Selection pressure on human STR loci and its relevance in repeat expansion disease.
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.
Institute for Comprehensive Medical Science, Fujita Health University, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Aichi, 470-1192, Japan. mshimada@fujita-hu.ac.jp.|National Institute of Advanced Industrial Science and Technology, 2-3-26 Aomi Koto-ku, Tokyo, 135-0064, Japan. mshimada@fujita-hu.ac.jp.|Japan Biological Informatics Consortium, 10F TIME24 Building, 2-4-32 Aomi, Koto-ku, Tokyo, 135-8073, Japan. mshimada@fujita-hu.ac.jp.
Makoto K
MK
Shimada
Japan Biological Informatics Consortium, 10F TIME24 Building, 2-4-32 Aomi, Koto-ku, Tokyo, 135-8073, Japan.
Ryoko
R
Sanbonmatsu
National Institute of Advanced Industrial Science and Technology, 2-3-26 Aomi Koto-ku, Tokyo, 135-0064, Japan.|Tohoku Medical Megabank Organization, Tohoku University, 2-1 Seiryo-machi, Aoba-ku, Sendai, 980-8573, Japan.
Yumi
Y
Yamaguchi-Kabata
National Institute of Advanced Industrial Science and Technology, 2-3-26 Aomi Koto-ku, Tokyo, 135-0064, Japan.|Japan Biological Informatics Consortium, 10F TIME24 Building, 2-4-32 Aomi, Koto-ku, Tokyo, 135-8073, Japan.
Chisato
C
Yamasaki
Graduate School of Natural Sciences, Nagoya City University, 1 Yamanohata, Mizuho-cho, Mizuho-ku, Nagoya, Aichi, 467-8501, Japan.
Yoshiyuki
Y
Suzuki
Health Science Center, University of North Texas, 3500 Camp Bowie Blvd., Fort Worth, TX, 76107, USA.
Ranajit
R
Chakraborty
National Institute of Advanced Industrial Science and Technology, 2-3-26 Aomi Koto-ku, Tokyo, 135-0064, Japan.|Computational Bioscience Research Center, King Abdullah University of Science and Technology, Ibn Al-Haytham Building (West), Thuwal, 23955-6900, Kingdom of Saudi Arabia.
Takashi
T
Gojobori
National Institute of Advanced Industrial Science and Technology, 2-3-26 Aomi Koto-ku, Tokyo, 135-0064, Japan.|Department of Molecular Life Science, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa, 259-1193, Japan.
Tadashi
T
Imanishi
D004194:Disease / Q000235:genetics*; D019143:Evolution, Molecular; D015894:Genome, Human; D006801:Humans; D018895:Microsatellite Repeats; D055495:Neurogenesis; D012641:Selection, Genetic; D017422:Sequence Analysis, DNA; D020539:Sequence Analysis, Protein
Database for human polymorphism (VarySysDB); Human evolution; STR polymorphism; Single amino-acid repeat; Triplet-repeat expansion disease