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Background: The enlarged and globular brain is the most distinctive anatomical feature in human evolution that set us apart from our extinct and extant modern human relatives. In a petite evolutionary time the magnitude of human brain is three fold expanded as compared to our closest living kin chimpanzee. Major episodes of human brain size expansion occurred during the upper Pliocene to early Pleistocene era and yet again in middle Pleistocene epochs. The exact genetic basis of these evolutionary changes that bifurcate the highly cognitive human brain from supposedly lesser cognitive nonhuman hominids brain still remain enigmatic. However, it is presumed that complex and larger human brain emerged by essential changes in genes and noncoding regulatory elements. One approach to comprehending the evolution of human brain is to scrutinize the evolution of genes indispensable for normal brain development. Although brain development is genetically complex process, genes associated with early brain development are the best candidate genes in order to understand the mechanism involved in the evolutionary expansion of human brain size. Primary microcephaly genes were selected as their key role in early brain development and mutations in these genes cause severe reduction in cerebral cortex size that is most notably expanded during recent human history. The brain size of microcephalic patients is similar with the size of Pan troglodyte brain and the very early hominid the gracile australopithecine Australopithecus afarensis (average brain size of Australopithecines is 450 cm3), suggesting that primary microcephaly genes likely to have been evolutionary targets in the enlargement of human brain evolution. In this study, the implications of primary microcephaly genes in the evolutionary enlargement of human brain size has been explored by executing a comprehensive evolutionary analysis on ten newly identified microcephaly genes (WDR62, STIL, CEP135, ZNF335, PHC1, CDK6, SASS6, MFSD2A, CIT, and KIF14) across 48 euthrian species. Subsequently also try to explored what are the mechanisms that associate the evolutionary expansion of human brain size with Parkinson‘s disease by studying the molecular evolution of Parkinson‘s disorder linkedalpha synuclein gene. Results: By employing codon substitutions site models based on maximum likelihood method, signatures of pervasive positive selection were identified in five MCPH genes (KIF14, ZNF335, SASS6, CIT and KIF14). For primates, positive selection was found solely in KIF14. Whereas, in nonprimate placental mammals four genes STIL, ZNF335, SASS6, and CIT have exhibit the signature of adaptive evolution. However, pervasive positive selection has acted in STIL, ZNF335 and KIF14 for placental mammals. This study also identified acceleration in the coding sequences of WDR62 and STIL for human terminal branch both by codon substitutions and frequency based methods. However, acceleration in STIL gene is not significant by codon substitutions based method. Furthermore, the signatures of divergent selection constraints between clades are significant for only two genes STIL and SASS6. In the present study, in an endeavor to elucidate whether and why Parkinson‘s disorder affects solely Homo sapiens. Evolutionary study of Parkinson‘s disease associated α synuclein gene revealed that α synuclein gene has been originated specifically at the root of jawed vertebrates and no evolutionary substitutions was accumulated in the α synuclein amino acid sequence during the last 35 million years of evolution. Furthermore, structural dynamics enlighten that during the course of vertebrate evolutionary history, region of amino terminal domain (32 to 58 amino acids) of α synuclein was continuously evolved at structural level, in spite of high sequence conservation at sequence level. Conclusion: This study concluded that evolutionary enlargement of human brain size during Pliocene-Pleistocene period might have not associated to the human MCPH coding sequences exclusively. The joint human specific changes in coding and noncoding regions of human microcephaly loci might have been conducive to the modification in the function of MCPH genes in humans that likely to be responsible for the human brain evolution during the last two million years. Current study on evolution of α synuclein gene provide that region encompassing 3258 amino acid residues of amino terminal domain is critical for normal cellular function and Parkinson‘s disease pathogenesis.
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