{"_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": ["23"]}, "author_link": ["0", "0", "0"], "item_1_biblio_info_21": {"attribute_name": "書誌情報（ソート用）", "attribute_value_mlt": [{"bibliographicIssueDates": {"bibliographicIssueDate": "2008-03-19", "bibliographicIssueDateType": "Issued"}, "bibliographic_titles": [{}]}]}, "item_1_creator_2": {"attribute_name": "著者名", "attribute_type": "creator", "attribute_value_mlt": [{"creatorNames": [{"creatorName": "金, 慧琳"}], "nameIdentifiers": [{"nameIdentifier": "0", "nameIdentifierScheme": "WEKO"}]}]}, "item_1_creator_3": {"attribute_name": "フリガナ", "attribute_type": "creator", "attribute_value_mlt": [{"creatorNames": [{"creatorName": "キム, ヘリム"}], "nameIdentifiers": [{"nameIdentifier": "0", "nameIdentifierScheme": "WEKO"}]}]}, "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_1": {"attribute_name": "ID", "attribute_value_mlt": [{"subitem_description": "2008071", "subitem_description_type": "Other"}]}, "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\u003cbr /\u003eactivity of humans, and I have focused on genes related to sphingolipid (SL)\u003cbr /\u003emetabolism. SL regulates neuronal developments by involving signal transduction.\u003cbr /\u003eSome genetic disorder of SL metabolism (lipid storage disease) show typical\u003cbr /\u003esymptoms of mental retardation and dysfunction of nervous system. In the\u003cbr /\u003e evolutionary process of the acquisition of human specific mental activity, genes related\u003cbr /\u003e to SL metabolism are likely to play important roles and to be candidate genes on which\u003cbr /\u003epositive Darwinian selection operated. \u003cbr /\u003e　　To identify genes selected positively, the long range-haplotype test was applied\u003cbr /\u003eto eight genes associated with lipid storage diseases using the HapMap data. The test\u003cbr /\u003eshows that a particular haplotype of the \u003ci\u003eN-acylsphingosine amidohydrolase (ASAHI;\u003c/i\u003e \u003cbr /\u003eAcid ceramidase) gene has maintained stronger and longer linkage disequilibrium (LD)\u003cbr /\u003ethan haplotypes of simulated neutral genes. Positive selection has resulted in the spread\u003cbr /\u003eof a selected variant in an ancestral population so rapidly that not enough time is there\u003cbr /\u003efor recombination to dacay the LD of the variant. Thus the result suggests that positive\u003cbr /\u003eselection might have operated on the evolution of \u003ci\u003eASAHI\u003c/i\u003e. \u003cbr /\u003e　　To examine the evolution of \u003ci\u003eASAHI\u003c/i\u003e in the human population, I determined\u003cbr /\u003enucleotide sequences (～11 kb) of \u003ci\u003eASAHI\u003c/i\u003e from a world-wide sample of 60 \u003cbr /\u003echromosomes. In the strong LD region (SL region; ～4.4 kb) of the sequenced region, I \u003cbr /\u003efound that two allelic lineages (V and M) have been maintained for 2.4 ± 0.4 million \u003cbr /\u003eyears (my) in the human population. Computer simulations suggest that the long \u003cbr /\u003epersistence of the allelic lineages is likely to be attributed to population structure of\u003cbr /\u003ehumans in Africa before the Pleistocene period. The genetic diversity and the time to\u003cbr /\u003ethe most resent common ancestor (TMRCA) of the other loci are compatible with the\u003cbr /\u003edemographic history revealed by \u003ci\u003eASAHI\u003c/i\u003e. Therefore, it is speculated that each of the\u003cbr /\u003eallelic lineages has persisted in each subpopulations in Africa and an admixture of two\u003cbr /\u003elineages has occurred by time of the dispersal of modern humans from Africa. \u003cbr /\u003e　　In addition, signatures of positive Darwinian selection for haplotypes belonging \u003cbr /\u003e to the V lineage have been detected from the pattern and level of polymorphism of the\u003cbr /\u003e two lineages. The haplotypes of the V lineage are predominant (62%) but have\u003cbr /\u003eexhibited small nucleotide diversity (π = 0.05%), recent TMRCA (200～340 thousand\u003cbr /\u003eyears) and strong LD in the SL region. The diversity is significantly smaller in the SL\u003cbr /\u003eregion than the other regions but this reduction of diversiry is not seen in the \u003cbr /\u003ehaplotypes of the M lineage. These observations are consistent with the rapid\u003cbr /\u003e expansion of the haplotypes of the V lineage by positive selection. For the V lineage, I\u003cbr /\u003e found that the Val residue at the 72nd amino acid residue, characteristic of the V\u003cbr /\u003e lineage, is human specific among primates, suggesting that this Val could be a target of \u003cbr /\u003epositive selection.\u003cbr /\u003eNo variation at the 659 bp region surrounding this Val residue in the\u003cbr /\u003e V lineage is also consistent with this. Computer simulations with assuming various\u003cbr /\u003e ancestral population- structures have confirmed that the observed small nucleotide\u003cbr /\u003e diversity of the V lineage is not accounted for only by neutral evolution. From the\u003cbr /\u003e above observations, it has been argued that positive selection has operated on the\u003cbr /\u003e V lineage against to the M lineage since the \"out of Africa\" of modern humans. This is \u003cbr /\u003econsistent with the archeological evidence supports the emergence of behavioral\u003cbr /\u003e modernity of humans 70 ~ 80 kya in\u003cbr /\u003eAfrica. \u003cbr /\u003e　　Moreover, the subject of the study has been expanded to four genes possessing\u003cbr /\u003ethe domain of ceramidase activity besides the ASAHI gene. Phylogenetic analyses show\u003cbr /\u003ethat the origin of three kinds of ceramidase (acid, neutral, and alkaline) is prior to the\u003cbr /\u003esplit of vertebrates and invertebrates. The amino acid sequences of five groups of genes\u003cbr /\u003ehave been highly conserved in each group, which is consistent with the reported\u003cbr /\u003efunctional differentiation among ceramidase in the pathway of ceramide metabolism. \u003cbr /\u003eFurther, I found that two \u003ci\u003eN-acylsphingosine amidohydrolase 2 (ASAH2 )\u003c/i\u003e paralogs, \u003cbr /\u003e\u003ci\u003eASAH2B\u003c/i\u003e and \u003ci\u003eASAH2C\u003c/i\u003e are expressed in humans only and was born by duplication jn the\u003cbr /\u003ehuman lineage. Interestingly, a previous study showed significant decrease of ASAH2B\u003cbr /\u003etranscripts in the brain of Alzheimer\u0027s disease patients. This report has suggested a role\u003cbr /\u003eof ASAH2B in brain and the gene should be an attractive target of further study with\u003cbr /\u003erespect to the human evolution. \u003cbr /\u003e　　In this thesis, I have revealed the demographic history of human populations, the\u003cbr /\u003erecent positive selection on \u003ci\u003eASAHI\u003c/i\u003e, and human specific genes, \u003ci\u003eASAH2B\u003c/i\u003e and \u003ci\u003eASAH2C\u003c/i\u003e.\u003cbr /\u003eIt is crucial for elucidatin of the human evolution that the comprehension of \u003cbr /\u003edemographic history leading to modern humans and the human specific evolution of \u003cbr /\u003emental activity associated genes. \u003cbr /\u003e", "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": [{"nameIdentifier": "0", "nameIdentifierScheme": "WEKO"}]}]}, "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", "download_preview_message": "", "file_order": 0, "filename": "甲1178_要旨.pdf", "filesize": [{"value": "276.5 kB"}], "format": "application/pdf", "future_date_message": "", "is_thumbnail": false, "licensetype": "license_11", "mimetype": "application/pdf", "size": 276500.0, "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", "download_preview_message": "", "file_order": 1, "filename": "甲1178_本文.pdf", "filesize": [{"value": "15.2 MB"}], "format": "application/pdf", "future_date_message": "", "is_thumbnail": false, "licensetype": "license_11", "mimetype": "application/pdf", "size": 15200000.0, "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"], "permalink_uri": "https://ir.soken.ac.jp/records/1228", "pubdate": {"attribute_name": "公開日", "attribute_value": "2010-02-22"}, "publish_date": "2010-02-22", "publish_status": "0", "recid": "1228", "relation": {}, "relation_version_is_last": true, "title": ["Molecular evolutionary and population genetic analysis of mental activity-related genes in humans"], "weko_shared_id": -1}