The origins and functional effects of postzygotic mutations throughout the human life span

• 成果类型: Article
• 署名作者: Rockweiler, Nicole B.; Ramu, Avinash; Nagirnaja, Liina; Wong, Wing H.; Noordam, Michiel J.; Drubin, Casey W.; Huang, Ni; Miller, Brian; Todres, Ellen Z.; Vigh-Conrad, Katinka A.; Zito, Antonino; Small, Kerrin S.; Ardlie, Kristin G.; Cohen, Barak A.; Conrad, Donald F.
• 署名单位: Washington University (WUSTL); Oregon Health & Science University; Oregon National Primate Research Center; Washington University (WUSTL); Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; University of London; King's College London; Oregon Health & Science University; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Stanford University; Stanford University; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-12534
• DOI: 10.1126/science.abn7113
• 发表日期: 2023-04-13
• 关键词: somatic mutation; cell fate; rates; AGE; signatures; selection; cancer; MODEL; RISK; line

摘要

Postzygotic mutations (PZMs) begin to accrue in the human genome immediately after fertilization, but how and when PZMs affect development and lifetime health remain unclear. To study the origins and functional consequences of PZMs, we generated a multitissue atlas of PZMs spanning 54 tissue and cell types from 948 donors. Nearly half the variation in mutation burden among tissue samples can be explained by measured technical and biological effects, and 9% can be attributed to donor-specific effects. Through phylogenetic reconstruction of PZMs, we found that their type and predicted functional impact vary during prenatal development, across tissues, and through the germ cell life cycle. Thus, methods for interpreting effects across the body and the life span are needed to fully understand the consequences of genetic variants.