Lecture 16

Learning outcomes

1. Describe the Hardy Weinberg Law and equilibrium in genetic counseling

2. Describe assumptions on which the HW law rests, and describe factors that can disturb HW equilibrium

   • The Hardy-Weinberg principle has two critical components. The first is that under certain ideal conditions, a simple relationship exists between allele frequencies and genotype frequencies in a population.

     • Random mating: reproductive pairings are random with respect to the locus in question

     • No genetic drift: The population under study is sufficiently large such that alleles are not likely to dramatically rise or drop in frequency by random change

     • No mutation: rate of mutation is low such that allele frequencies are no impacted

     • No selection: individuals are equally capable of passing on their genes, regardless of genotype, preserving equality between each allele frequency and its chance of being inherited.

     • No gene flow: There has been no significant migration of individuals between populations with significantly different allele frequencies

3. Understand how to use the HW law to estimate the frequency of carriers of a rare genetic disease in a population where HW assumptions are met

4. Be able to do the above calculations for autosomal recessive and non-deleterious X-linked recessive disorders

   • The major practical application of the HW principle in medical genetics is in genetic counseling for autosomal recessive conditions.

   • For a disease such as PKU, there are hundreds of different pathogenic alleles with frequencies that vary among different population groups defined by geography and/or ethnicity.

     • For many conditions, it is convenient to consider all disease-causing alleles together and treat them as a single pathogenic allele, with frequency q, even when there is significant allele heterogeneity among pathogenic alleles.

     • Similarly, the combined frequency of all benign or non pathogenic alleles p, is given by 1-q.

   • The frequency of affected homozygotes for a disease can be determined by counting the number of babies born with PKU born divided by the total number of babies born, over a given time period.

     • Now, using HWE, we can calculate the pathogenic allele frequency.

   • With X-linked recessive disorders, we can only use non-deleterious conditions because if the mutation is harmful, there would be strong selection against hemizygous males.

     • Phenotypic frequencies in males will be the same all allele frequencies since males only have 1 X chromosome

5. Understand the implications of mutation-selection balance for genetic counseling

Key terms

Tyrosinemia type 1

• Rare autosomal recessive disease

• Mutations in FAH gene encoding fumarylacetoacetate hydrolysis

• Homozygotes have problems with kidneys, liver, and nervous system

Phenylketonuria

• Autosomal recessive condition

• PAH encodes phenylalanine hydroxylase

  • Unable to metabolize phenylalanine

• Profound intellectual disease

• Same pathway as tyrosinemia type 1 just one step above

Red-green colorblindness

Hardy-Weinberg law and equilibrium

Gene flow

Founder effect

Population stratification

Assortative mating

Mutation-selection equilibrium

Genetic lethal