Comparative Serum Challenges Show Divergent Patterns of Gene Expression and Open Chromatin in Human and Chimpanzee.

Abstract

Humans experience higher rates of age-associated diseases than our closest living evolutionary relatives, chimpanzees. Environmental factors can explain many of these increases in disease risk, but species-specific genetic changes can also play a role. Alleles that confer increased disease susceptibility later in life can persist in a population in the absence of selective pressure if those changes confer positive adaptation early in life. One age-associated disease that disproportionately affects humans compared with chimpanzees is epithelial cancer. Here, we explored genetic differences between humans and chimpanzees in a well-defined experimental assay that mimics gene expression changes that happen during cancer progression: A fibroblast serum challenge. We used this assay with fibroblasts isolated from humans and chimpanzees to explore species-specific differences in gene expression and chromatin state with RNA-Seq and DNase-Seq. Our data reveal that human fibroblasts increase expression of genes associated with wound healing and cancer pathways; in contrast, chimpanzee gene expression changes are not concentrated around particular functional categories. Chromatin accessibility dramatically increases in human fibroblasts, yet decreases in chimpanzee cells during the serum response. Many regions of opening and closing chromatin are in close proximity to genes encoding transcription factors or genes involved in wound healing processes, further supporting the link between changes in activity of regulatory elements and changes in gene expression. Together, these expression and open chromatin data show that humans and chimpanzees have dramatically different responses to the same physiological stressor, and how a core physiological process can evolve quickly over relatively short evolutionary time scales.

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Published Version (Please cite this version)

10.1093/gbe/evy041

Publication Info

Pizzollo, Jason, William J Nielsen, Yoichiro Shibata, Alexias Safi, Gregory E Crawford, Gregory A Wray and Courtney C Babbitt (2018). Comparative Serum Challenges Show Divergent Patterns of Gene Expression and Open Chromatin in Human and Chimpanzee. Genome biology and evolution, 10(3). 10.1093/gbe/evy041 Retrieved from https://hdl.handle.net/10161/16629.

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Scholars@Duke

Crawford

Gregory E. Crawford

Professor in Pediatrics

My research involves identifying gene regulatory elements across the genome to help us understand how chromatin structure dictates cell function and fate. For the last 30 years, mapping chromatin accessible sites has been the gold standard method to identify the location of active regulatory elements, including promoters, enhancers, silencers, and locus control regions. I have developed technologies that can identify most DNase I hypersensitive sites from potentially any cell type from any species with a sequenced genome. We are combining this data with other wet-lab and computational data types to better understand how these regulatory regions control global gene expression in a set of diverse tissues (normal and diseased) representative of the human body.

Wray

Gregory Allan Wray

Professor of Biology

I study the evolution of genes and genomes with the broad aim of understanding the origins of biological diversity. My approach focuses on changes in the expression of genes using both empirical and computational approaches and spans scales of biological organization from single nucleotides through gene networks to entire genomes. At the finer end of this spectrum of scale, I am focusing on understanding the functional consequences and fitness components of specific genetic variants within regulatory sequences of several genes associated with ecologically relevant traits. At the other end of the scale, I am developing molecular and analytical methods to detect changes in gene function throughout entire genomes, including statistical frameworks for detecting natural selection on regulatory elements and empirical approaches to identify functional variation in transcriptional regulation. At intermediate scales, I am investigating functional variation within a dense gene network in the context of wild populations and natural perturbations. My research leverages the advantages of several different model systems, but primarily focuses on sea urchins and primates (including humans).


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