Selection pressure on human STR loci and its relevance in repeat expansion disease

Handle URI:
http://hdl.handle.net/10754/621725
Title:
Selection pressure on human STR loci and its relevance in repeat expansion disease
Authors:
Shimada, Makoto K.; Sanbonmatsu, Ryoko; Yamaguchi-Kabata, Yumi; Yamasaki, Chisato; Suzuki, Yoshiyuki; Chakraborty, Ranajit; Gojobori, Takashi ( 0000-0001-7850-1743 ) ; Imanishi, Tadashi
Abstract:
Short 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.
KAUST Department:
Computational Bioscience Research Center (CBRC)
Citation:
Shimada 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.
Publisher:
Springer Nature
Journal:
Molecular Genetics and Genomics
Issue Date:
11-Jun-2016
DOI:
10.1007/s00438-016-1219-7
Type:
Article
ISSN:
1617-4615; 1617-4623
Sponsors:
We 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.
Appears in Collections:
Articles; Computational Bioscience Research Center (CBRC)

Full metadata record

DC FieldValue Language
dc.contributor.authorShimada, Makoto K.en
dc.contributor.authorSanbonmatsu, Ryokoen
dc.contributor.authorYamaguchi-Kabata, Yumien
dc.contributor.authorYamasaki, Chisatoen
dc.contributor.authorSuzuki, Yoshiyukien
dc.contributor.authorChakraborty, Ranajiten
dc.contributor.authorGojobori, Takashien
dc.contributor.authorImanishi, Tadashien
dc.date.accessioned2016-11-03T13:23:37Z-
dc.date.available2016-11-03T13:23:37Z-
dc.date.issued2016-06-11en
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.en
dc.identifier.issn1617-4615en
dc.identifier.issn1617-4623en
dc.identifier.doi10.1007/s00438-016-1219-7en
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.en
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.en
dc.publisherSpringer Natureen
dc.subjectDatabase for human polymorphism (VarySysDB)en
dc.subjectHuman evolutionen
dc.subjectSingle amino-acid repeaten
dc.subjectSTR polymorphismen
dc.subjectTriplet-repeat expansion diseaseen
dc.titleSelection pressure on human STR loci and its relevance in repeat expansion diseaseen
dc.typeArticleen
dc.contributor.departmentComputational Bioscience Research Center (CBRC)en
dc.identifier.journalMolecular Genetics and Genomicsen
dc.contributor.institutionInstitute for Comprehensive Medical Science, Fujita Health University, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Aichi, Japanen
dc.contributor.institutionNational Institute of Advanced Industrial Science and Technology, 2-3-26 Aomi Koto-ku, Tokyo, Japanen
dc.contributor.institutionJapan Biological Informatics Consortium, 10F TIME24 Building, 2-4-32 Aomi, Koto-ku, Tokyo, Japanen
dc.contributor.institutionTohoku Medical Megabank Organization, Tohoku University, 2-1 Seiryo-machi, Aoba-ku, Sendai, Japanen
dc.contributor.institutionGraduate School of Natural Sciences, Nagoya City University, 1 Yamanohata, Mizuho-cho, Mizuho-ku, Nagoya, Aichi, Japanen
dc.contributor.institutionHealth Science Center, University of North Texas, 3500 Camp Bowie Blvd., Fort Worth, TX, United Statesen
dc.contributor.institutionDepartment of Molecular Life Science, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa, Japanen
kaust.authorGojobori, Takashien
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