{"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":[{"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_12":{"attribute_name":"要旨","attribute_value_mlt":[{"subitem_description":" The aim of this thesis is to understand the human evolution, in particular mental
activity of humans, and I have focused on genes related to sphingolipid (SL)
metabolism. SL regulates neuronal developments by involving signal transduction.
Some genetic disorder of SL metabolism (lipid storage disease) show typical
symptoms of mental retardation and dysfunction of nervous system. In the
evolutionary process of the acquisition of human specific mental activity, genes related
to SL metabolism are likely to play important roles and to be candidate genes on which
positive Darwinian selection operated.
To identify genes selected positively, the long range-haplotype test was applied
to eight genes associated with lipid storage diseases using the HapMap data. The test
shows that a particular haplotype of the N-acylsphingosine amidohydrolase (ASAHI;
Acid ceramidase) gene has maintained stronger and longer linkage disequilibrium (LD)
than haplotypes of simulated neutral genes. Positive selection has resulted in the spread
of a selected variant in an ancestral population so rapidly that not enough time is there
for recombination to dacay the LD of the variant. Thus the result suggests that positive
selection might have operated on the evolution of ASAHI.
To examine the evolution of ASAHI in the human population, I determined
nucleotide sequences (～11 kb) of ASAHI from a world-wide sample of 60
chromosomes. In the strong LD region (SL region; ～4.4 kb) of the sequenced region, I
found that two allelic lineages (V and M) have been maintained for 2.4 ± 0.4 million
years (my) in the human population. Computer simulations suggest that the long
persistence of the allelic lineages is likely to be attributed to population structure of
humans in Africa before the Pleistocene period. The genetic diversity and the time to
the most resent common ancestor (TMRCA) of the other loci are compatible with the
demographic history revealed by ASAHI. Therefore, it is speculated that each of the
allelic lineages has persisted in each subpopulations in Africa and an admixture of two
lineages has occurred by time of the dispersal of modern humans from Africa.
In addition, signatures of positive Darwinian selection for haplotypes belonging
to the V lineage have been detected from the pattern and level of polymorphism of the
two lineages. The haplotypes of the V lineage are predominant (62%) but have
exhibited small nucleotide diversity (π = 0.05%), recent TMRCA (200～340 thousand
years) and strong LD in the SL region. The diversity is significantly smaller in the SL
region than the other regions but this reduction of diversiry is not seen in the
haplotypes of the M lineage. These observations are consistent with the rapid
expansion of the haplotypes of the V lineage by positive selection. For the V lineage, I
found that the Val residue at the 72nd amino acid residue, characteristic of the V
lineage, is human specific among primates, suggesting that this Val could be a target of
positive selection.
No variation at the 659 bp region surrounding this Val residue in the
V lineage is also consistent with this. Computer simulations with assuming various
ancestral population- structures have confirmed that the observed small nucleotide
diversity of the V lineage is not accounted for only by neutral evolution. From the
above observations, it has been argued that positive selection has operated on the
V lineage against to the M lineage since the \"out of Africa\" of modern humans. This is
consistent with the archeological evidence supports the emergence of behavioral
modernity of humans 70 ~ 80 kya in
Africa.
Moreover, the subject of the study has been expanded to four genes possessing
the domain of ceramidase activity besides the ASAHI gene. Phylogenetic analyses show
that the origin of three kinds of ceramidase (acid, neutral, and alkaline) is prior to the
split of vertebrates and invertebrates. The amino acid sequences of five groups of genes
have been highly conserved in each group, which is consistent with the reported
functional differentiation among ceramidase in the pathway of ceramide metabolism.
Further, I found that two N-acylsphingosine amidohydrolase 2 (ASAH2 ) paralogs,
ASAH2B and ASAH2C are expressed in humans only and was born by duplication jn the
human lineage. Interestingly, a previous study showed significant decrease of ASAH2B
transcripts in the brain of Alzheimer's disease patients. This report has suggested a role
of ASAH2B in brain and the gene should be an attractive target of further study with
respect to the human evolution.
In this thesis, I have revealed the demographic history of human populations, the
recent positive selection on ASAHI, and human specific genes, ASAH2B and ASAH2C.
It is crucial for elucidatin of the human evolution that the comprehension of
demographic history leading to modern humans and the human specific evolution of
mental activity associated genes.
","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","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"}