Lecture 24 (the human genome and disease)

Question 1

Mutations

Answer 1

Mutations can be inherited or acquired

Mutations are permanent changes to the DNA sequence

Question 2

Inherited mutations

Answer 2

Mutations that are inherited are called germ-line mutations and are passed on via the games (eggs and sperm)

Question 3

Somatic mutations

Answer 3

Mutations can also be acquired by somatic cells if DNA gets damaged or is copied incorrectly. Somatic mutations are not passed to the next generation

Cancer is a good example of a disease in somatic cells that isn’t necessarily passed on

Question 4

What do mutations do?

Answer 4

Genetic variations/mutations are a driving force for evolution

Mutations can have a beneficial effect, no effect, or a deleterious (damaging or harmful) effect on the organism

The vast majority of mutations have no effect at all

The outcome of a mutation can also depend on - environmental effects (e.g. diet, exposure to toxins) and other genes (‘genetic background’)

Question 5

Classifying mutations

Answer 5

Mutations can be classed in lots of different ways because they are complex and biological hence messy

The molecular basis of a mutation often is not consistent

Mutations in a single gene can have different effects. That’s why talk about alleles

This course concentrates on two ways of thinking of mutations - dominant vs recessive and loss of function and gain of function

Question 6

Dominant vs recessive alleles

Answer 6

Humans, like many eukaryotes, are diploid. That means that they have two copies of each of their genes (one maternal and one paternal). A mutation (allele) can therefore be either heterozygous (one mutant, one wild type allele) or homozygous (both alleles are mutant)

A dominant mutation is one that causes a phenotype when heterozygous

A recessive mutation is one that causes a phenotype only when homozygous

Question 7

Loss of function vs gain of function

Answer 7

For a mutation (allele) to have a phenotype, it must affect the function of the gene. A mutation might break a gene to cause it to not work as well as normal, or not work at all. This is called a ‘Loss of function’ mutation - loss of function mutations are often recessive, because a normal copy of the gene exists on the other chromosome which can replace the lost function.

Some times a mutation can cause a gene to work to well, or to do something unexpected. This is called a ‘Gain of function’ mutation - gain of function mutations are often dominant, because having an allele that works too well or does something novel, will not be replaced by the normal copy of the gene

Question 8

What can we find out from examining an inheritance pattern?

Answer 8

By examining an inheritance pattern of an allele we can determine if it is dominant or recessive and also if it is x-linked, y-linked or autosomal

Question 9

Haemophilia inheritance and how do we know?

Answer 9

Mutations are loss of function

One intact copy protects against the disease. Women have 2 X chromosomes and are rarely affected. Both Haemophilia A and B are X-linked recessive disorders.

X linked disorder since it mainly happens in men, also because it occurs in men in every generation and we know it is recessive because carriers that do not show haemophilia but can still pass it on .

Question 10

What is haemophilia?

Answer 10

Haemophilias are disorders of blood clotting

Question 11

Huntington disease inheritance and how do we know?

Answer 11

Autosomal dominant inheritance (even if you have a normal copy of the gene, having a defective copy will give you the disease.

Only affected people can pass on the allele

Question 12

What is Huntington’s disease?

Answer 12

Progressive tremor, involuntary movements, neurodegeneration. Onset in mid life (usually 30-50) and there is no effective treatment.

Caused by an expansion of a CAG triplet repeat in the HTT gene. Causes a protein that is unstable and fragments, clumping together in nerve cells and damaging them

Mutation occurs in a gene on chromosome 4 that codes for the protein Huntingtin

PCR is used to determine the length of the CAG repeat. Can determine who will develop the disease before the age at which symptoms develop. PCR used to amplify the specific region on chromosome 4 that encodes for the CAG repeat in the Huntingtin gene.

Question 13

Cystic fibrosis what is it?

Answer 13

Cystic fibrosis is a hereditary disease that affects the lungs and digestive system. The body produces thick and sticky mucus that can clog the lungs and obstruct the pancreas. Cystic fibrosis (CF) can be life-threatening, and people with the condition tend to have a shorter-than-normal life span.

Question 14

Cystic fibrosis mutations

Answer 14

Likely to be a loss of function mutation

Many different mutations in the CFTR gene can cause cystic fibrosis. Most common is a 3bp deletion, deltaF508

Question 15

Cystic fibrosis inheritance and how do we know?

Answer 15

Inheritance is autosomal recessive (need two broken copies to get the disease)

Should find it in males and females equally and it does matter if it is passed on to the male or female since it is not X linked

Question 16

Examples of autosomal recessive and characteristics of the pedigree chart

Answer 16

inability to taste PTC and cystic fibrosis

Typically not seen in every generation of an affected family

Passed on by two asymptomatic carriers

Males and females are equally likely to inherit

Males and females can be carriers, offspring may be unaffected but are carriers. Trait is passed on equally to female and male offspring.

Question 17

Examples of autosomal dominant and characteristics of the pedigree chart

Answer 17

Widow’s peak and Huntington’s disease

Occurs commonly in a pedigree

Affected individuals have an affected parents

Males and females are equally likely to inherit

Rarely skips a generation

Question 18

Examples of x linked recessive and characteristics of the pedigree chart

Answer 18

Haemophilia A and haemophilia B

Fathers cannot pass X-linked traits to their sons therefore there is no male to male transmission.

Most often affects males

Often skips a generation, through female carriers as males can never be carriers as they will always be affected

Question 19

X-linked dominant and characteristics of the pedigree chart

Answer 19

Rarely skips a generation

Males and females cannot be carriers as they will always be affected

Affected (heterozygous) females produces 50% affected offspring (both sexes. Affected males produce 100% affected daughters and no affected sons. (M

Question 20

Y-linked and characteristics of the pedigree chart

Answer 20

Male to male transmission (males can never be carriers, as they will always affected)

All males affected and no female affected

This is very rare to have this kind of inheritance pattern

Question 21

How to determine the inheritance pattern?

Answer 21

Examine the pedigree and look for individuals that break the rules for specific types of inheritance

Identify carriers who do not have the condition, if there are none, this might mean that the condition is dominant

Find the inheritance pattern that explains all the disease occurrence in a pedigree

Question 22

Finding potential disease genes

Answer 22

Sequence genome (s) (then look for differences in genes between affected and not affected individuals)

Then map these to the human reference genome. Find the common variants and then find the novel variants.

With the novel variants, find the ones that are predicted to be benign and find the ones predicted to be harmful

Validate and test the ones that are predicted to be harmful

Ask the question fo all the individuals that have this disease carry this gene?

Question 23

Polygenic disorders

Answer 23

Inheritance of a set of variants/mutations instead of a single gene // A disease caused by multiple genes and the interactions between them and their environment. e.g. Type II diabetes

Most disorders appear to have a genetic basis but do not follow straightforward inheritance patterns

Polygenic disorders involve several genes acting together or environmental factors interacting with genes

Examples include obesity, diabetes, rheumatoid arthritis, gout, bipolar (these disorders are genetic but the inheritance pattens are complex)

Identifying genes that are associated with polygenic disorders is very hard

Question 24

Finding polygenic disease genes

Answer 24

Sequence genomes of cases (10-100K) and controls (10-100K)

Identify variations

Find the common variants and any shared variants in cases that are not in the controls

Validate and test these shared variants in cases but not in controls. Figure out if these variants in the genes are likely to be associated with the disease

Question 25

Genetic determinism

Answer 25

For most disease, having a disease-related variation does not mean you will get the disease. Such diseases come about through a combination of variants and the environment. Different sufferer may have different disease mechanisms. Most genetic disorders are probabilistic, not deterministic. This is also true of most traits with a genetic component, your genes do not direct your destiny

Genetic determinism is the belief that human behaviour and biology is completely controlled by an individual’s genes, with little or no input from the environment.

Question 26

Pedigree analysis

Answer 26

Involve collecting phenotypic information for a particular trait over several generations of a family

Question 27

Pedigree chart

Answer 27

A diagrammatic representation of the occurrence of heritable characteristics of parents and offspring over multiple generations

Question 28

Gain of function mutation

Answer 28

A mutation when the DNA sequence is altered so the resulting protein has enhanced, negative or new functions. This is usually a dominant inheritance pattern.

Question 29

Loss of function mutation

Answer 29

A mutation in an organism’s DNA resulting in the formation either of a protein that no longer functions, or a complete loss of a protein. This is usually a recessive inheritance, but can be a problem if X-linked. An example would be mutations in the CFTR gene, which causes cystic fibrosis.