Abstract
BackgroundCernunnos-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.ResultsWe 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.ConclusionCernunnos-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.ReviewersThis article was reviewed by Chris Ponting and Richard Emes (nominated by Chris Ponting), Kateryna Makova, Gáspár Jékely and Eugene V. Koonin.
Highlights
Cernunnos-XLF is a nonhomologous end-joining factor that is mutated in patients with a rare immunodeficiency with microcephaly
Reviewers: This article was reviewed by Chris Ponting and Richard Emes, Kateryna Makova, Gáspár Jékely and Eugene V
Double-strand breaks (DSBs) are highly cytotoxic DNA lesions caused by ionizing radiation, spontaneous chromosomal breaks, activity of cellular endonucleases, or during replication of other DNA lesions such as singlestrand breaks
Summary
Cernunnos-XLF is a nonhomologous end-joining factor that is mutated in patients with a rare immunodeficiency with microcephaly. DSBs efficiently trigger arrest of cell cycle progression and cell death by apoptosis [1]. In response to this danger, cells have developed mechanisms (page number not for citation purposes). In contrast to HR, NHEJ does not require a highly identical undamaged partner DNA strand to repair DSBs and, after some processing, can ligate virtually any two DNA ends. This makes NHEJ a very efficient, yet error-prone DSB repair mechanism
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