MBE Advance Access originally published online on October 8, 2008
Molecular Biology and Evolution 2009 26(1):111-121; doi:10.1093/molbev/msn230
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Research Articles |
Hypermutability of Genes in Homo sapiens Due to the Hosting of Long Mono-SSR
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* Université Pierre et Marie Curie-Paris 6, Unité Mixte de recherche (UMR) 7592, Institut Jacques Monod, Paris, France
Centre National de la Recherche Scientifique (CNRS), UMR 7592, Institut Jacques Monod, Paris, France
Université Denis Diderot-Paris7, UMR 7592, Institut Jacques Monod, Paris, France
Université Pierre et Marie Curie Paris 6, UMR 7138, Systématique, Adaptation, Evolution, Paris, France
|| CNRS, UMR 7138, Systématique, Adaptation Evolution, Paris, France
¶ Museum National d'Histoire Naturelle, UMR 7138, Systématique Adaptation Evolution, Paris, France
# Institut National de al Sauté et de la Recherche Médicale, UMR 7138, Systématique, Adaptation Evolution, Paris, France
** Université Pierre et Marie Curie-Paris 6, Atelier de Bioinformatique, Paris, France
Université Pierre et Marie Curie-Paris 6, UMR_S 893, CdR Saint-Antoine, Paris, France
INSERM, UMR_S 893, CdR Saint-Antoine, Paris, France
E-mail: loire{at}abi.snv.jussieu.fr.
Accepted for publication October 5, 2008.
Simple sequence repeats (SSRs) are very common short repeats in eukaryotic genomes. "Long" SSRs are considered "hypermutable" sequences because they exhibit a high rate of expansion and contraction. Because they are potentially deleterious, long SSRs tend to be uncommon in coding sequences. However, several genes contain long SSRs in their exonic sequences. Here, we identify 1,291 human genes that host a mononucleotide SSR long enough to be prone to expansion or contraction, being called hypermutable hereafter. On the basis of Gene Ontology annotations, we show that only a restricted number of functions are overrepresented among those hypermutable genes including cell cycle and maintenance of DNA integrity. Using a probabilistic model, we show that genes involved in these functions are expected to host long SSRs because they tend to be long and/or are biased in nucleotide composition. Finally, we show that for almost all functions we observe fewer hypermutable sequences than expected under a neutral model. There are however interesting exceptions, for example, genes involved in protein and RNA transport, as well as meiosis and mismatch repair functions that have as many hypermutable genes as expected under neutrality. Conversely, there are functions (e.g., collagen-related genes) where hypermutable genes are more often avoided than in other functions. Our results show that, even though several functions harbor unusually long SSR in their exons, long SSRs are deleterious sequences in almost all functions and are removed by purifying selection. The strength of this purifying selection however greatly varies from function to function. We discuss possible explanations for this intriguing result.
Key Words: microsatellites • SSR • evolution • mutability • Homo sapiens
Naruya Saitou, Associate Editor
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