SSADH Variation in Primates: Intra- and Interspecific Data on a Gene with a Potential Role in Human Cognitive Functions
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In the present study we focus on the nucleotide and the inferred amino acid variation occurring in humans and other primate species for mitochondrial NAD+-dependent succinic semialdehyde dehydrogenase, a gene recently supposed to contribute to cognitive performance in humans. We determined 2527 bp of coding, intronic, and flanking sequences from chimpanzee, bonobo, gorilla, orangutan, gibbon, and macaque. We also resequenced the entire coding sequence on 39 independent chromosomes from Italian families. Four variable coding sites were genotyped in additional populations from Europe, Africa, and Asia. A test for constancy of the nonsynonymous vs. synonymous rates of nucleotide changes revealed that primates are characterized by largely variable d N /d S ratios. On a background of strong conservation, probably controlled by selective constraints, the lineage leading to humans showed a ratio increased to 0.42. Human polymorphic levels fall in the range reported for other genes, with a pattern of frequency and haplotype structure strongly suggestive of nonneutrality. The comparison with the primate sequences allowed inferring the ancestral state at all variable positions, suggesting that the c.538(C) allele and the associated functional variant is indeed a derived state that is proceeding to fixation. The unexpected pattern of human polymorphism compared to interspecific findings outlines the possibility of a recent positive selection on some variants relevant to new cognitive capabilities unique to humans.
KeywordsALDH5A1 GABA metabolism Evolutionary neutrality Positive selection Primate evolution
We gratefully acknowledge Dr. A. Di Rienzo and two anonymous reviewers for their helpful comments on the first draft of this work. We thank Dr. M. Basile for computational support. This work was supported by grants MIUR 60% to Prof. Carla Jodice, PRIN 2003 and 60% to A.N., and CEGBA (Centro di Eccellenza Geni in campo Biosanitario e Agroalimentare) and European Commission (INPRIMAT, QLRI-CT-2002-01325) to M.R.
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