Genetic Disease

by Kathryn Milward (September 2001)

Contents

Introduction

The human genome is composed of approximately 30 000 genes, each gene is a set of specific instructions in order for the body to make proteins. Every protein required for life can be made using the instructions within the genes. When a specific protein is required in the body, the body uses the relevant gene in order to make it.

A gene is a stretch of DNA, which is composed of a sequence of units known as nucleotides. There are four types of nucleotide known as A, T, C and G. The sequence of the nucleotides in a gene determines what protein is made from the gene and therefore the function of the gene.

Genetic diseases are caused by changes in the body’s ability to use the genes in order to produce proteins that are vital for normal body function.

Inheritance Patterns

There are various ways in which genetic diseases are passed from parents to children through generations. These are known as inheritance patterns and depend on the gene affected and the type of mutation.

The DNA within every cell is arranged into chromosomes. The majority of normal human cells contain 23 pairs of chromosomes, 22 pairs are known as autosomes and are the same in males and females. The 23rd pair are known as the sex chromosomes and differ between the sexes, males are said to have an X and a Y chromosome, a non-identical pair of chromosomes, while females are said to have two X chromosomes, which are identical.

As well as the location of the gene affected defining the inheritance pattern, the way in which the gene is affected is important when looking at inheritance. A gene mutation (a change in the gene,) can be said to be dominant or recessive. If the mutation is dominant then one mutation on one chromosome of the pair is sufficient to affect the body’s ability to use the gene and produce proteins and therefore can result in disease. If the mutation is said to be recessive, the body’s ability to utilise the gene and produce proteins is only severely affected enough to cause disease when there are mutations on both chromosomes in the pair.

Autosomal Dominant Inheritance

An example of an autosomal dominant disease is Huntingdon’s Disease

A genetic disease is described as autosomal dominant when the gene affected is found on an autosome (chromosomes 1 – 22) and when the mutation is dominant.

Case Study,

Jack suffers from Huntingdon’s Disease. Huntingdon’s Disease is an autosomal dominant disorder that present’s in later life. Jack has one mutation for Huntingdon’s Disease on one gene on one chromosome, the other chromosome of the pair is normal and has no mutation for Huntingdon’s Disease. Jack’s wife Claire is normal, she does not have any mutations for Huntingdon’s Disease. Jack and Claire have two children Joy and Dylan.

When fertilisation occurs the child inherits one chromosome from each pair from it’s mother and one chromosome from each pair from it’s father. This means that if the father has one mutated

chromosome and one normal chromosome in a pair as in this case, the children have a one in two chance of inheriting the mutated chromosome. As one mutated chromosome is sufficient to cause the disease in autosomal dominant disorders, Joy and Dylan have a 50% chance of inheriting the Huntingdon’s mutation from their father and therefore a 50% chance of developing the disease.

Autosomal Recessive Inheritance

An example of an autosomal recessive disease is Sickle Cell Anaemia.

A genetic disease is described as autosomal recessive when the gene affected is found on an autosome and when the mutation is recessive.

Case Study 1,

Joanne suffers from Sickle Cell Anaemia, therefore Joanne has the Sickle Cell Mutation on both genes on both chromosomes, her partner Barry is normal. Joanne and Barry visit a Genetic Counsellor to discuss the risk of Sickle Cell Anaemia in any children they may choose to have.

As Sickle Cell Anaemia is an autosomal recessive disorder, in order to suffer from the disease both copies of the gene on both chromosomes in the pair must carry the mutation. Any children that Joanne and Barry decide to have will inherit a normal chromosome from Barry and a mutated chromosome from Joanne, therefore if Joanne and Barry decide to have children, none of them will develop Sickle Cell Anaemia as they will all inherit one mutated gene and one normal gene, instead they will all be carriers of the disease.

Case Study 2,

Martin and Rebecca are both carriers of Sickle Cell Anaemia, this means that they both have one mutated copy of the Sickle Cell Gene and one normal copy of the Sickle Cell Gene. Martin and Rebecca decide they want to have children and visit a Genetic Counsellor to discuss the risk of Sickle Cell Anaemia in their children.

The Genetic Counsellor explains that when a child is conceived it receives one chromosome from each pair from it’s father and one chromosome from each pair from it’s mother to form a complete set of chromosome pairs. Which chromosome of the pair that is passed to the child is random, therefore a child of Martin and Rebecca’s has a 50% chance of inheriting a mutated gene from each parent. This means that a child of Martin and Rebecca’s will have a 25% chance of inheriting the mutated gene from both parents and therefore a 25% chance of developing the disease. A child with both parents as carriers also has a 25% chance of inheriting both normal copies of the Sickle Cell gene and therefore being normal. Martin and Rebecca’s children also have a 50% chance of inheriting a normal copy of the Sickle Cell gene from one parent but a mutated copy of the gene from the other and therefore a 50% chance of becoming a carrier of Sickle Cell Anaemia.

Sex (X) Linked Dominant Inheritance

A genetic disease is describes as X linked dominant when the gene affected is located on the X chromosome and when the mutation is dominant.

Males have one copy of the X chromosome and females have two copies of the X chromosome. One copy of a mutated gene is sufficient to cause the disease and therefore males and females are affected by X linked dominant disorders. Females receive two copies of the X chromosome, one from their mother and one from their father, males receive an X chromosome from their mother and a Y chromosome from their father.

Females and X Linked Dominant Disorders

Females can receive a copy of the mutated chromosome from either their mother or their father, as both the mother and the father pass on a copy of the X chromosome to their daughter. Therefore if one of either parents is affected by an X linked disorder the child has a 1 in 2 chance of inheriting a mutated gene on the X chromosome. Therefore if a child inherits one copy of the mutated gene they will develop the disorder. In the case where one parent carries an X linked dominant mutation there is a 1 in 2 chance of that parent passing on the normal X chromosome to a daughter and a 1 in 2 chance of that parent passing on the mutated X chromosome to the daughter, therefore a daughter has a 1 in 2 chance of inheriting the disorder from the parent.

A female with an X linked dominant mutation on one of her X chromosomes can pass the mutation on to sons and daughters, as the mother will pass on a copy of one of her X chromosomes to sons and daughters.

Males and X Linked Dominant Disorders

Males receive an X chromosome from their mother and a Y chromosome from their father. Therefore a male can only inherit an X linked Dominant Disorder from his mother.
If the father has an X linked dominant mutation he will not pass it to his sons, as sons inherit their father’s Y chromosome and not their X chromosome.
However a father with an X linked dominant mutation will pass the mutation to his daughters. Every daughter that a father with an X linked dominant mutation has, will inherit the mutated X chromosome and therefore inherit the disease.
If a female has a X linked dominant mutation on one of her X chromosomes there is a 1 in 2 chance that she will pass the mutated chromosome to her son.

Case Study 1,

Sarah has an X linked dominant disorder, she has one copy of the mutation on one of her X chromosomes, the other is normal. Sarah’s partner Neil is normal. Neil and Sarah decide to have children. Sarah will pass a X chromosome to any child that she has, as Sarah has one normal X chromosome and one mutated X chromosome, any child of Sarah’s has a 1 in 2 chance of inheriting the mutated chromosome and therefore inheriting the disease, male or female.

Case Study 2,

Jeff has an X linked dominant disorder, he has a mutation for the disorder on his X chromosome and a normal Y chromosome. Jeff’s wife Suzanne is normal. Jeff and Suzanne have children. Jeff will pass his normal Y chromosome to all his sons, therefore all Jeff’s sons will be normal. However Jeff will pass his mutated X chromosome to his daughters, all of Jeff’s daughter’s will inherit the mutation and therefore inherit the disease.

Sex (X) Linked Recessive Inheritance

An example of an X linked recessive disease is Haemophilia

A genetic disease is described as X linked recessive when the gene affected is located on the X chromosome and when the mutation is recessive.

Females have two copies of the X chromosome, while males only have one copy. As the mutation in X linked recessive disorders is recessive, if there is another normal copy of the gene affected the person will not suffer from the disease. This means that if a female has a mutated copy of the gene on one X chromosome, but a normal copy on the other X chromosome it means that she will not suffer from the disease, however she will be known as a carrier. However, if males inherit one copy of the mutated X chromosome they will develop the disease, as they don’t have another normal X chromosome.

Females and X linked recessive disorders.

If a female has one X chromosome with the mutated gene, but the other X chromosome is normal, they will not suffer from the disease. They are said to be carriers.
If a female has mutations on both X chromosomes she will suffer from the disease.
A female carrier of an X linked recessive disorder has a 1 in 2 chance of passing on the mutation to any children that she has.
A female sufferer of an X linked recessive disorder will pass a mutated X chromosome to any children that she has.

Males and X linked recessive disorders,

If a male inherits one copy of the mutated X chromosome they will develop the disease as they do not have another X chromosome. Males inherit a Y chromosome from their father and an X chromosome from their mother. As males only inherit X chromosomes from their mother, a male can only be affected by the disorder if their mother has a mutated copy(s) of the X chromosome.
Affected males will pass their normal Y chromosome to any sons that they have, therefore if the mother is normal all sons will be healthy.
Affected males will pass their mutated X chromosome to any daughters that they have, therefore if the mother is normal all daughters will have one copy of the mutated X chromosome and be carriers of the disease.
If an affected male has a son with a carrier female, their sons have a one in two chance of inheriting the mutated copy of the chromosome from their mother. As they will inherit the normal copy of the X chromosome from their father, they have a one in two chance of inheriting the disease from their mother.
If an affected male has a daughter with a carrier female, all daughters will receive a mutated X chromosome from their father, they also have a one in two chance of inheriting a normal X chromosome from their mother and becoming carriers and a one in two chance of inheriting the mutated X chromosome from there mother, thus inheriting two copies of the mutated X chromosome and developing the disease.

Case Study 1,

Tony suffers from an X Linked Recessive Disorder, he has a mutated X chromosome and a normal Y chromosome. Tony has children with his partner Helen who is normal. If Tony and Helen have a son, he will receive a normal X chromosome from Helen and a normal Y chromosome from Tony, therefore all sons will be healthy. If Helen and Tony have a daughter, she will receive a normal copy of the X chromosome from Helen and a mutated X chromosome from Tony, therefore she will become a carrier of the X linked recessive disorder.

Case Study 2,

Janey is a carrier of an X linked recessive disorder, therefore she has one normal X chromosome and a mutated chromosome. Her husband Bob is normal. Janey and Bob have a daughter Josie she will inherit a normal X chromosome from her father, however Josie has a 1 in 2 chance of inheriting the mutated X chromosome from her mother and therefore developing the disease. Josie also has a 1 in 2 chance of inheriting the normal X chromosome from her mother and therefore being normal. Janey and Bob have a son, Marcus. Marcus receives a normal Y chromosome from Bob, Marcus also inherits a X chromosome from his mother. Marcus has a 1 in 2 chance of inheriting the mutated X chromosome and developing the disease and a 1 in 2 chance of inheriting the normal X chromosome and being normal.

Case Study 3,

Shirley suffers from a X lined recessive disorder, therefore both of her X chromosomes carry the X linked recessive disorder mutation. Shirley’s partner Frederick is normal. All of Shirley’s children will inherit a mutated X chromosome from their mother. Shirley’s sons will suffer from the disease as they will have a mutated X chromosome and a normal Y chromosome. All of Shirley’s daughters will be carriers as they inherit a normal X chromosome from their father and a mutated X chromosome from their mother.

Y Linked Inheritance

The final type of inheritance is Y linked Inheritance. These disorders are extremely rare. The gene involved in Y linked disorders is found on the Y chromosome that is found only in males. As females do not have a Y chromosome they are not affected by Y linked disorders.

Case Studies

Andrew suffers from a Y linked disorder, therefore he has a normal X chromosome and a mutated Y chromosome. Andrew’s wife Lizzy is normal as females do not have a Y chromosome. Andrew and Lizzie have children. Andrew and Lizzy’s daughters inherit normal X chromosomes from their mother and father and are therefore normal. Andrew and Lizzie’s sons will inherit a normal X chromosome from Lizzie and a mutated Y chromosome from Andrew and therefore will inherit the disease.

Mutations

As stated before, genetic diseases are caused by changes in the genes that affect the body’s ability to use the genes to produce proteins normally. Abnormal DNA (e.g. number of chromosomes) or changes within the body’s DNA are known as mutations. There are many types of mutations some affect a single nucleotide while other’s affect whole chromosomes. Mutations within the genome are very common, everybody will have mutations within their DNA. However, relatively few mutations lead to genetic diseases, whether or not a mutation will cause disease depends on the type of mutation and the genes affected.

In order to understand how mutations affect the body’s ability to use the genes you must understand how genes are normally used to form proteins

DNA is composed of nucleotides which attach together to form a strand of DNA. Two strands of DNA join together so that they run parallel to one another, these parallel strands twist around each other to form the double helix shape of DNA. There are four types of nucleotide A, T, C and G found in DNA, the order of the nucleotides in the strand is extremely important.

Each gene codes for a single protein. Proteins are chains of molecules known as amino acids, these chains are highly folded to form a certain shape and configuration necessary for it’s function. How the protein chain folds is determined by the amino acids in the chain and their properties. Changes in amino acids will change the way in which the protein folds and therefore change the function of the protein.

When the body wants to use a gene to make a protein it looks at the nucleotide sequence, three nucleotides (a codon) at a time. Codons are specific instructions for the body for amino acids. One amino acid is coded for by more than one type of codon, i.e. more than one arrangement of three nucleotides. Starting from the beginning of the gene the body looks at the first three relevant (coding) nucleotides, the first codon. This tells the body what amino acid is to be the first in the amino acid chain. The body then looks at the next codon in the DNA sequence- this codon will code for the next amino acid in the amino acid chain. This process is repeated again and again until you reach the end of the gene, which is signalled by a STOP codon. Stop codons are arrangements of three nucleotides that prevent the body from adding more amino acids to the chain therefore they signal that the amino acid chain is complete, this completed chain then folds into a functional protein.

The sequence of nucleotides is important because changes may mean that a different amino acid is incorporated into the chain. Changes in the amino acids of a chain may affect the folding of the protein and therefore it’s function.

Diagram – This diagram illustrates how the nucleotide sequence codes for the amino acid chain.

 

Start of Gene

 

End of Gene

1st Codon

2nd Codon

 

Nth Codon

Nucleotide sequence

G C C

C G C

T G T

C A C

………….

A A G

G T T

G C T

T A A

 

Amino acid coded for

Alanine

Arginine

Cysteine

Histidine

…………..

Lysine

Valine

Alanine

STOP

Types of Mutation

There are many types of mutations that occur within the genome. They can be grouped into two main categories, microscopic changes, involving changes in whole chromosomes, or sub-microscopic changes which tend to affect only a few nucleotides. Generally the term mutation relates to the sub-microscopic type of mutation, however I shall discuss both types under the term mutation.

Sub-Microscopic Mutations

Sub-Microscopic Mutations affect only a few nucleotides within a gene. There are many different types that can be placed in three groups.

  1. Point Mutations (Substitutions)
  2. Deletions and Insertions
  3. Unstable Mutations

Point Mutations

A point mutation occurs when one nucleotide is substituted for another nucleotide. There are three main consequences of this type of mutation.

  1. Silent Mutation – One nucleotide is substituted for another, however there is no change in the amino acids are coded for, therefore the protein is not changed. As stated above, more than one codon can code for the same amino acid, for example the codons GCT, GCC, GCA GCG all code for the amino acid Alanine, therefore if the nucleotide sequence GCT was affected by a point mutation so that it became GCC, it would still code for the same amino acid and therefore there would be no change in the function of the protein formed or the gene.
  2. Missense Mutation – One nucleotide is substituted for another, however in missense mutations the amino acid coded for changes. A change in the amino acids in a chain can affect the folding of the protein chain and can therefore affect the protein’s function. For example the nucleotide sequence GAC codes for the amino acid Asparagine, if a point mutation occurred changing the sequence to GAA the sequence would code for the amino acid Glutamine, therefore when the gene was used to produce a protein, glutamine would be incorporated into the chain rather than asparagine, possibly altering the function of the protein produced.
  3. Nonsense Mutation – One nucleotide is substituted for another, however in nonsense mutations the resulting nucleotide sequence is a STOP codon. For example the nucleotide sequence TAC codes for the amino acid tyrosine. However, if a point mutation occurred changing the sequence to TAA, the sequence would be a stop codon. When the affected gene was used to produce a protein the body would use the gene normally until it reached the STOP codon, at which point it would stop the addition of amino acids to the chain. This type of mutation can severely affect the protein that is made.

Deletions and Insertions

Deletions and Insertions involve either the addition or deletion of nucleotides into the nucleotide sequence. Deletions and insertions of nucleotides can completely disrupt the gene and it’s function. The effect of deletions and insertions depends on the number of nucleotides inserted or deleted and the location of them.

1) Insertion of one nucleotide - The body reads DNA in codons, three nucleotides at a time. Therefore if a nucleotide is inserted into a sequence the body is said to be ‘thrown out of frame.’ This type of mutation is often referred to as frame-shift mutations. The diagram below illustrates how the insertion of one nucleotide changes all codons after the insertion, thus changing many amino acids and therefore the function of the protein.

Diagram – The effect of an insertion

Normal gene

G C C

C G C

T G T

C A C

A A G

G T T

G C T

Alanine

Arginine

Cysteine

Histidine

Lysine

Valine

Alanine

After the insertion of one nucleotide, (T inserted into second codon.)

G C C

C G T

C T G

T C A

C A A

G G T

T G C

Alanine

Arginine

Leucine

Serine

Glutamine

Glycine

Cysteine

2) Deletion of one nucleotide - The deletion of one nucleotide has a similar effect, as shown by the following diagram. If one nucleotide is deleted, the two remaining nucleotides from the codon will form a new codon with the first nucleotide in the next codon. This then has the effect of disrupting all subsequent codons, changing the ‘meaning’ of many codons and therefore altering the protein.

Diagram – The effect of a deletion

Normal Gene

G C C

C G C

T G T

C A C

A A G

G T T

G C T

Alanine

Arginine

Cysteine

Histidine

Lysine

Valine

Alanine

After the deletion of one nucleotide, (G removed from second codon.)

G C C

C C T

G T C

A C A

A G G

T T G

C T

 

Alanine

Proline

Valine

Threonine

Arginine

Leucine

 

3) The insertion of three nucleotides – If three nucleotides are inserted (or multiples of three) they may not disrupt the whole gene, instead they may only result in the addition of extra amino acids into the chain. This is illustrated by the following example.

Diagram – The effect of a three nucleotide insertion

Normal Gene

G C C

C G C

T G T

C A C

A A G

G T T

G C T

Alanine

Arginine

Cysteine

Histidine

Lysine

Valine

Alanine

After the insertion of three nucleotides

G C C

G C C

C G C

T G T

C A C

A A G

G T T

G C T

Alanine

Alanine

Arginine

Cysteine

Histidine

Lysine

Valine

Alanine

4) The deletion of three nucleotides – If three nucleotides are deleted (or multiples of three,) it will not disrupt the whole gene and all subsequent codons, instead it may result in the removal of amino acids from the chain.

Diagram – The effect of a three nucleotide deletion.

Normal Gene

G C C

C G C

T G T

C A C

A A G

G T T

G C T

Alanine

Arginine

Cysteine

Histidine

Lysine

Valine

Alanine

After the deletion of three nucleotides

G C C

T G T

C A C

A A G

G T T

G C T

Alanine

Cysteine

Histidine

Lysine

Valine

Alanine

C G C

Unstable Mutations

A major type of unstable mutation is the triplet repeat expansion mutation. This type of mutation is responsible for many disorders including Huntingdon’s Disease and Fragile X Syndrome. Within many genes are regions of three nucleotide repeats, these are regions where a specific sequence of nucleotide is repeated many times. For example there is a region of CAG repeats in the gene for the testosterone receptor. In a normal individual there are on average 20 repeats (CAGCAGCAGCAGCAGCAGetc.) However in X-Linked spinal bulbar muscular atrophy there are more than 40 CAG repeats, the CAG triplet is said to have expanded.

Microscopic Mutations

Microscopic mutations are also known as Chromosome Abnormalities. Rather than involving a few nucleotides, chromosome abnormalities can involve many genes, even whole chromosomes. These types of mutations can often be seen through the microscope and appear as structural abnormalities. There are two types of microscopic mutation that I shall discuss, 1) Changes in the number of chromosome sets and 2) Changes in the number of individual chromosomes.

1) Changes in the number of chromosome sets.

A normal human cell has 23 pairs of chromosomes. Euploidy is where a cell does not have the normal number of chromosome sets. The most common type of euploidy is triploidy where the cells have three chromosome sets. Triploidy occurs in 1 – 3% of all pregnancies, however most spontaneously abort and therefore few triploid pregnancies survive until term.

During fertilization the male sperm and female egg fuse together to form a zygote. The sperm and the egg both contain one copy of every chromosome, one chromosome set, therefore when they fuse the zygote that forms contains 23 chromosome pairs. Triploidy can occur by three mechanisms. The most common type is due to the fertilization of one egg by two separate sperm, this occurs in approximately 66% of cases. Triploidy can also occur by either the egg or the sperm containing 2 sets of chromosomes so that when fertilization occurs another set is introduced so the resulting gamete has 3 chromosome sets.

2) Changes in the number of individual chromosomes.

The term aneuploidy refers to when there are changes in the number of individual chromosomes. In a normal cell there are two copies of every chromosome, aneuploidy refers to when there is not two copies of a certain chromosome. For example, there may be 3 copies of chromosome 18 – trisomy, or only one copy of chromosome 18 – monosomy. Aneuploidy occurs during the process of meiosis when the sex cells are formed, these are cells that only contain one copy of every chromosome rather than chromosome pairs.

The process of meiosis

  1. A single cell containing a full set of chromosome pairs replicates it’s DNA so it contains 4 chromosome sets.
  2. The cell divides to form two cells both containing 2 chromosome sets – the first meiotic division
  3. Both cells then divide again to form 4 cells, each containing one chromosome set – the second meiotic division.

 

Aneuploidy occurs when the DNA fails to separate into different cells. This can either occur at the first meiotic division or at the second meiotic division.

For example Chromsome 21 triploidy.

At the first meiotic division:

A single cell containing four chromosome sets divides so that both cells contain 2 copies of every chromosome, the exception is for chromosome 21 which fails to separate during division so one cell does not contain a copy of chromosome 21 while the other cell contains four copies. These two cells then divide again, the cell without a copy of chromosome 21 divides so the two cells formed contain one copy of every chromosome except chromosome 21. The cell with four copies of chromosome 21 divide so the resulting cells contain a copy of every chromosome but two copies of chromosome 21. When normal fertilization occurs the cells without chromosome 21 will form a zygote with one copy of chromosome 21 – monosomy, while the cells with two copies of chromosome 21 will form a zygote with three copies of chromosome 21 – trisomy.

Diagram: Illustrating failure of meiosis, chromosome 21 at the first meiotic division resulting in aneuploidy.

Meosis_fail.gif (7739 bytes)

 

At the second meiotic division:

A single cell replicates it’s DNA so that it contains four chromosome sets. This cell then divides to form two cells that both contain two chromosome sets. These cells then divide again, however in our example chromosome 21 in one of the cells fails to separate during the second division. Therefore one of the resulting cells contains two copies of chromosome 21 while the other does not contain any copies of chromosome 21. When fertilization occurs the cell that contains two copies of chromosome 21 will form a zygote with three copies of chromosome 21 – trisomy, while the cell that does not contain chromosome 21 will form a zygote with one copy of chromosome 21 – monosomy.

Diagram: Illustrating the failure of meiosis, chromosome 21 at the second meiotic division resulting in aneuploidy,

Meosis_fail_2.gif (12991 bytes)

Most cases of aneuploidy cause spontaneous abortion and therefore seldom reach term. However, there some known disorders associated with aneuploidy as listed below.

Type of Aneuploidy

Disorder

Trisomy 21

Down’s Syndrome

Trisomy 18

Edward’s Syndrome

Trisomy 13

Pateau’s Syndrome

Sex Linked

X monosomy

Turner’s

XXY

Klinefelter’s

XXX

Triple X

XYY

XYY Syndrome

 

References.

HUMAN MOLECULAR GENETICS,
Tom Strachan, Andrew P.Read, 2nd Edition, BIOS Scientific Publishers, 1999.

BIOCHEMISTRY,   
Lubert Stryer, 4th Edition, W.H.Freeman and Company, 1995.

THE HUMAN GENOME, A USER’S GUIDE,
R. Scott Hawley, Catherine A. Mori, Academic Press, 1999.