Molecular Genetics and Genomics

, Volume 291, Issue 5, pp 1851–1869

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
Original Article

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.

Keywords

STR polymorphism Single amino-acid repeat Human evolution Triplet-repeat expansion disease Database for human polymorphism (VarySysDB) 

Abbreviation

STR

Short tandem repeat

SAR

Simple amino acids repeat

UTR

Untranslated region

CDS

Coding sequence region

c-triSTR

Coding trinucleotide short tandem repeat

INSDC

The international nucleotide sequence databases collaboration

H-GOLD/GDBS

Human-gene diversity of life-style related diseases/gene diversity database system

GO

Gene ontology

AHG2

Annotation data set for All Human Genes version 2

H-InvDB

H-invitational database

HIT

H-InvDB transcript

HIX

H-InvDB gene cluster defined by mapping of transcripts on genome sequence

GC3

Percentage of G or C at the third codon

Supplementary material

438_2016_1219_MOESM1_ESM.xlsx (57 kb)
Supplementary material 1 (XLSX 56 kb)
438_2016_1219_MOESM2_ESM.pdf (299 kb)
Supplementary material 2 (PDF 299 kb)
438_2016_1219_MOESM3_ESM.docx (786 kb)
Supplementary material 3 (DOCX 785 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Makoto K. Shimada
    • 1
    • 2
    • 3
  • Ryoko Sanbonmatsu
    • 3
  • Yumi Yamaguchi-Kabata
    • 2
    • 4
  • Chisato Yamasaki
    • 2
    • 3
  • Yoshiyuki Suzuki
    • 5
  • Ranajit Chakraborty
    • 6
  • Takashi Gojobori
    • 2
    • 7
  • Tadashi Imanishi
    • 2
    • 8
  1. 1.Institute for Comprehensive Medical ScienceFujita Health UniversityToyoakeJapan
  2. 2.National Institute of Advanced Industrial Science and TechnologyTokyoJapan
  3. 3.Japan Biological Informatics ConsortiumTokyoJapan
  4. 4.Tohoku Medical Megabank OrganizationTohoku UniversitySendaiJapan
  5. 5.Graduate School of Natural SciencesNagoya City UniversityNagoyaJapan
  6. 6.Health Science CenterUniversity of North TexasFort WorthUSA
  7. 7.Computational Bioscience Research CenterKing Abdullah University of Science and TechnologyThuwalKingdom of Saudi Arabia
  8. 8.Department of Molecular Life ScienceTokai University School of MedicineIseharaJapan

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