{"created":"2023-06-20T13:20:52.645266+00:00","id":940,"links":{},"metadata":{"_buckets":{"deposit":"fd0a61df-9ca1-4ee5-9639-2206a12318b3"},"_deposit":{"created_by":1,"id":"940","owners":[1],"pid":{"revision_id":0,"type":"depid","value":"940"},"status":"published"},"_oai":{"id":"oai:ir.soken.ac.jp:00000940","sets":["2:430:20"]},"author_link":["9976","9975","9977"],"item_1_creator_2":{"attribute_name":"著者名","attribute_type":"creator","attribute_value_mlt":[{"creatorNames":[{"creatorName":"角山, 和久"}],"nameIdentifiers":[{}]}]},"item_1_creator_3":{"attribute_name":"フリガナ","attribute_type":"creator","attribute_value_mlt":[{"creatorNames":[{"creatorName":"ツノヤマ, カズヒサ"}],"nameIdentifiers":[{}]}]},"item_1_date_granted_11":{"attribute_name":"学位授与年月日","attribute_value_mlt":[{"subitem_dategranted":"1999-03-24"}]},"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":"     In the protein-coding gene, nucleotide substitutions are classified into the synonymous and nonsynonymous substitutions. The synonymous substitution in a gene is defined as those not causing amino acid changes in the encoding protein, while the nonsynonymous substitution is defined as those causing amino acid changes in it. The synonymous substitution, by definition, is free from functional constraints of a protein contrary to the nonsynonymous substitution that is essentially constrained by protein function. Therefore, it is expected that for a given gene, the rate of synonymous substitution is constant over the nucleotide sites as long as mutation rate does not vary with the sites. It is also anticipated that synonymous substitutions take place more frequently than nonsynonymous substitutions. It follows that the difference between the numbers of synonymous and nonsynonymous substitutions reflects the degree of functional importance for a protein, meaning that the difference is larger as the degree is greater. I find these properties of synonymous and nonsynonymous substitutions useful for evaluating the functional importance for subunits as well as domains of a protein. Moreover, I could successfully show that the rate of synonymous substitution is variable with site not only among genes but also within a gene. I also find that for mammalian species, the intragenic variation of synonymous substitutions is mainly caused by mutation that preferentially occurs in non-randomly distributed CpG dinucleotides in a gene. <br />     In Chapter I, I outline my thesis, placing particular emphasis on the motivation and purpose of my study. In Chapter II, for nicotinic acetylcholine receptor subunit genes of different species, I examined the degree of functional importance of subunits by conducting comparative analysis of the numbers of synonymous and nonsynonymous substitutions. It is known that nicotinic acetylcholine receptor is divided into two types, the muscular and nervous. The muscular type is composed of five subunits, a1, a1, b1, g and e. There are four trans-membrane regions, M 1 - M4, in the receptor molecule. The structure of the nervous type is not well elucidated, but is known to be composed of a(2-9) and b(2-4) subunits. In particular, by computing the ratio (f) of the number of nonsynonymous substitutions to that of synonymous substitutions, I showed that the a1 subunit gene was the lowest in f value among the subunit genes in the muscle system, and so was a7 subunit gene in the nervous system. This result indicates that the two subunit genes in the two tissues have been subject to strong functional constraints in evolution. In fact, it is known that the two subunits of the receptor protein have crucial functions; a1 subunit has binding sites to the  ligand of the receptor, and a7-containing receptor regulates releasing the transmitter, acetylcholine. Moreover, the window analysis of f values shows that strong functional constraints have operated on M2 region in all the five muscle subunits. It is noted that M2 region is a part of the ion channel structure in the receptor molecule. Therefore, f value is shown to be useful for evaluating the degree of functional importance of not only a gene but also subregions within a gene.<br />     In Chapter III, I conducted a statistical test to examine whether the rate of synonymous substitution varies within a gene, by using 418 homologous gene pairs from Rattus norvegicus and Mus musculus and 84 orthologous gene pairs from the whole bacterial genomes of Mycoplasma genitalium and Mycoplasma pneumoniae. As a result, more than 90% of gene pairs for both comparisons are demonstrated to show a significant intragenic variation of synonymous substitution rate. By examining all conceivable possibilities for the cause of the intragenic variation of synonymous substitution rates, I finally found a significant correlation between synonymous substitution rates and the frequency of CpG dinucleotides in rodents. These findings suggest that intragenic variation of synonymous substitutions in mammals is caused mainly by a mutation due to methylation of CpG dinucleotides which are unevenly distributed in the genome. In Chapter IV, I described the summary and conclusion of the present study, and I also discussed the future development of this line of study. ","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405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":"生命科学研究科"}]},"item_1_select_9":{"attribute_name":"専攻","attribute_value_mlt":[{"subitem_select_item":"18 遺伝学専攻"}]},"item_1_text_10":{"attribute_name":"学位授与年度","attribute_value_mlt":[{"subitem_text_value":"1998"}]},"item_creator":{"attribute_name":"著者","attribute_type":"creator","attribute_value_mlt":[{"creatorNames":[{"creatorName":"TSUNOYAMA, Kazuhisa","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405_要旨.pdf","filesize":[{"value":"299.3 kB"}],"format":"application/pdf","licensetype":"license_11","mimetype":"application/pdf","url":{"label":"要旨・審査要旨 / Abstract, Screening Result","url":"https://ir.soken.ac.jp/record/940/files/甲405_要旨.pdf"},"version_id":"3cb07ff6-37e7-4c99-87f5-e6603279296e"},{"accessrole":"open_date","date":[{"dateType":"Available","dateValue":"2016-02-17"}],"displaytype":"simple","filename":"甲405_本文.pdf","filesize":[{"value":"8.5 MB"}],"format":"application/pdf","licensetype":"license_11","mimetype":"application/pdf","url":{"label":"本文","url":"https://ir.soken.ac.jp/record/940/files/甲405_本文.pdf"},"version_id":"14879811-c621-40c4-8477-0b076b4eb29d"}]},"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":"Intragenic Variation of SynonymousSubstitution Rates","item_titles":{"attribute_name":"タイトル","attribute_value_mlt":[{"subitem_title":"Intragenic Variation of SynonymousSubstitution Rates"},{"subitem_title":"Intragenic Variation of SynonymousSubstitution Rates","subitem_title_language":"en"}]},"item_type_id":"1","owner":"1","path":["20"],"pubdate":{"attribute_name":"公開日","attribute_value":"2010-02-22"},"publish_date":"2010-02-22","publish_status":"0","recid":"940","relation_version_is_last":true,"title":["Intragenic Variation of SynonymousSubstitution Rates"],"weko_creator_id":"1","weko_shared_id":1},"updated":"2023-06-20T14:41:55.401011+00:00"}