Molecular and Cellular Biology Graduate Program, University of Massachusetts Amherst.
Department of Biology, University of Massachusetts Amherst.
Genome Biol Evol. 2018 Mar 1;10(3):826-839. doi: 10.1093/gbe/evy041.
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.
人类比我们最亲近的进化亲属黑猩猩更容易患上与年龄相关的疾病。环境因素可以解释这些疾病风险增加的许多原因，但物种特异性的遗传变化也可能起作用。如果这些变化在生命早期赋予了积极的适应，那么在没有选择压力的情况下，赋予晚年疾病易感性增加的等位基因可能会在种群中持续存在。一种与年龄相关的疾病，与黑猩猩相比， disproportionately 会影响人类，那就是上皮癌。在这里，我们在一个明确的实验中探索了人类和黑猩猩之间的遗传差异，该实验模拟了发生在癌症进展过程中的基因表达变化：成纤维细胞血清挑战。我们使用来自人类和黑猩猩的成纤维细胞进行了这项实验，以探索使用 RNA-Seq 和 DNase-Seq 进行物种特异性基因表达和染色质状态的差异。我们的数据表明，人类成纤维细胞增加了与伤口愈合和癌症途径相关的基因表达；相比之下，黑猩猩的基因表达变化并不集中在特定的功能类别上。在血清反应过程中，人类成纤维细胞的染色质可及性急剧增加，而黑猩猩细胞的染色质可及性则降低。许多开放和关闭染色质的区域与编码转录因子或参与伤口愈合过程的基因非常接近，进一步支持了调节元件活性变化与基因表达变化之间的联系。这些表达和开放染色质数据表明，人类和黑猩猩对相同的生理应激有截然不同的反应，以及核心生理过程如何在相对较短的进化时间尺度内快速进化。
