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Open Access Highly Accessed Research article

Both selective and neutral processes drive GC content evolution in the human genome

Uberto Pozzoli1, Giorgia Menozzi1, Matteo Fumagalli1, Matteo Cereda1, Giacomo P Comi2, Rachele Cagliani1, Nereo Bresolin12 and Manuela Sironi1*

Author Affiliations

1 Scientific Institute IRCCS E. Medea, Bioinformatic Lab, Via don L. Monza 20, 23842 Bosisio Parini (LC), Italy

2 Dino Ferrari Centre, Department of Neurological Sciences, University of Milan, IRCCS Ospedale Maggiore Policlinico, Mangiagalli and Regina Elena Foundation, Via F. Sforza 35, 20100 Milan, Italy

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BMC Evolutionary Biology 2008, 8:99  doi:10.1186/1471-2148-8-99

Published: 27 March 2008

Abstract

Background

Mammalian genomes consist of regions differing in GC content, referred to as isochores or GC-content domains. The scientific debate is still open as to whether such compositional heterogeneity is a selected or neutral trait.

Results

Here we analyze SNP allele frequencies, retrotransposon insertion polymorphisms (RIPs), as well as fixed substitutions accumulated in the human lineage since its divergence from chimpanzee to indicate that biased gene conversion (BGC) has been playing a role in within-genome GC content variation. Yet, a distinct contribution to GC content evolution is accounted for by a selective process. Accordingly, we searched for independent evidences that GC content distribution does not conform to neutral expectations. Indeed, after correcting for possible biases, we show that intron GC content and size display isochore-specific correlations.

Conclusion

We consider that the more parsimonious explanation for our results is that GC content is subjected to the action of both weak selection and BGC in the human genome with features such as nucleosome positioning or chromatin conformation possibly representing the final target of selective processes. This view might reconcile previous contrasting findings and add some theoretical background to recent evidences suggesting that GC content domains display different behaviors with respect to highly regulated biological processes such as developmentally-stage related gene expression and programmed replication timing during neural stem cell differentiation.