Relating enhancer genetic variation across mammals to complex phenotypes using machine learning

• 成果类型: Article
• 署名作者: Kaplow, Irene M.; Lawler, Alyssa J.; Schaffer, Daniel E.; Srinivasan, Chaitanya; Sestili, Heather H.; Wirthlin, Morgan E.; Phan, BaDoi N.; Prasad, Kavya; Brown, Ashley R.; Zhang, Xiaomeng; Foley, Kathleen; Genereux, Diane P.; Karlsson, Elinor K.; Lindblad-Toh, Kerstin; Meyer, Wynn K.; Pfenning, Andreas R.
• 署名单位: Carnegie Mellon University; Carnegie Mellon University; Carnegie Mellon University; Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh; Lehigh University; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; University of Massachusetts System; UMass Chan Medical School; University of Massachusetts Worcester; Uppsala University; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Allen Institute for Brain Science; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; University of Iowa
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-9283
• DOI: 10.1126/science.abm7993
• 发表日期: 2023-04-28
• 页码: 364-+
• 关键词: reveals principles; human genome; EVOLUTION; proteins; mechanisms; chromatin; dna; CONSERVATION; deficiency; vertebrate

摘要

Protein-coding differences between species often fail to explain phenotypic diversity, suggesting the involvement of genomic elements that regulate gene expression such as enhancers. Identifying associations between enhancers and phenotypes is challenging because enhancer activity can be tissue-dependent and functionally conserved despite low sequence conservation. We developed the Tissue-Aware Conservation Inference Toolkit (TACIT) to associate candidate enhancers with species' phenotypes using predictions from machine learning models trained on specific tissues. Applying TACIT to associate motor cortex and parvalbumin-positive interneuron enhancers with neurological phenotypes revealed dozens of enhancer-phenotype associations, including brain size-associated enhancers that interact with genes implicated in microcephaly or macrocephaly. TACIT provides a foundation for identifying enhancers associated with the evolution of any convergently evolved phenotype in any large group of species with aligned genomes.