Human Genetics for the Molecular Lab

Genes, loci, and alleles

A gene is a stretch of DNA read as a unit, usually encoding a protein or functional RNA ¹. Its address on a chromosome is its locus. Most loci come in two copies, one from each parent, and the versions a locus can carry are alleles. A variant is what makes one allele differ from another.

Genotype, zygosity, and allele fraction

The genotype is the pair of alleles at a locus; the phenotype is the trait or clinical state. The lab measures genotype; the clinic sees phenotype; they don’t map one to one ².

Zygosity can change a result’s meaning entirely, so reports always state it. A germline variant far from 50% or 100% suggests mosaicism, a sample mix-up, or an artifact.

Dominant and recessive

An allele is dominant if one copy produces the effect and recessive if it shows only in the homozygous state ². These describe an allele relative to a phenotype, not a property of the sequence: a sickle cell carrier (one copy) is healthy but has a measurable laboratory phenotype (sickling under extreme conditions).

Two carriers (A = reference, a = variant):

Recessive trait: 1/4 affected (aa), 1/2 carriers, 1/4 neither. Each pregnancy is independent - a 1/4 risk doesn’t mean one in four children.

Three Mendelian patterns

²

Also worth knowing: X-linked dominant (affected fathers pass to all daughters, no sons), mitochondrial (from the mother to all her children, with variable severity from heteroplasmy), and anticipation, where repeat-expansion disorders like Huntington or fragile X worsen or start earlier in successive generations as the repeat grows.

Carriers and carrier math

A carrier is heterozygous for a recessive variant and unaffected, but can pass it on; two carriers can have an affected child ². X-linked carriers are typically female. A carrier result is reported as a heterozygous, unaffected state, never as a diagnosis.

Hardy-Weinberg links genotype and allele frequencies in a large, randomly mating population: with allele frequencies p and q (p + q = 1), genotypes occur at p², 2pq, and q². For rare recessive disorders it gives a quick carrier estimate:

• Cystic fibrosis in Northern Europeans: about 1 in 2,500 births = q².
• q = √(1/2,500) = 1/50.
• Carriers = 2pq ≈ 2 × (1/50) = about 1 in 25.

Carrier screening panels use exactly this reasoning, and residual risk after a negative screen depends on how many of the population’s variants the panel covers.

Penetrance and expressivity

• Penetrance: the fraction of people with a genotype who show any phenotype. With incomplete penetrance, some carriers of a pathogenic variant never get the disease - many BRCA1 carriers never develop cancer, and HFE C282Y homozygotes often never develop iron overload ².
• Expressivity: how severely or in what form the phenotype shows. Variable expressivity gives one relative mild disease and another severe disease from the same variant ².

A genotype is a probability, not a verdict.

Frequency and pathogenicity

Allele frequency is the first interpretive filter: a variant common in healthy populations is part of normal diversity, while a rare variant that tracks with disease in families is a candidate ². Population databases like gnomAD supply these frequencies. Frequency filters, it doesn’t prove: founder variants can be common and pathogenic (HFE C282Y in Northern Europeans, BRCA1 c.68_69del in Ashkenazi Jewish populations).

SNPs and STRs

STRs underlie identity, parentage, and bone-marrow engraftment testing (see the Identity and Engraftment lessons); both marker types power linkage studies ³. Ordinary STR length variation is harmless; only expansion past a threshold in certain genes causes disease.

Germline versus somatic

Mendelian genetics is about germline variants, present in every cell and heritable ¹. Variants acquired in body cells during life are somatic, don’t follow Mendelian patterns, and drive cancer. At the bench the questions differ: an inherited-disease test asks what a person was born with (blood or saliva); a tumor test compares the tumor with the person’s own normal genome ². A tumor result can incidentally reveal a germline variant, which then needs confirming in normal tissue.

What to take from this

Alleles are versions of a gene at a locus; zygosity (homo-, hetero-, hemizygous, compound heterozygous) shows up as about 100% or 50% variant reads. Carrier × carrier gives 1/4 affected. Autosomal dominant appears in every generation, autosomal recessive skips generations through carriers, and X-linked recessive affects mostly males with no father-to-son transmission. Hardy-Weinberg turns disease incidence into carrier frequency (CF: 1/2,500 → 1/25). Penetrance and expressivity make genotype a probability. SNPs and STRs are the workhorse markers, and germline and somatic testing answer different questions.