Phenotype-Genotype Studies in Non-Human Primate Model of Social Behavior

National Human Genome Research Institute

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Abstract

Nonhuman primates and especially rhesus macaques (Macaca mulatta) have been indispensable animal models for studies of various aspects of neurobiology, developmental psychology, and other aspects of neuroscience. While remarkable progress has been made in our understanding of the causes of autism spectrum disorders (ASD), many significant questions remain and access to a tractable and highly translational animal model would benefit efforts to investigate risk factors, developmental mechanisms, and potential therapies for ASD. To study genetic influences on key aspects of the ASD phenotype individual competence and/or motivation for specific aspects of social behavior we analyzed individual variation in social interactions among juvenile rhesus macaques. All study subjects were housed in species-typical mixed-sex matrilineal social groups, providing opportunities for normal social development among these juveniles. We quantified individual variation in social behavior using both a standard macaque ethogram and a macaque-relevant modification of the human Social Responsiveness Scale. Our analyses demonstrate that various aspects of juvenile social behavior exhibit significant genetic heritability, including similar levels to those described for ASD in humans. We also performed whole exome sequencing and analyzed variants in 143 genes previously suggested to influence risk for human ASD. We find preliminary evidence for genetic association between specific variants and both individual behaviors and multi-behavioral factor scores. To our knowledge, this is the first demonstration that spontaneous social behaviors performed by free-ranging juvenile rhesus macaques display significant genetic heritability and that some variation may be associated with genes known to influence risk of ASD in children. Based on these data, we are moving forward with genome sequencing of the same macaque genomic samples, with plans to analyze the data for copy number variants (CNVs). These data will be crucial because CNVs have been shown in humans to contribute at least 1.4 times the risk for development of ASD phenotypes when compared to single nucleotide variants (SNVs), such as those we identified through exome sequencing. The combination of SNVs, CNVs, and detailed behavioral observation in the macaque samples will generate a powerful new picture of the relationships between genomic variation and social behavior in free-ranging juvenile rhesus macaques.