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MBE Advance Access published online on October 8, 2008
Molecular Biology and Evolution, doi:10.1093/molbev/msn230
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© The Author 2008. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

Research Article

Hypermutability of genes in Homo sapiens due to the hosting of long mono-SSR

Etienne Loire18,§, Françoise Praz9,10, Dominique Higuet47, Pierre Netter13 and Guillaume Achaz48

1 UPMC Univ Paris 06, UMR 7592, Institut Jacques Monod, F-75005, Paris, France
2 CNRS, UMR 7592, Institut Jacques Monod, F-75005, Paris, France
3 Université Denis Diderot-Paris7, UMR 7592, Institut Jacques Monod, F-75005, Paris, France
4 UPMC Univ Paris 06, UMR 7138, Systématique, Adaptation, Evolution, F-75005, Paris, France
5 CNRS, UMR 7138, Systématique, Adaptation Evolution, F-75005, Paris, France
6 MNHN, UMR 7138, Systématique Adaptation Evolution, F-75005, Paris, France
7 IRD, UMR 7138, Systématique, Adaptation Evolution, F-75005, Paris, France
8 UPMC Univ Paris 06, Atelier de Bioinformatique, F-75005, Paris, France
9 UPMC Univ Paris 06, UMR_S 893, CdR Saint-Antoine, F-75012, Paris, France
10 INSERM, UMR_S 893, CdR Saint-Antoine, F-75012, Paris, France

§ Corresponding author: Etienne Loire, Atelier de Bioinformatique, Université Pierre et Marie Curie, 4 place Jussieu, 75252 Paris Cedex 05, Tel: 33 1 44 27 68 91, Fax: 33 1 44 27 63 12, E-mail: loire{at}abi.snv.jussieu.fr

Received for publication April 17, 2008. Revision received September 5, 2008. Accepted for publication October 5, 2008.

Simple Sequence Repeats (SSRs) are very common short repeats in eukaryotic genomes. Long SSRs are considered "hypermutable" sequences since 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 mono-nucleotide SSR (mono-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


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