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Background The temporal coordination of biological processes into daily cycles is a common feature of most living organisms. In humans, disruption of circadian rhythms is commonly observed in psychiatric diseases, including schizophrenia, bipolar disorder, depression and autism. Light therapy is the most effective treatment for seasonal affective disorder and circadian-related treatments sustain antidepressant response in bipolar disorder patients. Day/night cycles represent a major circadian synchronizing signal and vary widely with latitude. Results We apply a geographically explicit model to show that out-of-Africa migration, which led humans to occupy a wide latitudinal area, affected the evolutionary history of circadian regulatory genes. The SNPs we identify using this model display consistent signals of natural selection using tests based on population genetic differentiation and haplotype homozygosity. Signals of natural selection driven by annual photoperiod variation are detected for schizophrenia, bipolar disorder, and restless leg syndrome risk variants, in line with the circadian component of these conditions. Conclusions Our results suggest that human populations adapted to life at different latitudes by tuning their circadian clock systems. This process also involves risk variants for neuropsychiatric conditions, suggesting possible genetic modulators for chronotherapies and candidates for interaction analysis with photoperiod-related environmental variables, such as season of birth, country of residence, shift-work or lifestyle habits. Electronic supplementary material The online version of this article (doi:10.1186/s13059-014-0499-7) contains supplementary material, which is available to authorized users.

Analysis of the human beta defensin 1 promoter region in six human populations reveals a signature of balancing selection., Background Defensins, small endogenous peptides with antimicrobial activity, are pivotal components of the innate immune response. A large cluster of defensin genes is located on human chromosome 8p; among them the beta defensin 1 (DEFB1) promoterhas been extensively studied since discovery that specific polymorphisms and haplotypes associate with asthma and atopy, susceptibility to severe sepsis, as well as HIV and Candida infection predisposition. Results Here, we characterize the sequence variation and haplotype structure of the DEFB1 promoter region in six human populations. In all of them, we observed high levels of nucleotide variation, an excess of intermediate-frequency alleles, reduced population differentiation and a genealogy with common haplotypes separated by deep branches. Indeed, a significant departure from the expectation of evolutionary neutrality was observed in all populations and the possibility that this is due to demographic history alone was ruled out. Also, we verified that the selection signature is restricted to the promoter region and not due to a linked balanced polymorphism. A phylogeny-based estimation indicated that the two major haplotype clades separated around 4.5 million years ago, approximately the time when the human and chimpanzee lineages split. Conclusion Altogether, these features represent strong molecular signatures of long-term balancing selection, a process that is thought to be extremely rare outside major histocompatibility complex genes. Our data indicate that the DEFB1 promoter region carries functional variants and support previous hypotheses whereby alleles predisposing to atopic disorders are widespread in modern societies because they conferred resistance to pathogens in ancient settings.

Methods and results Our aim was to analyze the selective processes acting on variants with an opposite effect on two or more diseases and to test the hypothesis whereby balancing selection has shaped the frequency of these alleles. Since balancing selection signatures are expected to extend over short genomic portions, we restricted our analyses to 10 regions carrying putative functional polymorphisms that might represent the disease variants (and the selection targets). Resequencing of 20 HapMap subjects with European ancestry (CEU) revealed no exceptional nucleotide diversity for ZSCAN23, HLADMB, VARS2, PTPN22, BAT3, and C6orf47; summary statistics were consistent with evolutionary neutrality for these gene regions. Conversely, the regions we analysed in CDSN/PSORSC1, TRIM10/TRIM40, BTNL2, and TAP2 showed extremely high nucleotide diversity and most tests rejected neutrality, suggesting the action of balancing selection. The possibility that the signatures we observed at TAP2 and BTNL2 are secondary to linkage disequilibrium with HLA class II genes was ruled out. We extended population genetic analyses to Yoruba and East Asians and verified that balancing selection has been acting in most populations on CDSN/PSORSC1, TRIM10/TRIM40, BTNL2, and TAP2. These data were also confirmed by the application of multi-locus HKA tests that revealed a significant excess of polymorphism compared to divergence. Consistently, estimation of the time to the most recent common ancestor yielded deeper coalescent times than expected under neutrality. Conclusions In summary, our data indicate that a portion of alleles with an opposite risk profile for different autoimmune diseases have evolved under a regime of long-standing balancing selection. Also, results herein indicate that balancing selection has operated on several non-HLA genes located in the xMHC. In addition to their involvement in autoimmunity, variants in TAP2 and TRIM10 influence the susceptibility to some viral infections, while CDSN, encoding corenodesmosin, is pivotal in maintaining the epidermal integrity, which serves as a barrier against invading pathogens. Therefore, we suggest that infectious diseases represent the selective pressure underlying the signatures we observed and contributed to shaping the genetic predisposition to autoimmunity in modern populations.

Transposable elements (TEs) represent more than 45% of the human and mouse genomes. Both parasitic and mutualistic features have been shown to apply to the host-TE relationship but a comprehensive scenario of the forces driving TE fixation within mammalian genes is still missing. We show that intronic multispecies conserved sequences (MCSs) have been affecting TE integration frequency over time. We verify that a selective economizing pressure has been acting on TEs to decrease their frequency in highly expressed genes. After correcting for GC content, MCS density and intron size, we identified TE-enriched and TE-depleted gene categories. In addition to developmental regulators and transcription factors, TE-depleted regions encompass loci that might require subtle regulation of transcript levels or precise activation timing, such as growth factors, cytokines, hormones, and genes involved in the immune response. The latter, despite having reduced frequencies of most TE types, are significantly enriched in mammalian-wide interspersed repeats (MIRs). Analysis of orthologous genes indicated that MIR over-representation also occurs in dog and opossum immune response genes, suggesting, given the partially independent origin of MIR sequences in eutheria and metatheria, the evolutionary conservation of a specific function for MIRs located in these loci. Consistently, the core MIR sequence is over-represented in defense response genes compared to the background intronic frequency. Our data indicate that gene function, expression level, and sequence conservation influence TE insertion/fixation in mammalian introns. Moreover, we provide the first report showing that a specific TE family is evolutionarily associated with a gene function category.