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Background  Cernunnos-XLF is a nonhomologous end-joining factor that is mutated in patients with a rare immunodeficiency with microcephaly. Several other microcephaly-associated genes such as  ASPM  and  microcephalin  experienced recent adaptive evolution apparently linked to brain size expansion in humans. In this study we investigated whether  Cernunnos-XLF  experienced similar positive selection during human evolution.    Results  We obtained or reconstructed full-length coding sequences of chimpanzee, rhesus macaque, canine, and bovine  Cernunnos-XLF  orthologs from sequence databases and sequence trace archives. Comparison of coding sequences revealed an excess of nonsynonymous substitutions consistent with positive selection on  Cernunnos-XLF  in the human lineage. The hotspots of adaptive evolution are concentrated around a specific structural domain, whose analogue in the structurally similar XRCC4 protein is involved in binding of another nonhomologous end-joining factor, DNA ligase IV.    Conclusion   Cernunnos-XLF  is a microcephaly-associated locus newly identified to be under adaptive evolution in humans, and possibly played a role in human brain expansion. We speculate that Cernunnos-XLF may have contributed to the increased number of brain cells in humans by efficient double strand break repair, which helps to prevent frequent apoptosis of neuronal progenitors and aids mitotic cell cycle progression.    Reviewers  This article was reviewed by Chris Ponting and Richard Emes (nominated by Chris Ponting), Kateryna Makova, Gáspár Jékely and Eugene V. Koonin.

Positive selection on the nonhomologous end-joining factor Cernunnos-XLF in the human lineage.