Abstract
Detecting the genomic changes underlying phenotypic changes between species is a main goal of evolutionary biology and genomics. Evolutionary theory predicts that changes in cis-regulatory elements are important for morphological changes. We combined genome sequencing, functional genomics and genome-wide comparative analyses to investigate regulatory elements in lineages that lost morphological traits. We first show that limb loss in snakes is associated with widespread divergence of limb regulatory elements. We next show that eye degeneration in subterranean mammals is associated with widespread divergence of eye regulatory elements. In both cases, sequence divergence results in an extensive loss of transcription factor binding sites. Importantly, diverged regulatory elements are associated with genes required for normal limb patterning or normal eye development and function, suggesting that regulatory divergence contributed to the loss of these phenotypes. Together, our results show that genome-wide decay of the phenotype-specific cis-regulatory landscape is a hallmark of lost morphological traits.
Highlights
Detecting the genomic changes underlying phenotypic changes between species is a main goal of evolutionary biology and genomics
Our combined comparative and functional genomics analysis shows that losses of complex morphological traits are associated with genome-wide divergence of the cis-regulatory landscape that is involved in the development of the trait
With regard to loss of limbs in snakes and degeneration of eyes in subterranean mammals, we consistently found that hundreds of coding elements (CNEs) diverged in the trait-loss species (i) are associated with genes that have key roles in development and function of this trait, (ii) significantly overlap regulatory elements that are active in the respective tissues, and (iii) exhibit a clear loss signature of relevant transcription factors (TFs)-binding sites
Summary
Detecting the genomic changes underlying phenotypic changes between species is a main goal of evolutionary biology and genomics. Modular cis-regulatory elements associated with this phenotype may directly contribute to its loss and are expected to evolve neutrally afterwards This should result in sequence divergence and decay of regulatory activity over time. Recent studies[8,9,10] found that numerous other limb enhancers are still conserved in snakes, despite limb reduction in this lineage dating back to more than 100 Mya[11], possibly due to pleiotropy of regulatory elements that drive expression in other non-limb tissues It remains an open question whether phenotype loss is generally associated with widespread divergence of the cis-regulatory landscape. We combine genome sequencing with functional and comparative genomics to systematically investigate the fate of cisregulatory elements in lineages that lost complex phenotypes: loss of limbs in snakes and degeneration of eyes in subterranean mammals. Our study provides a widely applicable comparative and functional genomics strategy to detect cis-regulatory element candidates that may underlie morphological differences between species
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