Positive Selection in Gene Regulatory Factors Suggests Adaptive Pleiotropic Changes During Human Evolution.

Area of Science:

• Genomics
• Evolutionary Biology
• Molecular Biology

Background:

• Gene regulatory factors (GRFs) are crucial for gene expression and have been implicated in speciation and adaptation.
• Zinc finger (ZNF) proteins, particularly those with a Krüppel-associated box (KRAB) domain, are the most abundant transcription factors in primate genomes.
• Understanding GRF evolution is key to deciphering primate evolutionary history.

Purpose of the Study:

• To investigate the evolutionary contributions of GRFs in primates.
• To identify GRFs that have undergone positive selection during human and great ape evolution.
• To explore the functional implications of selected GRFs in adaptation and speciation.

Main Methods:

• Comparative genomic analysis of GRF genes across 27 primate genomes.
• Application of two independent statistical tests (branch-site model in PAML and aBSREL in HyPhy) to detect positive selection on the human and great ape lineages.
• Rigorous filtering to minimize false positives, including ortholog exclusion, alignment correction, and cross-validation of detected sites.
• Analysis of human and non-human great ape population data and archaic human genomes to verify and date selected sites.

Main Results:

• Identified five GRFs with high confidence for positive selection on the human lineage and one on the great ape lineage.
• Four of the positively selected GRFs are KRAB-ZNF proteins, known to influence gene co-expression and interact with transposable elements.
• Positively selected GRFs are located on different chromosomes and exhibit diverse functions, suggesting independent contributions to human evolution.
• Multiple sites within each selected GRF showed evidence of positive selection, indicating pleiotropic effects.

Conclusions:

• Specific GRFs, particularly KRAB-ZNFs, have been under positive selection, contributing significantly to human evolution.
• These selected GRFs likely played independent roles in phenotypic adaptations and potentially speciation.
• The findings highlight the importance of GRFs in shaping primate evolutionary trajectories and human-specific traits.