1. ¹Dipartimento di Genetica e Biologia Molecolare, Sapienza Università di Roma, Rome, Italy
2. ²Centre de Recherche, Hôpital Sainte-Justine, Montréal, Quebec, Canada
3. ³Dipartimento di Scienze di Sanità Pubblica, Sezione di Parassitologia, Sapienza Università di Roma, Rome, Italy
4. ⁴Dipartimento di Genetica e Microbiologia, Università di Pavia, Pavia, Italy
5. ⁵Dipartimento di Biologia, Università di Padova, Padua, Italy

Correspondence: Professor R Scozzari, Dipartimento di Genetica e Biologia Molecolare, Sapienza Università di Roma, P.le Aldo Moro 5, Rome 00185, Italy. Tel: +39 06 49912826 (office) and +39 06 49912924 (lab); Fax: (39) 06 4456866; E-mail: rosaria.scozzari@uniroma1.it

Received 22 January 2008; Revised 31 March 2008; Accepted 7 May 2008; Published online 25 June 2008.

Abstract

Period 2 (PER2) is a key component of the mammalian circadian clock machinery. In humans, genetic variation of clock genes or chronic disturbance of circadian rhythmicity has been implied in the onset of several phenotypes, ranging from periodic insomnias to advanced or delayed sleep phases, to more severe disorders. Peculiar geographic diversity patterns in circadian genes might represent an adaptive response to different light/dark cycles or environmental changes to which different human populations are exposed. To investigate the degree and nature of PER2 gene variation in human populations of different geographic origin, and its possible correlation with different latitudes, we sequenced a 7.7 kb portion of the gene in 20 individuals worldwide. In total, 25 variable sites were identified. The geographic distribution of haplotypes defined by five polymorphic sites was analyzed in 499 individuals from 11 populations from four continents. No evidence for latitude-driven selective effects on PER2 genetic variability was found. However, a high and significant difference in the geographic distribution of PER2 polymorphisms was observed between Africans and non-Africans, suggesting a history of geographically restricted natural selection at this locus. In support of this notion, we found several signals for selection in the sequences. The putative selected haplotype showed a recent coalescent age (8.7 Kyr), and an unusually high frequency in non-African populations. Overall, these findings indicate that a human clock-relevant gene, PER2, might have been influenced by positive selection, and offer preliminary insights into the evolution of this functional class of genes.