Pedigrees and inheritance beyond a simple dominant model

MCAT content library / Biology & biochemistry / Pedigrees and inheritance beyond a simple dominant model

Use transmission patterns to eliminate incompatible models, then separate inheritance probability from penetrance and expressivity.

About 16 minutes, including the worked pedigree and checks.

Begin with what the pedigree can rule out

A pedigree is evidence about how a phenotype appears across related individuals. Its strongest use is often elimination: ask whether a proposed inheritance model is compatible with every informative parent–child relationship. A small pedigree may fit more than one model, so “consistent with” is safer than “proves” unless the alternatives have actually been excluded.

Start with the relationships that carry the most information: father-to-son transmission, affected mothers with multiple children, unaffected parents with an affected child, or a phenotype confined to one sex. Then ask whether penetrance, expressivity, or an environmental condition could change phenotype without changing transmission.

Concept: transmission and expression are different questions

Penetrance is the proportion of individuals with a genotype who display the associated phenotype under the stated conditions. Expressivity describes variation in the phenotype among individuals who express it. An allele can therefore be transmitted according to ordinary Mendelian segregation even when some carriers appear unaffected or affected individuals differ in severity.

That distinction matters when calculating risk. First determine the probability that the genotype is inherited. Then, if the problem supplies penetrance, multiply by the probability that the inherited genotype produces the scored phenotype. Do not quietly treat “unaffected” as “does not carry the allele” when penetrance is incomplete.

Pattern: use sex and parent of origin carefully

For an X-linked locus, a father gives his X chromosome to daughters and his Y chromosome to sons. Therefore direct father-to-son transmission is incompatible with a strictly X-linked allele. A Y-linked allele can pass from father to son but not to daughters. These rules concern chromosome transmission; penetrance can still affect whether a carrier displays the phenotype.

Mitochondrial DNA is transmitted through the egg in standard human pedigree models. An affected mother can transmit a mitochondrial variant to children of either sex, whereas an affected father does not transmit his mitochondrial genome to offspring. Real mitochondrial phenotypes can be complicated by heteroplasmy and threshold effects, but an MCAT problem should supply whatever additional assumptions are needed before asking for a quantitative prediction.

Worked application: an autosomal model with incomplete penetrance

An original family is studied for phenotype Q. The proposed model is an autosomal dominant allele Q with 75% penetrance in heterozygotes. Assume homozygous QQ does not occur in this family and that penetrance is independent between individuals. Individual I-1 has the phenotype and is known by sequencing to be Qq; I-2 is qq. They have three children:

• II-1: genotype Qq, phenotype present.
• II-2: genotype Qq, phenotype absent.
• II-3: genotype qq, phenotype absent.

The unaffected II-2 does not contradict the model. The sequencing result shows that II-2 inherited the allele, while incomplete penetrance explains why the phenotype is absent. If II-2 later has a child with a qq partner, the chance that a child inherits Q is 1/2. Conditional on inheriting Q, the chance of showing phenotype Q is 0.75. Under the stated assumptions, the chance of an affected child is therefore 1/2 × 0.75 = 0.375, or 37.5%.

Notice what changed when penetrance was introduced: the allele-transmission probability remained 1/2. Penetrance changed the phenotype probability after inheritance. If the question instead asked for the chance of inheriting the allele, 50% would still be the answer.

Rule: phenotype does not always reveal genotype

A pedigree symbol usually reports an observed phenotype, not a complete molecular genotype. With complete penetrance and a simple model, phenotype may strongly constrain genotype. With incomplete penetrance, variable expressivity, phenocopies, age-dependent onset, or multiple alleles, that shortcut becomes less reliable. Use any supplied molecular result, age criterion, or penetrance value rather than overriding it with a visual pattern.

Similarly, a rare pedigree pattern does not automatically imply a new inheritance mechanism. Before choosing mitochondrial, X-linked, or another specialized model, test whether a simpler autosomal model plus the stated penetrance or family size can account for the observations. Small families can produce apparently striking patterns by chance.

Check your reasoning

Choose an answer before opening its feedback.

Continue learning

• Mendelian inheritance: calculate from the cross, not the label
• Meiosis and recombination: track chromosomes, DNA, and allele combinations
• Reading PCR, sequencing, and DNA blot results
• Browse Biology & Biochemistry MCAT lessons

Sources

1. AAMC. What’s on the MCAT Exam? Content Outline. Biological and Biochemical Foundations, inheritance and variation.
2. National Human Genome Research Institute. Penetrance.
3. National Human Genome Research Institute. Expressivity.
4. National Human Genome Research Institute. X-Linked.
5. National Human Genome Research Institute. Mitochondrial DNA.