A phylogenetic protein-coding genome-phenome map of complex traits across 224 primate species

Leveraging 60 million years of primate evolutionary diversity, we conducted a large-scale cross-species genome-phenome analysis of protein-coding genes across 224 primate species and 263 phenotypic traits spanning five domains: behavior, ecology, life history, morphology, and physiology. Using phylogenetic comparative methods, we generated the Primate Protein-coding Genome-Phenome Map (P3GMap), available in the Primate Genome-phenome Archive (PGA https://pgarchive.github.io ), identifying over 29,000 convergent amino acid substitutions (CAASs) and 3,900 gene-trait associations. As case studies, we applied targeted analyses to insectivorous diet, white blood cell count, and maximum lifespan, uncovering lineage-specific adaptations and signatures of directional selection. We show that traits undergoing greater phylogenetic divergence were linked to more extensive genetic change, and that most CAASs were fixed in humans, suggesting a decoupling of macro- and microevolutionary processes. Notable specific findings include associations between mitochondrial metabolism genes and body mass, immune-related loci and lactation, and olfactory and xenobiotic-processing genes with white blood cell counts. Together, our results establish a scalable framework to explore the molecular basis of complex traits across evolutionary time and demonstrate the value of integrating intra- and interspecies data to understand the genetic foundations of human biology.

One-Sentence Summary: We conducted a comprehensive cross-species genome-phenome analysis of protein-coding genes across 224 primate species, uncovering thousands of candidate causal amino-acid changes linked with 263 phenotypes and demonstrating the value of integrating evolutionary perspectives to understand the genetic architecture of complex human traits.