Genetic adaptation of the human circadian clock to day-length latitudinal variations and relevance for affective disorders

Diego Forni,Elisabetta Bolognesi,Giorgia Menozzi,Mario Clerici,Giacomo Pietro Comi ,Claudia Tresoldi,Franca Rosa Guerini ,Nereo Bresolin,Rachele Cagliani,Stefania Riva,Manuela Sironi

doi:10.1186/preaccept-1049924751277672

Abstract

BackgroundThe 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.ResultsWe 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.ConclusionsOur 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.

Highlights

The temporal coordination of biological processes into daily cycles is a common feature of most living organisms
The binning in minor allele frequency (MAF) classes corrected for the fact that the power of the correlation tests was affected by the overall single nucleotide polymorphism (SNP) frequency in populations
Natural selection signals at circadian rhythm regulatory genes To validate the results reported above, and to gain further insight into the evolutionary history of the 84 Δphotoperiod-selected variants, we analyzed their normalized derived allele frequency (DAF): a progressive increase with Δphotoperiod was observed in most geographic areas, suggesting that selection has operated on these variants throughout human migration (Figure 1B)

Summary

Introduction

The temporal coordination of biological processes into daily cycles is a common feature of most living organisms. 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. Circadian cycles are determined by the presence of an internal cell-autonomous clock, they are synchronized (entrained) by environmental cues, most importantly visible light and external temperature [1]. The suprachiasmatic nucleus (SCN) represents the central circadian pacemaker. SCN neurons sustain cell-autonomous cycles and, through the retinohypothalamic tract, receive inputs from melanopsin-expressing photosensitive retinal ganglion cells (RGC). Many peripheral tissues display autonomous circadian oscillations, the SCN hierarchically coordinates. CRY/PER heterodimers translocate back into the nucleus and inhibit their own transcription by acting on the CLOCK/ARNTL complex. The degradation of CRY and PER relieves the inhibition and initiates a new cycle [3]

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Discussion

Conclusion