The rhesus macaque (Macaca mulatta) is an abundant primate species that diverged from the ancestors of Homo sapiens about 25 million years ago. Because they are genetically and physiologically similar to humans, rhesus monkeys are the most widely used nonhuman primate in basic and applied biomedical research. We determined the genome sequence of an Indian-origin Macaca mulatta female and compared the data with chimpanzees and humans to reveal the structure of ancestral primate genomes and to identify evidence for positive selection and lineagespecific expansions and contractions of gene families. A comparison of sequences from individual animals was used to investigate their underlying genetic diversity. The complete description of the macaque genome blueprint enhances the utility of this animal model for biomedical research and improves our understanding of the basic biology of the species.

Human evolution is characterized by a dramatic increase in brain size and complexity. To probe its genetic basis, we examined the evolution of genes involved in diverse aspects of nervous system biology. We found that these genes display significantly higher rates of protein evolution in primates than in rodents. Importantly, this trend is most pronounced for the subset of genes implicated in nervous system development. Moreover, within primates, the acceleration of protein evolution is most prominent in the lineage leading from ancestral primates to humans. Thus, the remarkable phenotypic evolution of the human nervous system has a salient molecular correlate, i.e., accelerated evolution of the underlying genes, particularly those linked to nervous system development. In addition to uncovering broad evolutionary trends, our study also identified many candidate genes--most of which are implicated in regulating brain size and behavior--that might have played important roles in the evolution of the human brain.

The gene Microcephalin (MCPH1) regulates brain size and has evolved under strong positive selection in the human evolutionary lineage. We show that one genetic variant of Microcephalin in modern humans, which arose approximately 37,000 years ago, increased in frequency too rapidly to be compatible with neutral drift. This indicates that it has spread under strong positive selection, although the exact nature of the selection is unknown. The finding that an important brain gene has continued to evolve adaptively in anatomically modern humans suggests the ongoing evolutionary plasticity of the human brain. It also makes Microcephalin an attractive candidate locus for studying the genetics of human variation in brain-related phenotypes.

Summary The gut microbiome is widely studied by fecal sampling, but the extent to which stool reflects the commensal composition at intestinal sites is poorly understood. We investigated this relationship in rhesus macaques by 16S sequencing feces and paired lumenal and mucosal samples from 10 sites distal to the jejunum. Stool composition correlated highly with the colonic lumen and mucosa, and moderately with the distal small intestine. The mucosal microbiota varied most based on location and was enriched in oxygen-tolerant taxa (e.g. Helicobacter, Treponema), while the lumenal microbiota showed inter-individual variation and obligate anaerobe enrichment (e.g. Firmicutes). This mucosal and lumenal community variability corresponded to functional differences, such as nutrient availability. Additionally, Helicobacter, Faecalibacterium, and Lactobacillus levels in stool were highly predictive of their abundance at most other gut sites. These results quantify the composition and biogeographic relationships between gut microbial communities in macaques and support fecal sampling for translational studies.

The gene ASPM (abnormal spindle-like microcephaly associated) is a specific regulator of brain size, and its evolution in the lineage leading to Homo sapiens was driven by strong positive selection. Here, we show that one genetic variant of ASPM in humans arose merely about 5800 years ago and has since swept to high frequency under strong positive selection. These findings, especially the remarkably young age of the positively selected variant, suggest that the human brain is still undergoing rapid adaptive evolution.

Trace amine-associated receptor 1 (TAAR1) is a G proteincoupled receptor that directly responds to endogenous monoamines as well as amphetamine-related psychostimulants, including methamphetamine. In the present study, we demonstrate TAAR1 mRNA and protein expression in rhesus monkey brain regions associated with monoaminergic systems, variable cellular distribution of TAAR1 in rhesus monkey brain, and TAAR1 coexpression with the dopamine transporter (DAT) in a subset of dopamine neurons in both rhesus monkey and mouse substantia nigra. On this basis, we evaluated rhesus monkey TAAR1 activation by different compounds and its functional relation with monoamine transporters and the dopamine D2 receptor (D2) short isoform (D2s) autoreceptor in vitro using a cAMP response element-luciferase assay. TAAR1 activation by monoamines and amphetamine-related compounds was greatly enhanced by coexpression of dopamine, norepinephrine, or serotonin transporters, and the activation enhancement was blocked by monoamine transporter inhibitors. This enhancement did not occur in control experiments in which the dopamine D1 receptor (D1) was substituted for TAAR1. Furthermore, activation of TAAR1 by dopamine was completely inhibited by D2s when coexpressed with TAAR1, and this inhibition was blocked by the D2 antagonist raclopride. Last, dopamine activation of TAAR1 could induce c-FOS-luciferase expression but only in the presence of DAT, whereas dopamine activation of D1 resulted in equivalent c-FOS expression in the presence or absence of DAT. Together, these data reveal a broad agonist spectrum for TAAR1, a functional relation of TAAR1 with monoamine transporters and D2s, and a mechanism by which D2 receptor drugs can influence brain monoaminergic function and have efficacy through affecting TAAR1 signaling.

Positive selection has undoubtedly played a critical role in the evolution of Homo sapiens. Of the many phenotypic traits that define our species--notably the enormous brain, advanced cognitive abilities, complex vocal organs, bipedalism and opposable thumbs--most (if not all) are likely the product of strong positive selection. Many other aspects of human biology not necessarily related to the 'branding' of our species, such as host-pathogen interactions, reproduction, dietary adaptation and physical appearance, have also been the substrate of varying levels of positive selection. Comparative genetics/genomics studies in recent years have uncovered a growing list of genes that might have experienced positive selection during the evolution of human and/or primates. These genes offer valuable inroads into understanding the biological processes specific to humans, and the evolutionary forces that gave rise to them. Here, we present a comprehensive review of these genes, and their implications for human evolution.

Rhesus macaques (Macaca mulatta) are the most widely used nonhuman primate in biomedical research, have the largest natural geographic distribution of any nonhuman primate, and have been the focus of much evolutionary and behavioral investigation. Consequently, rhesus macaques are one of the most thoroughly studied nonhuman primate species. However, little is known about genome-wide genetic variation in this species. A detailed understanding of extant genomic variation among rhesus macaques has implications for the use of this species as a model for studies of human health and disease, as well as for evolutionary population genomics. Whole-genome sequencing analysis of 133 rhesus macaques revealed more than 43.7 million single-nucleotide variants, including thousands predicted to alter protein sequences, transcript splicing, and transcription factor binding sites. Rhesus macaques exhibit 2.5-fold higher overall nucleotide diversity and slightly elevated putative functional variation compared with humans. This functional variation in macaques provides opportunities for analyses of coding and noncoding variation, and its cellular consequences. Despite modestly higher levels of nonsynonymous variation in the macaques, the estimated distribution of fitness effects and the ratio of nonsynonymous to synonymous variants suggest that purifying selection has had stronger effects in rhesus macaques than in humans. Demographic reconstructions indicate this species has experienced a consistently large but fluctuating population size. Overall, the results presented here provide new insights into the population genomics of nonhuman primates and expand genomic information directly relevant to primate models of human disease.