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 Scopus citations

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
StatePublished - 1 Oct 2016

Keywords

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

Fingerprint Dive into the research topics of 'Selection pressure on human STR loci and its relevance in repeat expansion disease'. Together they form a unique fingerprint.

  • Cite this

    Shimada, M. K., 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, 291(5), 1851-1869. https://doi.org/10.1007/s00438-016-1219-7