Lecture 24 (the human genome and disease) Flashcards
Mutations
Mutations can be inherited or acquired
Mutations are permanent changes to the DNA sequence
Inherited mutations
Mutations that are inherited are called germ-line mutations and are passed on via the games (eggs and sperm)
Somatic mutations
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
What do mutations do?
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’)
Classifying mutations
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
Dominant vs recessive alleles
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
Loss of function vs gain of function
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
What can we find out from examining an inheritance pattern?
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
Haemophilia inheritance and how do we know?
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 .
What is haemophilia?
Haemophilias are disorders of blood clotting
Huntington disease inheritance and how do we know?
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
What is Huntington’s disease?
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.
Cystic fibrosis what is it?
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.
Cystic fibrosis mutations
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
Cystic fibrosis inheritance and how do we know?
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
Examples of autosomal recessive and characteristics of the pedigree chart
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.
Examples of autosomal dominant and characteristics of the pedigree chart
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
Examples of x linked recessive and characteristics of the pedigree chart
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
X-linked dominant and characteristics of the pedigree chart
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
Y-linked and characteristics of the pedigree chart
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
How to determine the inheritance pattern?
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
Finding potential disease genes
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?
Polygenic disorders
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
Finding polygenic disease genes
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
Genetic determinism
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.
Pedigree analysis
Involve collecting phenotypic information for a particular trait over several generations of a family
Pedigree chart
A diagrammatic representation of the occurrence of heritable characteristics of parents and offspring over multiple generations
Gain of function mutation
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.
Loss of function mutation
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.
