Factors Affecting Expression of Genotypes Flashcards
What is locus heterogeneity?
when a disease may be caused by mutations in any one of a number of different genes.
For example, BRCA1 is a DNA repair gene on chromosome 17. BRCA2 is a distinct repair gene on chromosome 13. Mutations in either gene may give rise to hereditary breast cancer.
Are most genetic disorders linked to loci heterogeneity autosomal recessive at both loci, or autosomal dominant?
Autosomal recessive at both (i.e 2 separate loci, A and B, associated with autosomal recessive hearing loss (aa = deaf; bb = deaf)
What is a double heterozygote in regards to loci heterogeneity?
Using the example of deafness which is a heterogeneitic autosomal recessive disease. When two parents (one aaBB and the other AAbb- both deaf)- have children who are heterozygous at both loci (i.e. AaBb) and are thus not affected by the autosomal recessive disease
This couple has ZERO chance of produce a deaf child
What is allelic heterogeneity?
Many different mutations within one gene may be responsible for a particular genetic disease.
Cystic fibrosis (autosomal recessive) provides a classic example of allelic heterogeneity. A couple thousand mutations have been identified in the CFTR gene. Each mutation causes partial or full loss of function of the CFTR protein (which regulates a cell membrane chloride channel).
Allelic heterogeneity is a very common phenomenon.
What is the big picture of allelic heterogeneity?
Different mutations of a gene can result in a spectrum of phenotypic effects. This is illustrated well in cystic fibrosis (i.e. a class 1 mutation of the CFTR protein results in reduced or absent synthesis of chloride channels while a class 4 mutation altered conductance of CFTR chloride channel, etc.)
All mutations in the CF gene cause (full or partial) loss of function in the protein
What is a compound heterozygote?
affected individuals carrying 2 different alleles – one mutation in one gene copy and a different mutation in the homolog (i.e. in cystic fibrosis, one allele has an F508del and the other has an N1303K mutation of the CFTR protein- so this person is not homozygous, but a compound heterozygote with two mutations that are both classified as ‘recessive’)
What is penetrance?
The proportion of individuals with a mutation who exhibit clinical symptoms of the disorder.
A condition has complete penetrance if clinical symptoms are present in all individuals who have a disease-causing mutation and to have (i.e Nmutation = Nclincial)
A condition has reduced or incomplete penetrance if clinical symptoms are not always present in individuals with a mutation (i.e. Nmutation > Nclinical)
On an individual basis, penetrance is an all or nothing event
What is the difference between penetrance and variable expressivity?
The concept of penetrance is often confused with variable expressivity, which is the variation in the type and severity of clinical features of a genetic disorder.
With penetrance, however, the severity of the condition is not important. The only factor that matters is whether or not the condition is expressed at all.
What is the ‘time scale’ of penetrance?
Sometimes penetrance can be referred to in terms of a time scale. For example, Huntington’s Disease has a lifetime penetrance of 100%, but has an age-related penetrance as follows:
At age 20 there is virtually no chance of showing signs of Huntington’s and by age 70 everyone who is going to be affected will have got it. If an individual has a positive test result at a relatively young age, we cannot predict with certainty at what age that individual will develop the condition. (i.e. a sigmoidal curve) This is one of the challenges associated with counseling for late-onset conditions.
What is natural selection in regards to mutation longevity?
As new mutations arise, they may be acted upon by natural selection. If a variant provides a selective advantage, the allele frequency will increase over time. If negative selection reduces the likelihood of the mutation to be passed on to future generations, it may disappear (or decrease in frequency).
In terms of natural selection, what is ‘heterozygous advantage?
In this situation, natural selection favors the heterozygote, while selecting against both homozygous normal and homozygous mutant.
A classic example is the sickle cell mutation, which provides some resistance to malarial infection. Thinking historically, in regions with endemic malaria, homozygous normal individuals are at a selective disadvantage due to malaria susceptibility, individuals affected with sickle cell anemia are at a disadvantage due to their disease, and heterozygotes are at an advantage. In autosomal recessive disorders, most mutant alleles exist in heterozygotes. In response to repeated malaria outbreaks, the frequency of the mutant allele increases over time, in spite of the negative consequences in terms of affected individuals.
Heterozygote advantage often is invoked as a possible explanation for high mutant allele frequencies in large populations that share a geographic history.
Name four examples of heterozygous advantage.
Sickle cell anemia / malaria
Thalassemia alleles / malaria
Cystic fibrosis / cholera; secretory diarrhea (It has been proposed that the most common mutation in cystic fibrosis (F508del) gained a heterozygote advantage because it provided some protection against salt loss as various pandemic plagues swept through Europe)
Hereditary hemochromatosis / anemia (an iron overload disorder, also common in European ancestry. Heterozygosity is hypothesized to provide some protection against iron-deficient anemia, especially during pregnancy.)
What is the Founder effect?
occurs when a previously rare allele increases in frequency within a small population isolate. Founder effect often is invoked to explain disease risk in small populations that tend to mate within their own group.
What is population stratification?
Population-specific variation in allele frequencies
E.g. In a disorder like Cystic Fibrosis that exhibits extensive allelic heterogeneity, it’s worth noting that the spectrum of mutations also may vary significantly. For example, the nonsense mutation W1282X is relatively rare in Europeans, but it is the most common mutation seen in Ashkenazi Jews. Thus, although the carrier frequency is the same in both groups, the specific mutations vary.
What is gene admixture?
The result of interbreeding between previously separate groups. Any population stratification between groups will alter allele frequencies in the admixed population.
