Objectives 1) To be comfortable drawing conclusions about inheritance patterns when interpreting family histories or looking at pedigrees 2) To understand how mutations are distributed in populations (Hardy-Weinberg) 3) To be able to calculate the change of having offspring with a recessive condition knowing the carrier frequency of a condition in the population 1) To be comfortable drawing conclusions about inheritance patterns when interpreting family histories or looking at pedigrees - Mutation in a single allele is enough to cause disaese!- Gene on X (X-linked)!- Genes on automsome (autosomal dominant)!- Mutation in both alleles is req. to cause disease!- Genes on autosome (autosomal recessive)!- Rare female homozygote for X-linked! 2) To understand how mutations are distributed in populations (Hardy-Weinberg) - Genes in populations: how recessive conidtions occur in population groups!- Ex. Deafness, usually mut. in GJB2. Hearing loss is the most common condition found at birth. Muts in connexin26 are a common cause of hearing loss.!- One method for determining the carrier frequency is to screen hearing individs for the presence of the gene mut. Carriers are heterozygotes (one reference and one mutant allele). Can use the Hardy-Weinberg law to determine the carrier frequency w/o testing lots of people!!- Hardy-Weinberg law= a math model for calculating allele and gene frequencies in a population!- Assumptions!1) Large population with random mating!2) Allele frequencies remain constant (no new mutations, no reproductive selection bias, no sig. immigration from populations with diff. allele frequencies 3) To be able to calculate the chance of having offspring with a recessive condition knowing the carrier frequency of a condition in the population Allele frequencies - p= the freq. of allele 1!- q= the freq. of allele 2!- p + q = 1 (sum of all alleles in a popn = 1)!- p^2= the number of homozygous normal WT individs in a population!- 2pq= the number of heterozygous carriers in a population!- q^2= the number of homozygous affected individs in a population!- Can solve for 2pq to find the carrier frequency!Ex. q^2= 1/2000, p^2 is about = 1. Solve for 2pq.!q= 0.02 p= 1 2pq=0.04= 4/100= 1/25. Carrier frequency is 1/25. They aren't affected though.!!Example clinical situation: Marie is of European descent and has a deaf sister. Marie wants to know herchange of having a deaf child caused by muts in Connexin 26 if the father of her child is of European descent. ! !Chance that father will be a carrier? See above calculation. 2pq= 0.04. Carrier frequency is 0.04 or 1/25. Father's chance of being a carrier= 1/25.!!!!!!!!!!!!!!!!Disturbances to HW Equilibrium - Selective advantage= one group survives better than another ex. sickle cell carriers have an advantage in resisting malaria!- Mutation= rare, in practice don't change it much unless there's a selective advantage!- Assortive mating ex. communities with high rates of consanguinity or a closed community (bottle-neck), the alleles will no longer be in equilibrium!- Founder effect!- bottleneck!- marriage restricted to small populations based on religion or ethnicity!- consanguinity!- restricted geographical mating e.g. an island!FOR HW, always assume that p^2= 1!!!
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