A geneticist is studying the inheritance of a trait in humans. She observes that two siblings who are both carriers of a specific disease have offspring with a 50% chance of developing the disease. Which of the following is the most likely genotype of the affected offspring?

Core Concept

PILLAR 1 — MOLECULAR/CONCEPTUAL MECHANISM

Step-by-Step Analysis

The transmission of heritable traits from parents to offspring depends on the behavior of chromosomes during meiosis, specifically the segregation of homologous chromosomes during anaphase I. Each somatic human cell contains 23 pairs of homologous chromosomes — one member of each pair inherited from the mother and one from the father. At a given gene locus, these homologues may carry identical alleles (homozygous) or different alleles (heterozygous). Molecularly, an allele represents a specific nucleotide sequence in the DNA that encodes a variant of a protein. For example, in cystic fibrosis, the CFTR gene on chromosome 7 can carry the functional wild-type sequence or the ΔF508 deletion that removes a phenylalanine residue at position 508, resulting in a misfolded chloride channel protein. A carrier possesses one functional allele and one disease-producing allele (heterozygous, denoted Aa), and for autosomal recessive conditions, the functional protein produced by the single wild-type allele is sufficient to maintain normal physiology. During meiosis I, homologous chromosomes — each consisting of two sister chromatids joined at the centromere — pair up along the metaphase plate. The spindle apparatus, composed of microtubules nucleated at the centrosomes, attaches to kinetochore protein complexes at the centromere. The subsequent separation of homologues during anaphase I ensures that each gamete receives only one allele at each locus. When both parents are heterozygous carriers (Aa × Aa), the four possible allele combinations in offspring — AA, Aa, aA, and aa — arise with equal 25% probability, because the segregation of maternal versus paternal homologues to each daughter cell is a random, independent event.

Why Other Options Are Wrong

PILLAR 2 — STEP-BY-STEP LOGIC

The stimulus states that two siblings are both carriers of a disease and that their offspring have a 50% chance of developing it. The phrase 'two siblings who are both carriers' identifies the parental generation: each parent is heterozygous (Aa) at the disease locus. A 50% chance of affected offspring is the signature of a cross between a heterozygous parent and a homozygous recessive parent (Aa × aa), which produces 50% Aa offspring and 50% aa offspring. Therefore, the disease must be inherited in an autosomal dominant manner: the presence of a single disease allele (a in this notation, or alternatively the dominant allele if we define 'A' as the disease allele) is sufficient to cause the phenotype. Under an autosomal dominant model, if we designate the dominant disease-causing allele as A and the normal allele as a, then the cross Aa × aa yields 50% Aa (affected) and 50% aa (unaffected). The affected offspring are invariably heterozygous — they carry one copy of the mutant allele encoding an aberrant protein (for instance, the huntingtin protein with an expanded polyglutamine tract in Huntington's disease, where the altered protein acquires a toxic gain-of-function) and one normal allele. The homozygous dominant genotype AA is extraordinarily rare in autosomal dominant disorders because it would require both parents to carry and transmit the disease allele, and in many cases homozygosity for the dominant allele is embryonic lethal. Thus, the 50% probability combined with a dominant inheritance mechanism pinpoints Aa as the genotype of affected offspring, corresponding to option B.

PILLAR 3 — DISTRACTOR ANALYSIS

Option A (AA) traps students who assume that affected individuals in any disease must be homozygous. This reflects a failure to distinguish between dominant and recessive inheritance patterns. In autosomal dominant disorders, the affected genotype is heterozygous (Aa), because one mutant allele is sufficient to produce the disease phenotype through mechanisms such as haploinsufficiency (where 50% of normal protein output is inadequate) or a dominant-negative effect (where the mutant polypeptide disrupts the function of the wild-type polypeptide, as seen in certain collagen disorders such as osteogenesis imperfecta). The homozygous dominant genotype AA would require both parents to contribute the disease allele, and if both parents are heterozygous carriers, only 25% of offspring would be AA — contradicting the observed 50% probability.

Option C (aa) appeals to students who correctly recognize that autosomal recessive diseases produce affected homozygous recessive individuals but then misapply this framework to a scenario that yields a 50% probability. If the disease were recessive and both parents were carriers (Aa × Aa), only 25% of offspring would be aa and thus affected — not 50%. The 50% figure is incompatible with a classic autosomal recessive carrier cross, so the aa genotype cannot explain the observed inheritance pattern. This distractor exploits the common habit of automatically equating 'affected' with 'homozygous recessive' without checking whether the probabilities match.

Option D (It cannot be determined) tempts students who are unsettled by the unusual wording of the question or who conflate different inheritance models. However, the 50% probability is highly diagnostic. It eliminates autosomal recessive inheritance (which gives 25% affected in a carrier × carrier cross) and points directly to autosomal dominant inheritance from a heterozygous parent. The genotype of affected offspring in an autosomal dominant condition with a 50% transmission rate is unambiguously Aa. Selecting this option reflects a reluctance to commit to a single inheritance model and a failure to recognize that the mathematical probability constrains the genetic explanation.