Genetics Block 3: B
Penetrance with relation to a population
A condition has complete penetrance if clinical symptoms are present in all individuals who have a disease-causing mutation and to have A condition has reduced or incomplete penetrance if clinical symptoms are not always present in individuals with a mutation
what kind of heterogeneity does compound heterozygosity go with and what does it mean?
Allelic Heterogeneity; Compound heterozygote: many affected individuals carry 2 different alleles - one mutation in one gene copy and a different mutation in the homolog.
What is allelic heterogeneity ? Example disease; how common?
Allelic heterogeneity Disease caused by any one of many possible mutations in one gene Cystic fibrosis: >2000 different mutations in cystic fibrosis gene (CFTR) The majority of genetic disorders exhibit allelic heterogeneity.
Penetrance with relation to the individual
At a given time, a condition can be either pentrant or nonpenetrant in terms of the individual; the severity doesn't matter. All that matters if that it is or is not expressed
When assessing simplex cases and autosomal recessive diseases, what should you consider? Genetic fitness acts on what genotype?
Autosomal recessive: Genetic fitness acts only on homozygotes (NOT on heterozygotes). Lethal diseases: All cases result from inherited mutations. Both parents are obligate carriers.
Which option offers the best explanation for Tay-Sachs disease in Emily Rapp's son? A. A new mutation occurred in Emily's son. (mutation-selection equilibrium) B. Emily carries a mutation other than those for which she was tested. (allelic heterogeneity) C. Emily and and her husband had mutations at different loci (double heterozygote) D. One or both parents were nonpenetrant for a Tay-Sachs mutation. (reduced penetrance)
B. remember that for autosomal recessive diseases, new mutations are super rare; B. Allelic heterogeneity. Emily is a Tay-Sachs carrier, but consistent with her non-Ashkenazi ancestry, she has a mutation other than the common Jewish mutations.
Heterozygote advantage
Balancing selection Selection against each homozygote; increased fitness of heterozygote Ex: sickle cell mutation & malaria
Compare OI Type 2 with Huntington's disease in terms of mutation selection equilibrium
Both are Autosomal Dominant; Huntington's disease has a much higher genetic fitness bc the affected person can have a child before the disease is expressed; OI Type 2 has a zero genetic fitness bc you die before you can even have kids and pass along the alleles. Thus the occurrence is always due to a new mutation
Both members of a couple have autosomal recessive deafness. Their hope is to have deaf children. Genetic testing reveals the following: Mother- 2 mutations in connexin 26: 35delG/M34T Father- homozygous mutant for the L236P mutation in the SLC26A4 gene What is their likelihood to have a deaf child?
Close to 0% chance, since deafness has a different genetic etiology in each parent (locus heterogeneity)
Differential reproductive fitness due to differences in genotype
Differential reproductive fitness due to differences in genotype Favorable alleles → frequency↑ Deleterious alleles → frequency↓
Both members of a couple have autosomal recessive deafness. Their hope is to have deaf children. Genetic testing reveals the following: Mother- 2 mutations in connexin 26: 35delG/M34T Father- homozygous mutant for the L236P mutation in the SLC26A4 gene Explain the role of each concept in the scenario. Locus heterogeneity Allelic heterogeneity Compound heterozygote Double heterozygote
Explain the role of each concept in the scenario. Locus heterogeneity - connexin 26 and SLC26A4 are two different deafness genes Allelic heterogeneity - mother illustrates allelic heterogeneity in connexin 26 (two different loss of function mutations) Compound heterozygote - mother is a compound heterozygote; two different mutations in the same gene Double heterozygote - their child will be a double heterozygote with normal hearing
Gene flow
Gene flow is the exchange of genes between different populations
Gene admixture
Genetic admixture - result of mating between previously isolated population subgroups
In people of African ancestry, the carrier frequency for sickle cell is slightly lower in the continental U.S. than in continental Africa. Why?
In U.S., genetic admixture affects changes in allele frequency faster than loss of selection pressure.
Pleiotropy
Multiple, often seemingly unrelated, phenotypic effects caused by genetic variation in one gene
Does a recessive allele always mean the same mutation?
No; you can have different mutations that cause defective phenotype
Population Stratification
Population-specific variation in allele frequencies; Elevated risk of autosomal recessive disease in population subgroups Ethnicity of genetic diseases Neutral polymorphisms and risk alleles for common diseases often exhibit stratification, a potential confounder in genetic research
What is locus heterogeneity
Similar disease caused by mutations in different genes BRCA1 & BRCA2 - both are hereditary breast cancer genes
What is penetrance?
The proportion of individuals with a mutation who exhibit clinical symptoms of the disorder
In what state do the vast majority of mutant alleles exist?
The vast majority of mutant alleles exist in the heterozygous state (as predicted by Hardy-Weinberg).
Variable Expressivity
Variable severity (of individual features or entire phenotype); severity ranging from mild to severe
Founder Effect
Within a small population, a previously rare allele becomes more common.
Evidence of locus heterogeneity
complementation; 2 separate loci, A and B, associated with autosomal recessive hearing loss (aa = deaf; bb = deaf) Offspring of II-6 & II-7 are *double heterozygotes* with normal hearing
Fitness
likelihood of abnormal alleles being transmitted to the next generation [range of 0-1, where 0 is a genetic lethal] Many genetic disorders are associated with reduced genetic fitness
Mutation-selection equilibrium
mutant alleles lost through selection (reduced fitness) are replaced by new mutations