Exploring gene-culture coevolution in humans by inferring neuroendophenotypes: A case study of the oxytocin receptor gene and cultural tightness.

The gene-culture coevolution (GCC) framework has gained increasing prominence in the social and biological sciences. While most studies on human GCC concern the evolution of low-level physiological traits, attempts have also been made to apply GCC to complex human traits, including social behavior and cognition. One major methodological challenge in this endeavor is to reconstruct a specific biological pathway between the implicated genes and their distal phenotypes. Here, we introduce a novel approach that combines data on population genetics and expression quantitative trait loci to infer the specific intermediate phenotypes of genes in the brain. We suggest that such "neuroendophenotypes" will provide more detailed mechanistic insights into the GCC process. We present a case study where we explored a GCC dynamics between the oxytocin receptor gene (OXTR) and cultural tightness-looseness. By combining data from the 1000 Genomes project and the Gene-Tissue-Expression project (GTEx), we estimated and compared OXTR expression in 10 brain regions across five human superpopulations. We found that OXTR expression in the anterior cingulate cortex (ACC) was highly variable across populations, and this variation correlated with cultural tightness and socio-ecological threats worldwide. The mediation models also suggested possible GCC dynamics where the increased OXTR expression in the ACC mediates or emerges from the tight culture and higher socio-ecological threats. Formal selection scans further confirmed that OXTR alleles linked to enhanced receptor expression in the ACC underwent positive selection in East Asian countries with tighter social norms. We discuss the implications of our method in human GCC research.