Positive selection in MAOA gene is human exclusive: determination of the putative amino acid change selected in the human lineage
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Monoamine oxidase A (MAOA) is the X-linked gene responsible for deamination and subsequent degradation of several neurotransmitters and other amines. Among other activities, the gene has been shown to play a role in locomotion, circadian rhythm, and pain sensitivity and to have a critical influence on behavior and cognition. Previous studies have reported a non-neutral evolution of the gene attributable to positive selection in the human lineage. To determine whether this selection was human-exclusive or shared with other species, we performed a population genetic analysis of the pattern of nucleotide variation in non-human species, including bonobo, chimpanzee, gorilla, and orangutan. Footprints of positive selection were absent in all analyzed species, suggesting that positive selection has been recent and unique to humans. To determine which human-unique genetic changes could have been responsible for this differential evolution, the coding region of the gene was compared between human, chimpanzee, and gorilla. Only one human exclusive non-conservative change is present in the gene: Glu151Lys. This human substitution affects protein dimerization according to a three-dimensional structural model that predicts a non-negligible functional shift. This is the only candidate position at present to have been selected to fixation in humans during an episode of positive selection. Divergence analysis among species has shown that, even under positive selection in the human lineage, the MAOA gene did not experience accelerated evolution in any of the analyzed lineages, and that tools such as Ka/Ks would not have detected the selective history of the gene.
KeywordsAncestral Sequence Human Lineage Variability Level Gorilla Gorilla Hydrophilic Amino Acid
The authors thank Monica Vallés (UPF) for technical support, Coralie de Hemptinne for sequencing assistance, and Judith R. Kidd (Yale University) for her invaluable help with primate DNA samples. We are indebted to Jorune Balciuniene and Elena Vazin (University of Minnesota) for sharing sequences from MAOA exons in chimpanzees and gorillas. We are also grateful to Yoav Gilad (Yale University) and Molly Przeworski (Brown University) for useful discussion, Francesc Calafell and David Comas (UPF) for valuable comments on the manuscript, and Tomàs Marquès (UPF) for help with RRTree program. Some primate samples were kindly supplied by the Barcelona Zoo (under the agreement of the Primate DNA Bank with Pompeu Fabra University). This study was supported by the Spanish Government (grant BCM 2001-0772) and by the Departament d’Universitats, Recerca i Societat de la Informació de la Generalitat de Catalunya (both to J.B.), and BOS2003-08070 (to A.N.). A.M.A. was financially supported by a fellowship from Generalitat de Catalunya (2000FI 00686).
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