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内容記述 |
The aim of this thesis is to understand the human evolution, in particular mental<br />activity of humans, and I have focused on genes related to sphingolipid (SL)<br />metabolism. SL regulates neuronal developments by involving signal transduction.<br />Some genetic disorder of SL metabolism (lipid storage disease) show typical<br />symptoms of mental retardation and dysfunction of nervous system. In the<br /> evolutionary process of the acquisition of human specific mental activity, genes related<br /> to SL metabolism are likely to play important roles and to be candidate genes on which<br />positive Darwinian selection operated. <br /> To identify genes selected positively, the long range-haplotype test was applied<br />to eight genes associated with lipid storage diseases using the HapMap data. The test<br />shows that a particular haplotype of the <i>N-acylsphingosine amidohydrolase (ASAHI;</i> <br />Acid ceramidase) gene has maintained stronger and longer linkage disequilibrium (LD)<br />than haplotypes of simulated neutral genes. Positive selection has resulted in the spread<br />of a selected variant in an ancestral population so rapidly that not enough time is there<br />for recombination to dacay the LD of the variant. Thus the result suggests that positive<br />selection might have operated on the evolution of <i>ASAHI</i>. <br /> To examine the evolution of <i>ASAHI</i> in the human population, I determined<br />nucleotide sequences (～11 kb) of <i>ASAHI</i> from a world-wide sample of 60 <br />chromosomes. In the strong LD region (SL region; ～4.4 kb) of the sequenced region, I <br />found that two allelic lineages (V and M) have been maintained for 2.4 ± 0.4 million <br />years (my) in the human population. Computer simulations suggest that the long <br />persistence of the allelic lineages is likely to be attributed to population structure of<br />humans in Africa before the Pleistocene period. The genetic diversity and the time to<br />the most resent common ancestor (TMRCA) of the other loci are compatible with the<br />demographic history revealed by <i>ASAHI</i>. Therefore, it is speculated that each of the<br />allelic lineages has persisted in each subpopulations in Africa and an admixture of two<br />lineages has occurred by time of the dispersal of modern humans from Africa. <br /> In addition, signatures of positive Darwinian selection for haplotypes belonging <br /> to the V lineage have been detected from the pattern and level of polymorphism of the<br /> two lineages. The haplotypes of the V lineage are predominant (62%) but have<br />exhibited small nucleotide diversity (π = 0.05%), recent TMRCA (200～340 thousand<br />years) and strong LD in the SL region. The diversity is significantly smaller in the SL<br />region than the other regions but this reduction of diversiry is not seen in the <br />haplotypes of the M lineage. These observations are consistent with the rapid<br /> expansion of the haplotypes of the V lineage by positive selection. For the V lineage, I<br /> found that the Val residue at the 72nd amino acid residue, characteristic of the V<br /> lineage, is human specific among primates, suggesting that this Val could be a target of <br />positive selection.<br />No variation at the 659 bp region surrounding this Val residue in the<br /> V lineage is also consistent with this. Computer simulations with assuming various<br /> ancestral population- structures have confirmed that the observed small nucleotide<br /> diversity of the V lineage is not accounted for only by neutral evolution. From the<br /> above observations, it has been argued that positive selection has operated on the<br /> V lineage against to the M lineage since the "out of Africa" of modern humans. This is <br />consistent with the archeological evidence supports the emergence of behavioral<br /> modernity of humans 70 ~ 80 kya in<br />Africa. <br /> Moreover, the subject of the study has been expanded to four genes possessing<br />the domain of ceramidase activity besides the ASAHI gene. Phylogenetic analyses show<br />that the origin of three kinds of ceramidase (acid, neutral, and alkaline) is prior to the<br />split of vertebrates and invertebrates. The amino acid sequences of five groups of genes<br />have been highly conserved in each group, which is consistent with the reported<br />functional differentiation among ceramidase in the pathway of ceramide metabolism. <br />Further, I found that two <i>N-acylsphingosine amidohydrolase 2 (ASAH2 )</i> paralogs, <br /><i>ASAH2B</i> and <i>ASAH2C</i> are expressed in humans only and was born by duplication jn the<br />human lineage. Interestingly, a previous study showed significant decrease of ASAH2B<br />transcripts in the brain of Alzheimer's disease patients. This report has suggested a role<br />of ASAH2B in brain and the gene should be an attractive target of further study with<br />respect to the human evolution. <br /> In this thesis, I have revealed the demographic history of human populations, the<br />recent positive selection on <i>ASAHI</i>, and human specific genes, <i>ASAH2B</i> and <i>ASAH2C</i>.<br />It is crucial for elucidatin of the human evolution that the comprehension of <br />demographic history leading to modern humans and the human specific evolution of <br />mental activity associated genes. <br /> |
要旨・審査要旨 (276.5 kB)
