Positive Selection on MAMLD1 Gene Human Lineage Suggests Pleiotropic Adaptation During Evolution

Abstract

Gene regulatory factors (GRFs) are essential regulators of human phenotypic diversity. Among these, MAMLD1 acts as a transcriptional co-activator critical for male genital development. Mutations in MAMLD1 are clinically associated with X-linked hypospadias type 2, a condition that alters the placement of the male urethral opening and potentially impacts reproductive fitness. In evolutionary biology, natural selection is often detected by comparing the rates of non-synonymous (dN) and synonymous (dS) substitutions (ω = dN/dS). Positive selection (ω > 1) represents the rapid fixation of beneficial mutations that enhance an organism’s fitness, distinguishing it from purifying selection (ω < 1), which removes deleterious mutations, and neutral evolution (ω = 1), which involves random genetic drift. Building upon broader genomic surveys, this study provides a high-resolution analysis of MAMLD1 using the PAML v4.9 suite across 20 primate species. By employing site models to assess selection across the primate phylogeny, we identified significant signals of positive selection. Findings suggest that MAMLD1 has undergone adaptive evolution, likely driven by sexual selection and its role in reproductive isolation. This research underscores the gene's multifaceted role in shaping human-specific developmental phenotypes and evolutionary strategies.