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Search for informative polymorphisms in candidate genes: clock genes and circadian behaviour in blue tits.

ABSTRACT: The identification of functional polymorphisms in genes that underlie behavioural trait variation is a challenging but intriguing task in evolutionary biology. Given the wealth of genomic data and the increasing number of genotype-phenotype association studies in model organisms, one can ask whether and how this information can be used for non-model organisms. Here we describe two strategies to search for likely functional polymorphisms in candidate genes in a bird species that has been intensively studied by behavioural and population ecologists, the blue tit Cyanistes caeruleus. In the first approach we searched for repeating elements in coding regions of the genome using information about repeats in Gallus gallus genes. The rationale is that tandem-repeat elements have a high potential to be polymorphic and functional. The second strategy aimed to replicate reported genotype-phenotype association studies by extrapolating results from model organisms to our study species. Both strategies showed high success rates with respect to finding homologous gene regions and potentially informative genetic variants in the genes AANAT, ADCYAP1, CKIepsilon, CLOCK, CREB1, NPAS2 and PERIOD2.

SUBMITTER: Steinmeyer C

PROVIDER: S-EPMC2832883 | biostudies-literature | 2009 May

REPOSITORIES: biostudies-literature

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Search for informative polymorphisms in candidate genes: clock genes and circadian behaviour in blue tits.

Steinmeyer C C Mueller J C JC Kempenaers B B

Genetica 20080916 1

The identification of functional polymorphisms in genes that underlie behavioural trait variation is a challenging but intriguing task in evolutionary biology. Given the wealth of genomic data and the increasing number of genotype-phenotype association studies in model organisms, one can ask whether and how this information can be used for non-model organisms. Here we describe two strategies to search for likely functional polymorphisms in candidate genes in a bird species that has been intensiv ...[more]

PMID: 18792794

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Project description:Most physiological processes in mammals are temporally regulated by means of a master circadian clock in the brain and peripheral oscillators in most other tissues. A transcriptional-translation feedback network of clock genes produces near 24 h oscillations in clock gene and protein expression. Here, we aim to identify novel additions to the clock network using a meta-analysis of public chromatin immunoprecipitation sequencing (ChIP-seq), proteomics and protein-protein interaction data starting from a published list of 1000 genes with robust transcriptional rhythms and circadian phenotypes of knockdowns.We identified 20 candidate genes including nine known clock genes that received significantly high scores and were also robust to the relative weights assigned to different data types. Our scoring was consistent with the original ranking of the 1000 genes, but also provided novel complementary insights. Candidate genes were enriched for genes expressed in a circadian manner in multiple tissues with regulation driven mainly by transcription factors BMAL1 and REV-ERB ?,?. Moreover, peak transcription of candidate genes was remarkably consistent across tissues. While peaks of the 1000 genes were distributed uniformly throughout the day, candidate gene peaks were strongly concentrated around dusk. Finally, we showed that binding of specific transcription factors to a gene promoter was predictive of peak transcription at a certain time of day and discuss combinatorial phase regulation.Combining complementary publicly-available data targeting different levels of regulation within the circadian network, we filtered the original list and found 11 novel robust candidate clock genes. Using the criteria of circadian proteomic expression, circadian expression in multiple tissues and independent gene knockdown data, we propose six genes (Por, Mtss1, Dgat2, Pim3, Ppp1r3b, Upp2) involved in metabolism and cancer for further experimental investigation. The availability of public high-throughput databases makes such meta-analysis a promising approach to test consistency between sources and tap their entire potential.

Project description:BackgroundVirtually all living organisms have evolved a circadian (~24 hour) clock that controls physiological and behavioural processes with exquisite precision throughout the day/night cycle. The suprachiasmatic nucleus (SCN), which generates these ~24 h rhythms in mammals, consists of several thousand neurons. Each neuron contains a gene-regulatory network generating molecular oscillations, and the individual neuron oscillations are synchronised by intercellular coupling, presumably via neurotransmitters. Although this basic mechanism is currently accepted and has been recapitulated in mathematical models, several fundamental questions about the design principles of the SCN remain little understood. For example, a remarkable property of the SCN is that the phase of the SCN rhythm resets rapidly after a 'jet lag' type experiment, i.e. when the light/dark (LD) cycle is abruptly advanced or delayed by several hours.ResultsHere, we describe an extensive parameter optimization of a previously constructed simplified model of the SCN in order to further understand its design principles. By examining the top 50 solutions from the parameter optimization, we show that the neurotransmitters' role in generating the molecular circadian rhythms is extremely important. In addition, we show that when a neurotransmitter drives the rhythm of a system of coupled damped oscillators, it exhibits very robust synchronization and is much more easily entrained to light/dark cycles. We were also able to recreate in our simulations the fast rhythm resetting seen after a 'jet lag' type experiment.ConclusionOur work shows that a careful exploration of parameter space for even an extremely simplified model of the mammalian clock can reveal unexpected behaviours and non-trivial predictions. Our results suggest that the neurotransmitter feedback loop plays a crucial role in the robustness and phase resetting properties of the mammalian clock, even at the single neuron level.

Dataset Information

Search for informative polymorphisms in candidate genes: clock genes and circadian behaviour in blue tits.

Publications

Search for informative polymorphisms in candidate genes: clock genes and circadian behaviour in blue tits.

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