Genetics and Genomics Core Knowledge: Molecular, Cytogenetic, Biochemical, and Population Principles
Mechanism first
Every core-knowledge question rewards knowing the underlying mechanism. For molecular genetics, the disease mechanism of the gene shapes variant interpretation: loss-of-function alleles in haploinsufficient genes behave differently from gain-of-function or dominant-negative alleles. Know transcription, splicing, translation, DNA repair, imprinting, uniparental disomy, and trinucleotide repeat instability.
For cytogenetics, learn ISCN ordering (chromosome, arm, band, then aberration type), the balanced versus unbalanced distinction, mosaicism notation, and resolution limits: a routine karyotype does not reliably detect deletions below roughly 5 to 10 Mb, which is why chromosomal microarray is the first-tier test for developmental delay.
Population and statistical genetics covers Hardy-Weinberg equilibrium, carrier frequency estimation, penetrance versus expressivity, linkage disequilibrium, founder effects, and consanguinity. Biochemical principles include enzyme kinetics, cofactor dependence, threshold effects, and the distinction between toxic metabolite accumulation (for example, phenylalanine in phenylketonuria) and product deficiency.
Traps
Treating a population allele frequency as a disease prevalence; assuming a 25% recurrence risk when inheritance is X-linked or mitochondrial; forgetting that mitochondrial variants show heteroplasmy, threshold effects, and maternal transmission with highly variable organ involvement; and misapplying Hardy-Weinberg in consanguineous families.
Rule of thumb
For a rare autosomal recessive condition, carrier frequency approximates twice the square root of disease incidence. If incidence is 1 in 40,000, then q = 1/200 and 2pq is about 1 in 100. This lets you estimate carrier risk mentally, without a calculator, on exam day.