STEPTRACKERGENETICS | PRINCIPLES | HIGH-YIELD REVIEW

Genetic Terms & Principles

The vocabulary Step 1 uses to describe how genes show up in people — each term has a classic disease attached.

FOCUS ON

Penetrance = how many carriers show the trait at all; expressivity = how severe it is in those who do. Anticipation = earlier/worse in each generation (repeat expansion). Pleiotropy = one gene, many organs. Locus heterogeneity = different genes, same disease; allelic heterogeneity = different mutations, same gene. Heteroplasmy = mixed mitochondria. Loss of heterozygosity = second hit in tumor suppressors.

TERM

MEANING

CLASSIC EXAMPLE

CLUE

Codominance

Both alleles fully expressed in the heterozygote

ABO blood groups (AB), HLA, α1-antitrypsin alleles

—

Variable expressivity

Same genotype, different severity

NF1 (café-au-lait only vs plexiform tumors)

Everyone affected, but differently

Incomplete penetrance

Not everyone with the genotype shows the phenotype

BRCA1 (not all carriers get cancer)

Skipped generation in AD pedigree

Pleiotropy

One gene affects multiple unrelated organs

PKU (skin, brain, odor), Marfan, CF

—

Anticipation

Earlier onset/greater severity in later generations

Huntington (paternal), myotonic dystrophy (maternal), fragile X (maternal)

Trinucleotide repeat expansion

Loss of heterozygosity

Inherited mutation + loss of the remaining normal allele in a cell → tumor

Retinoblastoma, Li-Fraumeni

Knudson two-hit hypothesis

Dominant negative

Mutant protein interferes with the normal one

Osteogenesis imperfecta (collagen), some p53 mutations

Worse than simple loss of one copy

Linkage disequilibrium

Alleles at nearby loci inherited together more often than chance

HLA haplotypes

Population-level, not family-level

Mosaicism

Two cell lines in one person — somatic (body) or gonadal (germ line)

McCune-Albright (GNAS), mosaic Turner · gonadal: healthy parents with two affected children (AD)

McCune-Albright lethal if not mosaic

Locus heterogeneity

Mutations in different genes give the same phenotype

Albinism, retinitis pigmentosa, familial hypercholesterolemia

—

Allelic heterogeneity

Different mutations in the same gene give a similar phenotype

β-thalassemia, CF

Hundreds of CFTR alleles

Heteroplasmy

Normal and mutant mitochondrial DNA in one cell; proportion varies by tissue

MELAS, MERRF, LHON

Explains variable severity in mitochondrial disease

Uniparental disomy

Both copies of a chromosome from one parent (heterodisomy = meiosis I error; isodisomy = meiosis II/duplication)

Prader-Willi, Angelman; isodisomy can unmask an AR disease

Normal chromosome number

Mechanism — Knudson two-hit

Hereditary1st hit inherited in every cell

→

One somatic hitEarly, bilateral, multifocal

SporadicBoth hits must occur in one cell

→

Two somatic hitsLater, unilateral

Tumor suppressors are recessive at the cell level but inherited as autosomal dominant cancer predisposition.

Penetrance vs expressivity

TERM

QUESTION IT ANSWERS

EXAMPLE

Penetrance

Does the carrier show it at all?

BRCA1 carrier never develops cancer

Expressivity

How much does it show?

NF1: mild in parent, severe in child

Anticipation

Does it worsen each generation?

Huntington earlier in son

How it's tested

COMMON CONFUSIONIncomplete penetrance lets a carrier look normal; variable expressivity means everyone with the gene has some sign, just at different strengths.

THE TRAPTwo affected children from unaffected parents with an AD disease points to gonadal mosaicism, not a new AR pattern.

YOUR APPROACHRead the scenario for "same gene, different severity", "skipped generation", "worse each generation", "many organs" → match the term.

If you see… think…

AB blood type expressing both antigens → codominance

Same NF1 mutation, mild mother, severe son → variable expressivity

AD disease skipping a generation → incomplete penetrance

Huntington earlier in each generation → anticipation

Café-au-lait spots, fibrous dysplasia, precocious puberty → McCune-Albright (somatic mosaicism)

Bilateral retinoblastoma in infancy → inherited first hit + LOH

Mutant collagen chains poison normal ones → dominant negative

Mitochondrial disease mild in mother, severe in child → heteroplasmy

AR disease in a child with only one carrier parent → uniparental isodisomy

Many genes can each cause retinitis pigmentosa → locus heterogeneity