Genetic Probability of Red Hair in Couples with Different MC1R Genotypes: A Case Study

Case Study by: Dr. Fabiano de Abreu Agrela Rodrigues, Post-PhD in Neuroscience and Genomics Specialist

Abstract: This case study explores the genetic probability of a couple having children with red hair, considering the presence of variants in the MC1R gene and its interaction with pigmentation modifiers. The analysis is based on hypothetical genetic data, with the aim of illustrating how classical Mendelian inheritance and genetic epistasis influence phenotypes such as red hair, even under low probability conditions.

Introduction

Red hair is a rare and fascinating trait that affects approximately 1–2% of the global population, with a higher prevalence in populations of European origin, particularly in Celtic regions. The expression of this phenotype is strongly associated with variants in the MC1R (melanocortin-1 receptor) gene , which regulates melanin production. Mutations in this gene favor the production of pheomelanin , responsible for red pigment, to the detriment of eumelanin , a pigment associated with darker hair and skin.

This study addresses the probability of red-haired children in a couple with different MC1R genotypes, also analyzing the influence of modifying genes on the final result.

Methodology

Genotypes Evaluated:

• Father: Heterozygous for MC1R (one copy mutated in the rs1805009 – Asp294His variant) and carrier of several modifier variants associated with light pigmentation.
• Mother: Functional homozygous for MC1R (no mutation in the analyzed variants) and with mixed ancestry (black mother and white father of German descent).

Genetic Analysis:

1. Main MC1R variants evaluated:
   1. rs1805007 (Arg151Cys), rs1805008 (Arg160Trp), rs1805009 (Asp294His), among others.
2. Modifier genes included:
   1. HERC2 (rs12913832), SLC45A2 (rs16891982), ASIP (rs2424984), TYRP1 (rs1408799), SLC24A5 (rs1426654).
3. Analysis methods based on Mendelian inheritance and epistatic interactions between genes.

Results

1. Father’s Genotype

The father presented genotypes that contribute to the redhead phenotype:

• Heterozygous in rs1805009 (MC1R) , with a mutated copy that favors the production of pheomelanin.
• Relevant modifying genes:
  • HERC2 (rs12913832): AA , associated with light eyes and lower melanin production.
  • SLC45A2 (rs16891982): CG , contributing to lighter pigmentation tones.
  • ASIP (rs2424984): CT , reducing eumelanin production.
  • SLC24A5 (rs1426654): AA , linked to light skin and hair tones.

2. Mother’s Genotype

The mother, being functionally homozygous for MC1R, does not have mutations associated with the red-haired phenotype. However, variants in modifier genes indicate a possible interaction:

• SLC45A2 (rs16891982): CC , no significant reduction in melanin.
• HERC2 (rs12913832): AA , indicating possible melanin reduction in descendants due to European ancestry.

3. Probability of Red-Haired Children

Based on genetic data:

• The probability of classic red hair (homozygosity in MC1R) is 0% , as the mother does not have mutations in MC1R.
• However, the interaction between the modifier genes can amplify the expression of the single mutated copy of MC1R, resulting in clear reddish hues.
• Estimated probability of redhead phenotype or light reddish tones : 1-2% .

Discussion

The results demonstrate that, although the classic redhead phenotype depends on homozygosity for mutations in MC1R, modifier genes such as HERC2, SLC45A2, ASIP and TYRP1 may contribute to the partial expression of the phenotype in offspring. These genes, by reducing eumelanin production, may amplify the effect of a single mutated copy of MC1R, creating lighter or reddish tones in hair.

Additionally, the mother’s mixed ancestry (African and European) introduces unique genetic variants that may interact in unexpected ways with those of the father, resulting in rare phenotypes. This case reflects the complexity of genetic interactions in determining phenotypic traits such as hair color.

Conclusion

1. Classic red hair requires homozygosity for mutated variants of MC1R, a condition absent in this couple.
2. The interaction between modifier genes can generate light or reddish tones, even in the absence of two mutated copies of MC1R.
3. The estimated probability of light or reddish phenotypes is 1-2% , reinforcing the importance of considering genetic modifiers and epistasis in the analysis of complex phenotypes.

This study highlights how the genetics of pigmentation is influenced by multiple factors beyond the MC1R gene, emphasizing the relevance of integrated genomic analyses in cases of complex inheritance.

References

• Box, NF, Wyeth, JR, O’Gorman, LE, Martin, NG, & Sturm, RA (1997). Characterization of melanocortin-1 receptor variant alleles in twins with red hair. Human Molecular Genetics, 6 (11), 1891–1897. https://doi.org/10.1093/hmg/6.11.1891
• Flanagan, N., Healy, E., Ray, A., Philips, S., Todd, C., Jackson, I.J., … & Rees, J.L. (2000). Pleiotropic effects of the melanocortin 1 receptor (MC1R) gene on human pigmentation. Human Molecular Genetics, 9 (17), 2531–2537. https://doi.org/10.1093/hmg/9.17.2531
• Han, J., Kraft, P., Nan, H., Guo, Q., Chen, C., Qureshi, A., & Hunter, D. J. (2008). A genome-wide association study identifies novel alleles associated with hair color and skin pigmentation. PLoS Genetics, 4 (5), e1000074. https://doi.org/10.1371/journal.pgen.1000074
• Valverde, P., Healy, E., Jackson, I., Rees, J. L., & Thody, A. J. (1995). Variants of the melanocyte–stimulating hormone receptor gene are associated with red hair and fair skin in humans. Nature Genetics, 11 (3), 328–330. https://doi.org/10.1038/ng1195-328
• Sturm, R. A., & Duffy, D. L. (2012). Human pigmentation genes under environmental selection. Genome Biology, 13 (9), 248. https://doi.org/10.1186/gb-2012-13-9-248

Neurogenomic