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Natural selection acts when genotypes differ in their reproductive success (fitness). Over generations it changes allele frequencies in predictable directions: eliminating deleterious variants, fixing beneficial ones, and occasionally maintaining both alleles together (balancing selection). The interplay between selection and mutation explains why many disease alleles persist in human populations.
- Fitness (w) = relative reproductive success of a genotype, normalized so the most-fit genotype has w = 1.
- Selection coefficient (s) = 1 − w. The bigger s, the faster the allele is removed.
- Fitness is context-dependent: sickle-cell trait is advantageous where malaria is endemic and neutral elsewhere.
- Purifying (negative) selection: removes deleterious alleles. The default for most disease variants.
- Positive (directional) selection: favors a new allele, driving it to higher frequency. Example: lactase persistence (LCT regulatory SNPs) in dairying populations.
- Balancing selection: maintains multiple alleles at higher frequencies than mutation-selection alone would predict. Sub-types include heterozygote advantage and frequency-dependent selection.
- Stabilizing selection: favors intermediate phenotypes; typical for polygenic traits like birth weight.
Carriers (heterozygotes) have higher fitness than either homozygote. Maintains both alleles in the population despite the cost of the homozygous disease.
- Sickle cell anemia (HbS / HbA): HbS homozygotes have sickle disease; HbS carriers are protected against severe P. falciparum malaria. Carrier frequency up to 25% in some sub-Saharan African populations.
- Thalassemias: beta-thalassemia carriers also confer malaria resistance, explaining high carrier rates along the Mediterranean and in Southeast Asia.
- G6PD deficiency: X-linked; hemizygous males and some heterozygous females show partial protection from malaria.
- Cystic fibrosis (hypothesis): CF carriers may have had historic protection from cholera or typhoid; still debated.
- Tay-Sachs (hypothesis): proposed resistance to tuberculosis in Ashkenazi communities; evidence is mixed.
- Equilibrium between new mutations entering a population and selection removing them.
- For a fully recessive disease: q² = μ / s, so q ≈ √(μ/s).
- For a dominant disease (against lethal/sublethal): p ≈ μ / s.
- Explains why disease alleles persist even under strong selection: new mutations constantly replenish the pool. About 80% of achondroplasia cases are new (paternal-origin) FGFR3 mutations, reflecting high μ under strong s.
- Disease-allele frequency: targeted-panel hit rates depend heavily on population-specific selection and drift.
- New (de novo) mutations account for a growing share of dominant developmental disorders diagnosed via trio exome/genome sequencing. Because s ≈ 1 (severe dominant disease reduces reproduction drastically), observed frequency reflects μ, not inheritance.
- Ethics of "carrier advantage" framing: describing a disease allele as "protective" in carriers can minimize the homozygote's burden; balance in counseling is important.
- w = 1 − s. Know how to convert between selection coefficient and fitness.
- Heterozygote advantage is the clean explanation for sickle cell and thalassemia frequencies. Don't over-invoke it for other conditions without evidence.
- For a lethal dominant disease, observed allele frequency ≈ mutation rate. Every generation, mutations replenish; every affected individual usually doesn't reproduce.
- For a fully recessive disease with carrier frequency 2pq, mutation-selection balance gives q = √(μ/s). Useful when you have disease incidence but no genotype data.