{"created":"2023-06-20T13:21:07.637078+00:00","id":1228,"links":{},"metadata":{"_buckets":{"deposit":"2d54acb8-c2b8-4a4f-9878-e2975be6936c"},"_deposit":{"created_by":1,"id":"1228","owners":[1],"pid":{"revision_id":0,"type":"depid","value":"1228"},"status":"published"},"_oai":{"id":"oai:ir.soken.ac.jp:00001228","sets":["2:431:23"]},"author_link":["0","0","0"],"item_1_creator_2":{"attribute_name":"著者名","attribute_type":"creator","attribute_value_mlt":[{"creatorNames":[{"creatorName":"金, 慧琳"}],"nameIdentifiers":[{}]}]},"item_1_creator_3":{"attribute_name":"フリガナ","attribute_type":"creator","attribute_value_mlt":[{"creatorNames":[{"creatorName":"キム, ヘリム"}],"nameIdentifiers":[{}]}]},"item_1_date_granted_11":{"attribute_name":"学位授与年月日","attribute_value_mlt":[{"subitem_dategranted":"2008-03-19"}]},"item_1_degree_grantor_5":{"attribute_name":"学位授与機関","attribute_value_mlt":[{"subitem_degreegrantor":[{"subitem_degreegrantor_name":"総合研究大学院大学"}]}]},"item_1_degree_name_6":{"attribute_name":"学位名","attribute_value_mlt":[{"subitem_degreename":"博士（理学）"}]},"item_1_description_12":{"attribute_name":"要旨","attribute_value_mlt":[{"subitem_description":"　　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 />","subitem_description_type":"Other"}]},"item_1_description_18":{"attribute_name":"フォーマット","attribute_value_mlt":[{"subitem_description":"application/pdf","subitem_description_type":"Other"}]},"item_1_description_7":{"attribute_name":"学位記番号","attribute_value_mlt":[{"subitem_description":"総研大甲第1178号","subitem_description_type":"Other"}]},"item_1_select_14":{"attribute_name":"所蔵","attribute_value_mlt":[{"subitem_select_item":"有"}]},"item_1_select_8":{"attribute_name":"研究科","attribute_value_mlt":[{"subitem_select_item":"先導科学研究科"}]},"item_1_select_9":{"attribute_name":"専攻","attribute_value_mlt":[{"subitem_select_item":"21 生命体科学専攻"}]},"item_1_text_10":{"attribute_name":"学位授与年度","attribute_value_mlt":[{"subitem_text_value":"2007"}]},"item_creator":{"attribute_name":"著者","attribute_type":"creator","attribute_value_mlt":[{"creatorNames":[{"creatorName":"KIM, Hielim","creatorNameLang":"en"}],"nameIdentifiers":[{}]}]},"item_files":{"attribute_name":"ファイル情報","attribute_type":"file","attribute_value_mlt":[{"accessrole":"open_date","date":[{"dateType":"Available","dateValue":"2016-02-17"}],"displaytype":"simple","filename":"甲1178_要旨.pdf","filesize":[{"value":"276.5 kB"}],"format":"application/pdf","licensetype":"license_11","mimetype":"application/pdf","url":{"label":"要旨・審査要旨","url":"https://ir.soken.ac.jp/record/1228/files/甲1178_要旨.pdf"},"version_id":"2a877438-a1d2-46b9-b4ef-519231a807d8"},{"accessrole":"open_date","date":[{"dateType":"Available","dateValue":"2016-02-17"}],"displaytype":"simple","filename":"甲1178_本文.pdf","filesize":[{"value":"15.2 MB"}],"format":"application/pdf","licensetype":"license_11","mimetype":"application/pdf","url":{"label":"本文","url":"https://ir.soken.ac.jp/record/1228/files/甲1178_本文.pdf"},"version_id":"7fa9d810-e319-4e0c-accb-ae64c4393f6e"}]},"item_language":{"attribute_name":"言語","attribute_value_mlt":[{"subitem_language":"eng"}]},"item_resource_type":{"attribute_name":"資源タイプ","attribute_value_mlt":[{"resourcetype":"thesis","resourceuri":"http://purl.org/coar/resource_type/c_46ec"}]},"item_title":"Molecular evolutionary and population genetic analysis of mental activity-related genes in humans","item_titles":{"attribute_name":"タイトル","attribute_value_mlt":[{"subitem_title":"Molecular evolutionary and population genetic analysis of mental activity-related genes in humans"},{"subitem_title":"Molecular evolutionary and population genetic analysis of mental activity-related genes in humans","subitem_title_language":"en"}]},"item_type_id":"1","owner":"1","path":["23"],"pubdate":{"attribute_name":"公開日","attribute_value":"2010-02-22"},"publish_date":"2010-02-22","publish_status":"0","recid":"1228","relation_version_is_last":true,"title":["Molecular evolutionary and population genetic analysis of mental activity-related genes in humans"],"weko_creator_id":"1","weko_shared_id":-1},"updated":"2023-06-20T16:07:17.772548+00:00"}