Asthana Saurabh, Noble William S, Kryukov Gregory, Grant Charles E, Sunyaev Shamil, Stamatoyannopoulos John A
Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.
Proc Natl Acad Sci U S A. 2007 Jul 24;104(30):12410-5. doi: 10.1073/pnas.0705140104. Epub 2007 Jul 17.
It is widely assumed that human noncoding sequences comprise a substantial reservoir for functional variants impacting gene regulation and other chromosomal processes. Evolutionarily conserved noncoding sequences (CNSs) in the human genome have attracted considerable attention for their potential to simplify the search for functional elements and phenotypically important human alleles. A major outstanding question is whether functionally significant human noncoding variation is concentrated in CNSs or distributed more broadly across the genome. Here, we combine whole genome sequence data from four nonhuman species (chimp, dog, mouse, and rat) with recently available comprehensive human polymorphism data to analyze selection at single-nucleotide resolution. We show that a substantial fraction of active purifying selection in human noncoding sequences occurs outside of CNSs and is diffusely distributed across the genome. This finding suggests the existence of a large complement of human noncoding variants that may impact gene expression and phenotypic traits, the majority of which will escape detection with current approaches to genome analysis.
人们普遍认为，人类非编码序列包含大量影响基因调控和其他染色体过程的功能性变异。人类基因组中进化上保守的非编码序列（CNSs）因其简化功能元件搜索和具有表型重要性的人类等位基因搜索的潜力而备受关注。一个主要的悬而未决的问题是，功能上重要的人类非编码变异是集中在CNSs中，还是更广泛地分布在整个基因组中。在这里，我们将来自四个非人类物种（黑猩猩、狗、小鼠和大鼠）的全基因组序列数据与最近可得的全面人类多态性数据相结合，以单核苷酸分辨率分析选择情况。我们表明，人类非编码序列中相当一部分活跃的纯化选择发生在CNSs之外，并在整个基因组中呈分散分布。这一发现表明存在大量可能影响基因表达和表型特征的人类非编码变异，其中大多数将无法通过当前的基因组分析方法检测到。
