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

Makoto K. Shimada, Ryoko Sanbonmatsu, Yumi Yamaguchi-Kabata, Chisato Yamasaki, Yoshiyuki Suzuki, Ranajit Chakraborty, Takashi Gojobori, Tadashi Imanishi

Research output: Contribution to journalArticle

6 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1851-1869
Number of pages19
JournalMolecular Genetics and Genomics
Volume291
Issue number5
DOIs
Publication statusPublished - 01-10-2016

Fingerprint

Microsatellite Repeats
Pressure
Neurodegenerative Diseases
DNA
Biological Phenomena
Proline
Codon
Base Pairing
Single Nucleotide Polymorphism
Amino Acid Sequence
Healthy Volunteers
Genome
Databases
Apoptosis
Population
Genes
Proteins

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics

Cite this

Shimada, M. K., Sanbonmatsu, R., Yamaguchi-Kabata, Y., Yamasaki, C., Suzuki, Y., Chakraborty, R., ... Imanishi, T. (2016). Selection pressure on human STR loci and its relevance in repeat expansion disease. Molecular Genetics and Genomics, 291(5), 1851-1869. https://doi.org/10.1007/s00438-016-1219-7
Shimada, Makoto K. ; Sanbonmatsu, Ryoko ; Yamaguchi-Kabata, Yumi ; Yamasaki, Chisato ; Suzuki, Yoshiyuki ; Chakraborty, Ranajit ; Gojobori, Takashi ; Imanishi, Tadashi. / Selection pressure on human STR loci and its relevance in repeat expansion disease. In: Molecular Genetics and Genomics. 2016 ; Vol. 291, No. 5. pp. 1851-1869.
@article{96bafe5defe84fb2a2430ac57c0aad3c,
title = "Selection pressure on human STR loci and its relevance in repeat expansion disease",
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.",
author = "Shimada, {Makoto K.} and Ryoko Sanbonmatsu and Yumi Yamaguchi-Kabata and Chisato Yamasaki and Yoshiyuki Suzuki and Ranajit Chakraborty and Takashi Gojobori and Tadashi Imanishi",
year = "2016",
month = "10",
day = "1",
doi = "10.1007/s00438-016-1219-7",
language = "English",
volume = "291",
pages = "1851--1869",
journal = "Molecular Genetics and Genomics",
issn = "1617-4615",
publisher = "Springer Verlag",
number = "5",

}

Shimada, MK, Sanbonmatsu, R, Yamaguchi-Kabata, Y, Yamasaki, C, Suzuki, Y, Chakraborty, R, Gojobori, T & Imanishi, T 2016, 'Selection pressure on human STR loci and its relevance in repeat expansion disease', Molecular Genetics and Genomics, vol. 291, no. 5, pp. 1851-1869. https://doi.org/10.1007/s00438-016-1219-7

Selection pressure on human STR loci and its relevance in repeat expansion disease. / Shimada, Makoto K.; Sanbonmatsu, Ryoko; Yamaguchi-Kabata, Yumi; Yamasaki, Chisato; Suzuki, Yoshiyuki; Chakraborty, Ranajit; Gojobori, Takashi; Imanishi, Tadashi.

In: Molecular Genetics and Genomics, Vol. 291, No. 5, 01.10.2016, p. 1851-1869.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Selection pressure on human STR loci and its relevance in repeat expansion disease

AU - Shimada, Makoto K.

AU - Sanbonmatsu, Ryoko

AU - Yamaguchi-Kabata, Yumi

AU - Yamasaki, Chisato

AU - Suzuki, Yoshiyuki

AU - Chakraborty, Ranajit

AU - Gojobori, Takashi

AU - Imanishi, Tadashi

PY - 2016/10/1

Y1 - 2016/10/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84983416217&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84983416217&partnerID=8YFLogxK

U2 - 10.1007/s00438-016-1219-7

DO - 10.1007/s00438-016-1219-7

M3 - Article

VL - 291

SP - 1851

EP - 1869

JO - Molecular Genetics and Genomics

JF - Molecular Genetics and Genomics

SN - 1617-4615

IS - 5

ER -

Shimada MK, Sanbonmatsu R, Yamaguchi-Kabata Y, Yamasaki C, Suzuki Y, Chakraborty R et al. Selection pressure on human STR loci and its relevance in repeat expansion disease. Molecular Genetics and Genomics. 2016 Oct 1;291(5):1851-1869. https://doi.org/10.1007/s00438-016-1219-7