BIOLOGISTS / AQUARISTS
Mapping epigenetic divergence in the massive radiation of Lake Malawi cichlid fishes
Nature Communications 12, Article number: 5870 (2021)
Abstract
Epigenetic variation modulates gene expression and can be heritable. However, knowledge of the contribution of epigenetic divergence to adaptive diversification in nature remains limited. The massive evolutionary radiation of Lake Malawi cichlid fishes displaying extensive phenotypic diversity despite extremely low sequence divergence is an excellent system to study the epigenomic contribution to adaptation. Here, we present a comparative genome-wide methylome and transcriptome study, focussing on liver and muscle tissues in phenotypically divergent cichlid species. In both tissues we find substantial methylome divergence among species. Differentially methylated regions (DMR), enriched in evolutionary young transposons, are associated with transcription changes of ecologically-relevant genes related to energy expenditure and lipid metabolism, pointing to a link between dietary ecology and methylome divergence. Unexpectedly, half of all species-specific DMRs are shared across tissues and are enriched in developmental genes, likely reflecting distinct epigenetic developmental programmes. Our study reveals substantial methylome divergence in closely-related cichlid fishes and represents a resource to study the role of epigenetics in species diversification.
Introduction
Trait inheritance and phenotypic diversification are primarily explained by the transmission of genetic information encoded in the DNA sequence. In addition, a variety of epigenetic processes have recently been reported to mediate heritable transmission of phenotypes in animals and plants1,2,3,4,5,6,7. However, the current understanding of the evolutionary significance of epigenetic processes, and of their roles in organismal diversification, is in its infancy.
DNA methylation, or the covalent addition of a methyl group onto the 5th carbon of cytosine (mC) in DNA, is a reversible epigenetic mark present across multiple kingdoms8,9,10, can be heritable, and has been linked to transmission of acquired phenotypes in plants and animals2,5,6,11,12,13. The importance of this mechanism is underlined by the fact that proteins involved in the deposition of mC (‘writers’, DNA methyltransferases [DNMTs]), in mC maintenance during cell division, and in the removal of mC (‘erasers’, ten-eleven translocation methylcytosine dioxygenases [TETs]), are mostly essential and show high degrees of conservation across vertebrates species14,15,16,17. In addition, some ancestral functions of methylated cytosines are highly conserved, such as in the transcriptional silencing of exogenous genomic elements (transposons)18,19. In vertebrates, DNA methylation functions have evolved to play an important role in the orchestration of cell differentiation during normal embryogenesis/development through complex interactions with histone post-translational modifications (DNA accessibility) and mC-sensitive readers (such as transcription factors)19,20,21,22,23,24,25, in particular at cis-regulatory regions (i.e., promoters, enhancers). Early-life establishment of stable DNA methylation patterns can thus affect transcriptional activity in the embryo and persist into fully differentiated cells26. DNA methylation variation has also been postulated to have evolved in the context of natural selection by promoting phenotypic plasticity and thus possibly facilitating adaptation, speciation, and adaptive radiation2,4,12,27.
Studies in plants have revealed how covarying environmental factors and DNA methylation variation underlie stable and heritable transcriptional changes in adaptive traits2,6,11,12,13,28. Some initial evidence is also present in vertebrates2,5,29,30,31. In the cavefish, for example, an early developmental process—eye degeneration—has been shown to be mediated by DNA methylation, suggesting mC variation as an evolutionary factor generating adaptive phenotypic plasticity during development and evolution29,32. However, whether correlations between environmental variation and DNA methylation patterns promote phenotypic diversification more widely among natural vertebrate populations remains unknown.
In this study, we sought to quantify, map and characterise natural divergence in DNA methylation in the context of the Lake Malawi haplochromine cichlid adaptive radiation, one of the most spectacular examples of rapid vertebrate phenotypic diversification33. In total, the radiation comprises over 800 endemic species34, that are estimated to have evolved from common ancestry approximately 800,000 years ago35. Species within the radiation can be grouped into seven distinct ecomorphological groups based on their ecology, morphology, and genetic differences: (1) shallow benthic, (2) deep benthic, (3) deep pelagic zooplanktivorous/piscivorous Diplotaxodon, (4) the rock-dwelling ‛mbuna’, (5) zooplanktivorous ‛utaka’, (6) Astatotilapia calliptera specialised for shallow weedy habitats (also found in surrounding rivers and lakes), and (7) the midwater pelagic piscivores Rhamphochromis36,37. Recent large-scale genetic studies have revealed that the Lake Malawi cichlid flock is characterised by an overall very low genetic divergence among species (0.1−0.25%), combined with a low mutation rate, a high rate of hybridisation and extensive incomplete lineage sorting (shared retention of ancestral genetic variation across species)34,36,38,39. Multiple molecular mechanisms may be at work to enable such an explosive phenotypic diversification. Therefore, investigating the epigenetic mechanisms in Lake Malawi cichlids represents a remarkable opportunity to expand our comprehension of the processes underlying phenotypic diversification and adaptation.
Here we describe, quantify, and assess the divergence in liver methylomes in six cichlid species spanning five of the seven ecomorphological groups of the Lake Malawi haplochromine radiation by generating high-coverage whole-genome liver bisulfite sequencing (WGBS). We find that Lake Malawi haplochromine cichlids exhibit substantial methylome divergence, despite conserved underlying DNA sequences, and are enriched in evolutionary young transposable elements. Next, we generated whole liver transcriptome sequencing (RNAseq) in four of the six species and showed that differential transcriptional activity is significantly associated with between-species methylome divergence, most prominently in genes involved in key hepatic metabolic functions. Finally, by generating WGBS from muscle tissues in three cichlid species, we show that half of methylome divergence between species is tissue-unspecific and pertains to embryonic and developmental processes, possibly contributing to the early establishment of phenotypic diversity. This represents a comparative analysis of natural methylome variation in Lake Malawi cichlids and provides initial evidence for substantial species-specific epigenetic divergence in cis-regulatory regions of ecologically-relevant genes. Our study represents a resource that lays the groundwork for future epigenomic research in the context of phenotypic diversification and adaptation.
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