McCoy Rajiv C, Wakefield Jon, Akey Joshua M
Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
Department of Statistics, University of Washington, Seattle, WA 98195, USA; Department of Biostatistics, University of Washington, Seattle, WA 98195, USA.
Cell. 2017 Feb 23;168(5):916-927.e12. doi: 10.1016/j.cell.2017.01.038.
Regulatory variation influencing gene expression is a key contributor to phenotypic diversity, both within and between species. Unfortunately, RNA degrades too rapidly to be recovered from fossil remains, limiting functional genomic insights about our extinct hominin relatives. Many Neanderthal sequences survive in modern humans due to ancient hybridization, providing an opportunity to assess their contributions to transcriptional variation and to test hypotheses about regulatory evolution. We developed a flexible Bayesian statistical approach to quantify allele-specific expression (ASE) in complex RNA-seq datasets. We identified widespread expression differences between Neanderthal and modern human alleles, indicating pervasive cis-regulatory impacts of introgression. Brain regions and testes exhibited significant downregulation of Neanderthal alleles relative to other tissues, consistent with natural selection influencing the tissue-specific regulatory landscape. Our study demonstrates that Neanderthal-inherited sequences are not silent remnants of ancient interbreeding but have measurable impacts on gene expression that contribute to variation in modern human phenotypes.
影响基因表达的调控变异是物种内部和物种之间表型多样性的关键因素。不幸的是，RNA降解速度太快，无法从化石残骸中恢复，这限制了我们对已灭绝的古人类亲属的功能基因组学认识。由于古代杂交，许多尼安德特人的序列在现代人类中得以留存，这为评估它们对转录变异的贡献以及检验有关调控进化的假设提供了机会。我们开发了一种灵活的贝叶斯统计方法，用于量化复杂RNA测序数据集中的等位基因特异性表达（ASE）。我们发现尼安德特人和现代人类等位基因之间存在广泛的表达差异，这表明基因渗入对顺式调控具有普遍影响。与其他组织相比，大脑区域和睾丸中尼安德特人等位基因的表达显著下调，这与自然选择影响组织特异性调控格局一致。我们的研究表明，从尼安德特人遗传下来的序列并非古代杂交的沉默残余，而是对基因表达有可测量的影响，这有助于现代人类表型的变异。
