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dc.contributor.authorShimada, Makoto K.
dc.contributor.authorSanbonmatsu, Ryoko
dc.contributor.authorYamaguchi-Kabata, Yumi
dc.contributor.authorYamasaki, Chisato
dc.contributor.authorSuzuki, Yoshiyuki
dc.contributor.authorChakraborty, Ranajit
dc.contributor.authorGojobori, Takashi
dc.contributor.authorImanishi, Tadashi
dc.date.accessioned2016-11-03T13:23:37Z
dc.date.available2016-11-03T13:23:37Z
dc.date.issued2016-06-11
dc.identifier.citationShimada MK, Sanbonmatsu R, Yamaguchi-Kabata Y, Yamasaki C, Suzuki Y, et al. (2016) Selection pressure on human STR loci and its relevance in repeat expansion disease. Mol Genet Genomics 291: 1851–1869. Available: http://dx.doi.org/10.1007/s00438-016-1219-7.
dc.identifier.issn1617-4615
dc.identifier.issn1617-4623
dc.identifier.pmid27290643
dc.identifier.doi10.1007/s00438-016-1219-7
dc.identifier.urihttp://hdl.handle.net/10754/621725
dc.description.abstractShort Tandem Repeats (STRs) comprise repeats of one to several base pairs. Because of the high mutability due to strand slippage during DNA synthesis, rapid evolutionary change in the number of repeating units directly shapes the range of repeat-number variation according to selection pressure. However, the remaining questions include: Why are STRs causing repeat expansion diseases maintained in the human population; and why are these limited to neurodegenerative diseases? By evaluating the genome-wide selection pressure on STRs using the database we constructed, we identified two different patterns of relationship in repeat-number polymorphisms between DNA and amino-acid sequences, although both patterns are evolutionary consequences of avoiding the formation of harmful long STRs. First, a mixture of degenerate codons is represented in poly-proline (poly-P) repeats. Second, long poly-glutamine (poly-Q) repeats are favored at the protein level; however, at the DNA level, STRs encoding long poly-Qs are frequently divided by synonymous SNPs. Furthermore, significant enrichments of apoptosis and neurodevelopment were biological processes found specifically in genes encoding poly-Qs with repeat polymorphism. This suggests the existence of a specific molecular function for polymorphic and/or long poly-Q stretches. Given that the poly-Qs causing expansion diseases were longer than other poly-Qs, even in healthy subjects, our results indicate that the evolutionary benefits of long and/or polymorphic poly-Q stretches outweigh the risks of long CAG repeats predisposing to pathological hyper-expansions. Molecular pathways in neurodevelopment requiring long and polymorphic poly-Q stretches may provide a clue to understanding why poly-Q expansion diseases are limited to neurodegenerative diseases. © 2016, Springer-Verlag Berlin Heidelberg.
dc.description.sponsorshipWe are grateful to Hidetoshi Inoko for support to use H-GOLD/GDBS data, Yasuyuki Fujii, Katsuhiko Murakami, Yoshiharu Sato and Jun-ichi Takeda for providing gene structure and annotation data, Ryuzo Matsumoto and Yosuke Hayakawa for useful suggestion on computer programming, and other former member of the H-Invitational 2 consortium, Genome Information Integration Project (GIIP), the Integrated Database and Systems Biology Team of BIRC, AIST for their helpful support. This research was financially supported by the Ministry of Economy, Trade and Industry of Japan (METI) and the Japan Biological Informatics Consortium (JBIC). Also, this work is partly supported by the Grants-in-Aid for Scientific Research (C) to MKS (JSPS Grant Numbers 24510271 and 21510205), and the Saito Gratitude Foundation to MKS.
dc.publisherSpringer Nature
dc.subjectDatabase for human polymorphism (VarySysDB)
dc.subjectHuman evolution
dc.subjectSingle amino-acid repeat
dc.subjectSTR polymorphism
dc.subjectTriplet-repeat expansion disease
dc.titleSelection pressure on human STR loci and its relevance in repeat expansion disease
dc.typeArticle
dc.contributor.departmentBiological and Environmental Sciences and Engineering (BESE) Division
dc.contributor.departmentBioscience Program
dc.contributor.departmentComputational Bioscience Research Center (CBRC)
dc.identifier.journalMolecular Genetics and Genomics
dc.contributor.institutionInstitute for Comprehensive Medical Science, Fujita Health University, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Aichi, Japan
dc.contributor.institutionNational Institute of Advanced Industrial Science and Technology, 2-3-26 Aomi Koto-ku, Tokyo, Japan
dc.contributor.institutionJapan Biological Informatics Consortium, 10F TIME24 Building, 2-4-32 Aomi, Koto-ku, Tokyo, Japan
dc.contributor.institutionTohoku Medical Megabank Organization, Tohoku University, 2-1 Seiryo-machi, Aoba-ku, Sendai, Japan
dc.contributor.institutionGraduate School of Natural Sciences, Nagoya City University, 1 Yamanohata, Mizuho-cho, Mizuho-ku, Nagoya, Aichi, Japan
dc.contributor.institutionHealth Science Center, University of North Texas, 3500 Camp Bowie Blvd., Fort Worth, TX, United States
dc.contributor.institutionDepartment of Molecular Life Science, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa, Japan
kaust.personGojobori, Takashi
dc.date.published-online2016-06-11
dc.date.published-print2016-10


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