Two Red-Haired Children, Two Distinct Mechanisms: Compound Heterozygosity and Epistasis in MC1R

• DOI: https://doi.org/10.22533/at.ed.01596626110514

• Palavras-chave: MC1R; Epistasis; Genetic Intelligence Project; Red phenotype; IRF4; ASIP; SLC45A2; Compound heterozygosity; NYGC imputation; Pheomelanin.

• Keywords: MC1R; Epistasis; Genetic Intelligence Project; Red phenotype; IRF4; ASIP; SLC45A2; Compound heterozygosity; NYGC imputation; Pheomelanin.

• Abstract:

  When a father and mother without red hair have two red-haired children from different relationships, the tendency is to seek an exceptional explanation. This study shows that there is no exception: there is probability, recessive inheritance, and, in one of the two cases, an epistatic mechanism that conventional genetic tests cannot reveal.
  We report here the systematic genomic investigation of nine members across three generations of a family, conducted by the first author with a focus on understanding the origin of the red-haired phenotype in two of his biological children with different mothers. The study utilized whole-genome sequencing (WGS, 30x) for the proband and high-depth genomic imputation via the NYGC 1000 Genomes panel for the other family members, with analysis of Polygenic Risk Scores using the Genetic Intelligence Project (GIP, CPAH) platform and data from the PGS Catalog.
  The proband, his sister, and his father carry the rs1805009 (D294H) allele in MC1R, a recessive variant with high penetrance for the red-haired phenotype. In the case of daughter Gabriela, a copper-redhead, the most parsimonious hypothesis is that of compound heterozygosity: the mother, with Italian ancestry on both sides of the family, was not genotyped in this study, but populations in northern Italy exhibit a frequency of loss-of-function alleles in MC1R comparable to that of Celtic-Germanic populations, making the model biologically plausible. In the case of her son Nuno, a redhead, the situation is genetically more complex and more instructive: in the imputed data evaluated, his mother Jennifer carries no MC1R variant with a documented effect, but carries a set of modifier alleles in IRF4, ASIP, and SLC45A2 that, according to the literature, reduce the capacity for eumelanin synthesis in melanocytes. It is proposed that this profile creates a genetic context favorable to the expression of pheomelanin from a single paternal allele of MC1R, without asserting definitive causality. The proband’s sister, who carries the same paternal allele, had three children in two relationships and none with red hair, which reinforces that recessive inheritance is a probability per pregnancy, not a certainty.
  The study precisely distinguishes between direct data, verified imputed data, and model-based inference. Limitations are detailed, and no conclusion goes beyond what the data allow us to state.