Genome-wide comparison of genetic and epigenetic regulatory mechanisms in primates. Y. Gilad, A. Pai, R. Pique-Regi, C. Cain, J. Degner, N. Lewellen, K. Michelini, J. Pritchard The University of Chicago, Human Genetics, Chicago, IL.

   Changes in gene regulation are thought to play an important role in adaptation and speciation, notably in primates. However, the extent to which changes in different regulatory mechanisms underlie gene expression evolution is not yet known. To address this gap, we comparatively characterized gene expression (using RNA sequencing) and genetic and epigenetic regulatory mechanisms in humans, chimpanzees, and rhesus macaques, using LCLs from 8 individuals from each species. Specifically, we used ChIP-seq to obtain genome-wide profiles of H3K4me3, H3K4me1, H3K27me3 and H3K27ac histone modifications, as well as binding of RNA polymerase II. We also collected DNaseI-sequencing from the same LCLs, and by using the CENTIPEDE algorithm we measured the strength of transcription factor binding for over 200 transcription factors in all three species. These data allowed us to identify both conserved and species-specific enhancer and repressor regulatory elements, as well as characterize similarities and differences across species in transcription factor binding to these regulatory elements. We found that that transcription factor binding and histone modifications in more than 67% of regulatory elements in putative promoter regions is conserved across the three species. In turn, by considering sequence conservation at genomic locations that showed differences in regulatory mechanisms across species we were able to better understand the extent to which changes in transcription factor binding are due to either cis- or trans- differences across species. Finally, we analyzed correlations between inter-species differences in the genetic and epigenetic regulatory mechanisms and variation in gene expression levels across species using a system of logistic regression models. Assuming that these correlations do imply a causal regulatory relationship, we estimate that up to 70% of inter-species gene expression differences can be accounted for by corresponding changes in transcription factor binding and/or the presence of histone modification marks.

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