单分子分辨率的体细胞突变图谱，这一成果由英国威康桑格研究所Iigo Martincorena小组经过不懈努力而取得。2021年4月28日出版的《自然》杂志在线发表了这一最新研究成果。
为了克服对体细胞突变认识的限制，研究人员研发了纳米速率测序（NanoSeq），这是一种双工测序方法，该方法的错误率在细胞群单个DNA分子中可达到每十亿碱基对错误小于5个。该速率比经典的体细胞突变负荷低两个数量级，从而可以独立于克隆性而研究任何组织中的体细胞突变。研究人员使用这种单分子敏感性方法研究了跨多个组织非分裂细胞的体细胞突变，将比较了干细胞和分化细胞在没有细胞分裂情况下的诱变作用。尽管成熟的血细胞经历了更多次分裂，但血液和结肠中分化的细胞显示出与它们干细胞非常相似的突变负荷和特征。
随后，研究人员表征了有丝分裂后神经元和多克隆平滑肌的突变态势，证实了神经元在整个生命中以恒定的速率积累体细胞突变而无细胞分裂，其速率与有丝分裂活跃组织相似。
总的来说，该研究结果表明，独立于细胞分裂的突变过程是体细胞诱变的重要贡献者。研究人员预计，可靠地单DNA分子中突变检测可能会改变人们对体细胞诱变的理解，并使大规模人群的非侵入性研究成为可能。
研究人员表示，体细胞突变促进癌症的发展，并可能导致衰老和其他疾病。尽管它们很重要，但只能检测存在于单个细胞或小克隆中的突变导致人们对体细胞诱变的知识局限在少数组织中。
附：英文原文
Title: Somatic mutation landscapes at single-molecule resolution
Author: Federico Abascal, Luke M. R. Harvey, Emily Mitchell, Andrew R. J. Lawson, Stefanie V. Lensing, Peter Ellis, Andrew J. C. Russell, Raul E. Alcantara, Adrian Baez-Ortega, Yichen Wang, Eugene Jing Kwa, Henry Lee-Six, Alex Cagan, Tim H. H. Coorens, Michael Spencer Chapman, Sigurgeir Olafsson, Steven Leonard, David Jones, Heather E. Machado, Megan Davies, Nina F. bro, Krishnaa T. Mahubani, Kieren Allinson, Moritz Gerstung, Kourosh Saeb-Parsy, David G. Kent, Elisa Laurenti, Michael R. Stratton, Raheleh Rahbari, Peter J. Campbell, Robert J. Osborne, Iigo Martincorena
Issue&Volume: 2021-04-28
Abstract: Somatic mutations drive the development of cancer and may contribute to ageing and other diseases1,2. Despite their importance, the difficulty of detecting mutations that are only present in single cells or small clones has limited our knowledge of somatic mutagenesis to a minority of tissues. Here, to overcome these limitations, we developed nanorate sequencing (NanoSeq), a duplex sequencing protocol with error rates of less than five errors per billion base pairs in single DNA molecules from cell populations. This rate is two orders of magnitude lower than typical somatic mutation loads, enabling the study of somatic mutations in any tissue independently of clonality. We used this single-molecule sensitivity to study somatic mutations in non-dividing cells across several tissues, comparing stem cells to differentiated cells and studying mutagenesis in the absence of cell division. Differentiated cells in blood and colon displayed remarkably similar mutation loads and signatures to their corresponding stem cells, despite mature blood cells having undergone considerably more divisions. We then characterized the mutational landscape of post-mitotic neurons and polyclonal smooth muscle, confirming that neurons accumulate somatic mutations at a constant rate throughout life without cell division, with similar rates to mitotically active tissues. Together, our results suggest that mutational processes that are independent of cell division are important contributors to somatic mutagenesis. We anticipate that the ability to reliably detect mutations in single DNA molecules could transform our understanding of somatic mutagenesis and enable non-invasive studies on large-scale cohorts.
DOI: 10.1038/s41586-021-03477-4
Source: https://www.nature.com/articles/s41586-021-03477-4
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
本期文章：《自然》：Online/在线发表
