小柯机器人

美国Illumina人工智能实验室Kyle Kai-How Farh等研究人员合作在239种灵长类基因组中鉴定约束序列元件。2023年11月29日，国际知名学术期刊《自然》在线发表了这一成果。

研究人员构建了239个物种的全基因组比对，代表了灵长类所有现存物种的近一半。利用这一资源，研究人员发现了在灵长类和其他哺乳动物中受到选择性限制的人类调控元件，错误发现率为5%。研究人员发现了111318个DNase I超敏位点和267410个转录因子结合位点，这些位点在灵长类动物中受到特异性限制，而在其他胎盘哺乳动物中则没有，并验证了它们对基因表达的顺式调控作用。这些调控元件富含影响基因表达和复杂性状及疾病的人类基因变异。这些研究结果凸显了近期演化在调控序列元件中的重要作用，这些元件将灵长类动物（包括人类）与其他胎盘哺乳动物区分开来。

据悉，非编码DNA是人们了解人类基因调控和复杂疾病的核心，测量演化序列约束可以确定人类基因组中假定调控元件的功能相关性。与编码蛋白质的DNA相比，非编码DNA的演化速度更快，灵长类动物物种之间的时间尺度相对较短，而且以前全基因组序列的可用性有限，这些因素都阻碍了识别灵长类动物基因组中特别受限的元件。

附：英文原文

Title: Identification of constrained sequence elements across 239 primate genomes

Author: Kuderna, Lukas F. K., Ulirsch, Jacob C., Rashid, Sabrina, Ameen, Mohamed, Sundaram, Laksshman, Hickey, Glenn, Cox, Anthony J., Gao, Hong, Kumar, Arvind, Aguet, Francois, Christmas, Matthew J., Clawson, Hiram, Haeussler, Maximilian, Janiak, Mareike C., Kuhlwilm, Martin, Orkin, Joseph D., Bataillon, Thomas, Manu, Shivakumara, Valenzuela, Alejandro, Bergman, Juraj, Rouselle, Marjolaine, Silva, Felipe Ennes, Agueda, Lidia, Blanc, Julie, Gut, Marta, de Vries, Dorien, Goodhead, Ian, Harris, R. Alan, Raveendran, Muthuswamy, Jensen, Axel, Chuma, Idriss S., Horvath, Julie E., Hvilsom, Christina, Juan, David, Frandsen, Peter, Schraiber, Joshua G., de Melo, Fabiano R., Bertuol, Fabrcio, Byrne, Hazel, Sampaio, Iracilda, Farias, Izeni, Valsecchi, Joo, Messias, Malu, da Silva, Maria N. F., Trivedi, Mihir, Rossi, Rogerio, Hrbek, Tomas, Andriaholinirina, Nicole, Rabarivola, Clment J., Zaramody, Alphonse, Jolly, Clifford J., Phillips-Conroy, Jane, Wilkerson, Gregory, Abee, Christian, Simmons, Joe H., Fernandez-Duque, Eduardo, Kanthaswamy, Sree, Shiferaw, Fekadu, Wu, Dongdong, Zhou, Long, Shao, Yong, Zhang, Guojie, Keyyu, Julius D., Knauf, Sascha, Le, Minh D., Lizano, Esther

Issue&Volume: 2023-11-29

Abstract: Noncoding DNA is central to our understanding of human gene regulation and complex diseases1,2, and measuring the evolutionary sequence constraint can establish the functional relevance of putative regulatory elements in the human genome3,4,5,6,7,8,9. Identifying the genomic elements that have become constrained specifically in primates has been hampered by the faster evolution of noncoding DNA compared to protein-coding DNA10, the relatively short timescales separating primate species11, and the previously limited availability of whole-genome sequences12. Here we construct a whole-genome alignment of 239 species, representing nearly half of all extant species in the primate order. Using this resource, we identified human regulatory elements that are under selective constraint across primates and other mammals at a 5% false discovery rate. We detected 111,318 DNase I hypersensitivity sites and 267,410 transcription factor binding sites that are constrained specifically in primates but not across other placental mammals and validate their cis-regulatory effects on gene expression. These regulatory elements are enriched for human genetic variants that affect gene expression and complex traits and diseases. Our results highlight the important role of recent evolution in regulatory sequence elements differentiating primates, including humans, from other placental mammals.

DOI: 10.1038/s41586-023-06798-8

Source: https://www.nature.com/articles/s41586-023-06798-8

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html