreich ataxia
-single / multiple exons deleted: Duchenne / Becker Muscular dystrophy
-single / multiple exons duplicated: Duchenne / Becker Muscular dystrophy
-single / few base pairs removed: common
-single / few base pairs inserted: common
-point mutations (missense, nonsense, splice-site mutations): very common
-From: L. V. B. Anderson, page 72, chapter in Karpati, George, Hilton-Jones, David and Griggs, Robert C. (eds.) (2001). Disorders of Voluntary Muscle. (7th Edition), Cambridge University Press.

Synopsis of the major neuromuscular diseases.

Motor Neurone Diseases:
-Amyotrophic Lateral Sclerosis (ALS): ALS is a progressive disease that attacks specialized nerve cells called motor neurons, which control the movement of voluntary muscles. ALS is an adult onset disease that affects motor neurons in the brain, brainstem and spinal cord, and causes them to gradually disintegrate. As damage accumulates, these nerves are prevented from delivering chemical signals and essential nourishment that muscles depend on for normal function. Genetics: About 10 percent of those who develop ALS have a family history of the disorder, and about 15 percent of these patients have a mutation in the SOD1 gene on chromosome 21. The inheritance pattern is autosomal dominant.
-Spinal Muscular Atrophy (SMA): Spinal muscular atrophy is a term for a group of inherited neuromuscular diseases. All forms of the disease affect specialized nerve cells called motor neurons, which control the movement of voluntary muscles. SMA causes lower motor neurons in the base of the brain and the spinal cord to disintegrate, preventing them from delivering electrical and chemical signals that muscles depend on for normal function. The muscles in the proximal area (the center of the body) and the legs are most affected. This includes the muscles that control swallowing and breathing.
Genetics: The three major childhood-onset forms of SMA are now usually called type I, type II and type III. Types I and III are sometimes referred to by the names of the doctors who first described them. Werdnig-Hoffmann disease is sometimes used for type I SMA and Kugelberg-Welander disease for type III. All three types are also known as autosomal recessive SMA because of the way they are inherited. Both parents must pass on the defective gene in order for their children to inherit the disease. Types I, II and III appear to be variants of the same condition, because they all appear to arise from a defect in the same gene on chromosome 5. Type I (50% of cases) strikes before 6 months of age involves profound weakness and is fatal by age 2. Type I and III are less severe, type II with an onset of between 6 and 18 months involves intermediate weakness, type III with an onset after 18 months is milder, both are quite variable. There is also a type IV that has an adult onset and is marked by a mild slow progression.
SMA is caused by a genetic mutation that depletes a key protein leading to motor neuron loss and then muscle wasting. In the case of SMA, the gene affected is called the survival of motor neuron 1, telomeric (SMN1) gene. Produces survival of motor neuron protein (SMN1). In SMA patients, both SMN1 gene copies are deleted or defective: they don't get enough SMN1 protein. A nearby gene is nearly identical to the SMN1 gene, called the SMN2 gene, it can make up to 30% of the normal SMN1 protein needed. The exact genetic mechanisms involving these two genes is complex and the number of SMN2 genes present can vary quite a bit even in 'normal' people. Mutations of SMN1 often convert it to the SMN2 gene. People with SMA therefore often have 'extra' copies of the SMN2 gene. People with SMA often have no SMN1 gene but they must have at least one SMN2 gene to make some SMN protein or they would not have survived gestation. SMA cases with multiple SMN2 genes get more SMN1 protein the more SMN1 protein the cells get, the milder the SMA symptoms (as seen in the continuum of SMAII and SMAIII symptoms).
SMN1: Gene mutations:
-Deletion of gene yields most severe SMA
-Conversion of SMN1 to SMN2 gene yields milder SMA
All SMA cases have at least 1 SMN2 gene
Multiple copies of SMN2 = milder SMA.
SMN2 mutations alone don't produce SMA.
Summary: The SMN1 gene makes the amounts of SMN1 protein we need, SMN2 makes a little. In SMA: SMN1 gene is deleted or defective. SMN1 gene mutations can also convert it to SMN2. The more SMN protein the SMN2 genes make, the later the onset & the milder the SMA. If both genes are severely impacted and little SMN1 protein is made, the results are rapidly fatal.

-Spinal Bulbar Muscular Atrophy (SBMA) (Also known as Kennedy's Disease): an inherited disease that causes the death of nerve cells in the spinal cord and in the bulb-like (bulbar) part of the brainstem, leading to muscle weakness and wasting (atrophy). The weakness mostly affects muscles in the proximal (toward the center) part of the body, and is especially prominent in muscles of the face and throat. The full-blown disease affects only men, and its typical onset is between 30 and 50 years of age. Genetics of SBMA: SMBA is caused by a genetic mutation that affects the androgen receptor -- a protein that allows cells to respond to androgens (masculinizing hormones such as testosterone). The mutation, called a trinucleotide repeat expansion, is sort of like a run-on sentence in DNA (the chemical letters that make up our genes). In most people, he phrase "CAG" is repeated about 21 times in the androgen receptor gene, but in people with SBMA, it's repeated between 40 and 62 times. Those expanded CAG repeats create an abnormal structure within the androgen receptor (called expanded polyglutamine) which, for reasons that aren't clear, makes the receptor toxic to nerve cells. The androgen receptor gene is located on the X chromosome, and SBMA is inherited in an X-linked, recessive manner.

Diseases of the Peripheral Nerve:
-Charcot-Marie-Tooth Disease (CMT): Charcot-Marie-Tooth (CMT) disease is a common neuromuscular disorder named for the three physicians -- Jean Martin Charcot, Pierre Marie and Howard Henry Tooth -- who first identified it more than 100 years ago. CMT is actually a broad term used to describe a group of genetic disorders that affects the peripheral nerves, which carry motor (relating to movement) and sensory (relating to sensation) signals between the brain and spinal cord and the rest of the body. CMT most frequently affects the lower legs, feet and hands, resulting in weakness and atrophy, or loss of muscle bulk. About one in 2,500 people has a form of CMT. CMT disorders are sometimes referred to as hereditary motor and sensory neuropathies (HMSNs). An old name for CMT is peroneal muscular atrophy (PMA). CMT is usually divided into types 1 and 2, according to the specific site of the peripheral nerve problem. About two-thirds of people with CMT have type 1, which affects the myelin sheath, the insulating covering that surrounds nerve fibers. In CMT1, the nerves conduct impulses more slowly, on average about half as fast as a normal nerve. Approximately one-third of patients have type 2, which affects the nerve fibers (also called axons) themselves. The peripheral nerves are made of bundles of these fibers. In CMT2, the axon lowly degenerates, however, nerve conduction speed is normal or borderline. Some physicians use the term type 3 CMT to describe a disease that is also known as Dejerine-Sottas disease. This is a severe form of CMT. Genetics: Overall. autosomal dominant, autosomal recessive and X-linked inheritance forms affect both males and females.

Diseases of the Neuromuscular Junction:
-Myasthenia Gravis (MG) (including Lambert-Eaton Syndrome-LES and Congenital Myasthenic Syndrome-CMS): "Grave muscular weakness" Myasthenia gravis and the less common Lambert-Eaton (myasthenic) syndrome are diseases affecting how nerve impulses are transmitted to muscle at the neuromuscular junction. Both are "autoimmune" diseases in which the body generates an immune system attack against parts of itself. Although people with myasthenia virtually always do very well when treated properly, myasthenia gravis (MG) and Lambert-Eaton syndrome (LEMS) can be life-threatening when muscle weakness interferes with respiration.
Myasthenia gravis is a neuromuscular disease that causes weakness and fatigue, most commonly in the muscles of the eyes, face, throat and limbs. MG affects acetylcholine receptors of the skeletal muscles. Myasthenic patients have decreased numbers of these receptors. Acetylcholine receptors are protein molecules on the muscles cell's surface that contain channels which allow electrically charged sodium atoms, or ions, to flow into the cell. When sodium ions enter the muscle cells, they trigger a chain of events leading to muscle contraction. It's an autoimmune disease, meaning it's caused by an attack of the body's own immune system. MG is an acquired disease, meaning it isn't inherited as a genetic disease is. MG is not contagious, and can't be passed from person to person.

Muscular Dystrophies:
Muscular dystrophies are genetic disorders characterized by progressive muscle wasting and weakness that begin with microscopic changes in the muscle. As muscles degenerate over time, the person's muscle strength declines. It is now believed that the majority of MDs are caused by genetic mutations that affect specific muscle protein production. There are many types of proteins involved in muscle function and all are important to some degree. Mutations can cause problems in the manufacture of these proteins that can disrupt their function and the function of other proteins they interact with. The more critical the protein affected, the more severe the disorder. There are many subtypes of MDs based upon exactly which protein is affected. In many cases, the protein (and related gene) has not yet been discovered.
-Duchenne Muscular Dystrophy (DMD): In DMD, boys begin to show signs of muscle weakness as early as age 3. The disease gradually weakens the skeletal or voluntary muscles, those in the arms, legs and trunk. By the early teens or even earlier, the boy's heart and respiratory muscles may also be affected. DMD occurs when a particular gene on the X chromosome fails to make the protein dystrophin. Genetics: Duchenne muscular dystrophy is X-linked with males affected. In 1986, a defect was located on a segment of the X chromosome (called Xp21). The gene's failure to make a working version of the muscle protein dystrophin is the cause of the disease. This is a major muscle protein, therefore, this disease has severe impact on the muscle.
Also see http://www.ich.ucl.ac.uk/cmgs/dmdgt98.htm

Myopathies:
Myopathies are diseases that cause problems with the tone and contraction of skeletal muscles (muscles that control voluntary movements.) These problems range from stiffness (called myotonia) to weakness, with different degrees of severity.
-Myotonia Congenita (MC) (Also known as Thomsen's or Becker's Disease): This disease is caused by mutations in the gene for a chloride channel that's necessary for shutting off the electrical excitation that causes muscle contraction. Onset: early to late childhood Symptoms: The main problems faced by people with this disease are delayed muscle relaxation and muscle stiffness, typically provoked by sudden movements after rest. The stiffness can interfere with simple activities like walking, grasping and chewing, but is usually manageable by doing warm-up movements. The disease doesn't cause any muscle wasting; instead, it can sometimes cause muscle enlargement and increased muscle strength. Becker-type myotonia is the most common form of myotonia congenita, while Thomsen's disease is a very rare, relatively mild form. Inheritance: autosomal recessive (Becker-type), autosomal dominant (Thomsen's).
-Central Core Disease (CCD): Causes: This rare disease appears to have multiple origins. But it's commonly caused by defects in a channel that acts like a gate to internal calcium stores. The defect causes leakage of calcium from the stores, which appears to damage muscle cells. Inheritance: autosomal dominant, possibly autosomal recessive in rare cases. Onset: congenital Symptoms: The disease is named for damaged areas within muscle cells (the cores), where the filament proteins are disorganized, and mitochondria are missing. The impact of the cores on disease severity isn't clear. This disease causes poor muscle tone (hypotonia) and persistent muscle weakness in infants.
-Nemaline Myopathy (NM): Causes: This disease is caused by a variety of genetic defects, each one affecting one of the filament proteins required for muscle tone and contraction. Inheritance: autosomal recessive, autosomal dominant. Onset: congenital to adulthood. Symptoms: The disease gets its name from the fact that the muscle cells contain abnormal clumps of threadlike material - probably disorganized filament proteins - called nemaline bodies (nema is Greek for "thread"). It causes weakness and poor tone (hypotonia) in the muscles of the face, neck and upper limbs, and often affects the respiratory muscles (those that control breathing).
-Myotubular Myopathy (MTM or MM): Causes: The most common form (X-linked) is caused by defects or deficiencies of myotubularin, a protein thought to promote normal muscle development. Inheritance: X-linked, autosomal recessive, autosomal dominant Onset: congenital (X-linked); infancy to early adulthood (autosomal recessive); childhood to adulthood (autosomal dominant). Symptoms: X-linked myotubular myopathy usually affects only boys, and causes severe muscle weakness and hypotonia noticeable at birth and sometimes before. The weakness and hypotonia interfere with posture and movement, and cause life-threatening difficulties with feeding and respiration.
Inflammatory Myopathies:
-Polymyositis (PM), Dermatomyositis (DM): Polymyositis and dermatomyositis are related diseases, both involving inflammation -- swelling or irritation -- of the voluntary muscles, those that normally govern movement, such as the muscles of the arms and legs. Myositis means inflammation of muscle. Polymyositis means inflammation of many muscles, and dermatomyositis means inflammation of muscle and skin. The results of either condition are weakened muscles and often muscle pain. These conditions are seldom fatal, but in the most severe cases a person may need a wheelchair or require assistance with activities of daily living. The muscle inflammation in these two forms of myositis results from a disturbance in the body's immune system.
Inclusion Body Myositis (IBM): Another type of inflammatory muscle disorder, characterized by severe cellular pathology. Cause unknown. Usually has a late onset (over 50), it is a common muscle disorder in those over 50.

Metabolic Diseases of the Muscle: Each of these disorders is caused by a different genetic defect that impairs the body's metabolism, the collection of chemical changes that occur within cells during normal functioning. Specifically, the metabolic diseases of muscle interfere with chemical reactions involved in drawing energy from food. The mitochondria inside each cell could be called the cell's "engines." The metabolic muscle diseases are caused by problems in the way certain fuel molecules are processed before they enter the mitochondria, or by the inability to get fuel molecules into mitochondria.
Above based on: http://www.mdausa.org/

11B). Summary of the genetics of neuromuscular disorders (some other major disease types also listed):

-Autosomal Recessive:
Limb-girdle muscular dystrophy (most forms)
Scapulohumeral muscular dystrophy
Scapuloperoneal muscular dystrophy
Congenital muscular dystrophy (includes Fukuyama)
Miyoshi dystrophy
Spinal Muscular Atrophy (most types)
Recessive childhood muscular dystrophy
Retinitis pigmentosa
Severe combined immunodeficiency (adenosine deaminase deficiency).
Cystic fibrosis
Sickle cell anemia
Tay-Sachs disease
Phenylketonuria

- Autosomal Dominant:
Limb-girdle muscular dystrophy (certain forms)
Facioscapulohumeral Muscular Dystrophy
Oculopharyngeal muscular dystrophy
Welander
Markesbery-Griggs
Bethlem myopathy
Myotonic muscular dystrophy
Charcot-Marie-Tooth, type IA
Huntington's disease
Marfan syndrome
APP (early onset Alzheimers)
Polycystic Kidney Disease, types 1 and 2
Retinitis pigmentosa

- X-linked Recessive:
Duchenne and Becker muscular dystrophies
Scapuloperoneal muscular dystrophy
Myotubular myopathy
Emery-Dreifuss dystrophy
Spinal and bulbar muscular atrophy (Kennedy's disease)
Fragile X syndrome
Hemophilia A
Retinitis pigmentosa

- X-linked Dominant:
Mitochondrial DNA Abnormalities:
MERRF: Myoclonus epilepsy with ragged-red fibers
MNGIE: Myogastrointestinal encephalomyopathy
Rett syndrome

11C). Websites on Neuromuscular diseases.

A Collection of High Quality Online Resources for Health Professionals:http://www.neuropat.dote.hu/nmd.htm

Also see: web.htm

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12). X Chromosome Inactivation and Skewed X Chromosome Inactivation: Manifesting carriers in X-linked neuromuscular disorders:

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13). U. S. Department of Energy Human Genome Primer.

This site provides a tremendous amount of information.
Homepage: http://www.ornl.gov/hgmis/
Genomics and Its Impact on Medicine and Society. A 2001 Primer: http://www.ornl.gov/hgmis/publicat/primer2001/index.html

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