Genetic Terms: Dominant Negative & Linkage Disequilibrium to Conditions for Hardy-Weinberg Equilibrium

Dominant Negative Mutation

Exerts a dominant effect. A heterozygote produces a nonfunctional altered protein that also prevents the normal gene product from functioning.

Example: A single mutated p53 tumor suppressor gene results in a protein that is able to bind DNA and block the wild type p53 from binding to the promoter.

Linkage Disequilibrium

Tendency for certain alleles to occur in close proximity on the same chromosome more or less often than expected by chance. Measured in a population, not in a family, and often varies in different populations.

Mosaicism

Presence of genetically distinct cell lines in the same individual.

Somatic mosaicism—mutation arises from mitotic errors after fertilization and propagates through multiple tissues or organs.

Germline (gonadal) mosaicism—mutation only in egg or sperm cells. If parents and relatives do not have the disease, suspect gonadal (or germline) mosaicism.

Example: McCune-Albright Syndrome

Due to Gs-protein activating mutation. Presents with unilateral café-au-lait spots A with ragged edges, polyostotic fibrous dysplasia (bone is replaced by collagen and fibroblasts), and at least one endocrinopathy (eg, precocious puberty). Lethal if mutation occurs before fertilization (affecting all cells), but survivable in patients with mosaicism.

Locus Heterogeneity

Mutations at different loci result in the same disease.

Example: Albinism, retinitis pigmentosa, familial hypercholesterolemia.

Allelic Heterogeneity

Different mutations in the same locus result in the same disease.

Example: β-thalassemia.

Heteroplasmy

Presence of both normal and mutated mtDNA, resulting in variable expression in mitochondrially inherited disease.

Example: mtDNA passed from mother to all children.

Uniparental Disomy

Offspring receives 2 copies of a chromosome from 1 parent and no copies from the other parent.

Heterodisomy (heterozygous) indicates a meiosis I error.

Isodisomy (homozygous) indicates a meiosis II error or postzygotic chromosomal duplication of one of a pair of chromosomes, and loss of the other of the original pair.

Example: Uniparental is euploid (correct number of chromosomes). Most occurrences of uniparental disomy (UPD) → normal phenotype. Consider isodisomy in an individual manifesting a recessive disorder when only one parent is a carrier. Examples: Prader-Willi and Angelman syndromes.

Hardy-Weinberg Population Genetics

If p and q represent the frequencies of the alleles A and a, respectively, in a population, then p + q = 1.

• p² = frequency of homozygosity for allele A
• q² = frequency of homozygosity for allele a
• 2pq = frequency of heterozygosity (carrier frequency, if an autosomal recessive disease)

Therefore, the sum of the frequencies of these genotypes is p² + 2pq + q² = 1.

The frequency of an X-linked recessive disease in males = q and in females = q².

Hardy-Weinberg Law Assumptions

• No mutation occurring at the locus
• Natural selection is not occurring
• Completely random mating
• No net migration
• Large population

If a population is in Hardy-Weinberg equilibrium, then the values of p and q remain constant from generation to generation.

Topics Covered:

• Genetic Terms: Dominant Negative & Linkage Disequilibrium
• Understanding Mosaicism
• McCune-Albright Syndrome as Mosaicism
• Genetic Heterogeneity and Heteroplasmy
• Understanding Uniparental Disomy
• Hardy-Weinberg Principle: Allele and Genotype Frequencies
• Conditions for Hardy-Weinberg Equilibrium