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Genetic variation in the human serotonin system has long-been studied because of its functional consequences and links to various behavior-related disorders and it being routinely targeted in research and development for drug therapy. However, aside from clinical studies, little is known about this genetic diversity and how it differs within and between human populations with respect to haplotype structure, which can greatly impact phenotype association studies. In addition, no evolutionary approach among humans and other primates has examined how long- and short-term selective pressures explain existing serotonin variation. Here, we examine DNA sequence variation in natural population samples of 192 human and 40 chimpanzee chromosome sequences for the most commonly implicated approximately 38-kb serotonin transporter (SLC6A4) and approximately 63-kb serotonin 2A receptor (HTR2A) genes. Our comparative population genetic analyses find significant linkage disequilibrium associated with functionally relevant variants in humans, as well as geographic variation for these haplotypes, at both loci. In addition, although amino acid divergence is consistent with purifying selection, promoter and untranslated regions exhibit significantly high divergence in both species lineages. These evolutionary analyses imply that the serotonin system may have accumulated significant regulatory variation over both recent and ancient periods of time in both humans and chimpanzees. We discuss the implications of this variation for disease association studies and for the evolution of behavior-related phenotypes during the divergence of humans and our closest primate relatives.

molecular biology and evolution

Haplotype Structure and Divergence at Human and Chimpanzee Serotonin Transporter and Receptor Genes: Implications for Behavioral Disorder Association Analyses