英国惠康桑格研究所David J. Adams、Andrew J. Waters研究小组取得一项新突破。他们的最新研究通过对BAP1的饱和基因组编辑完成了体细胞变异和种系变异的功能分类。相关论文于2024年7月5日发表在《自然-遗传学》杂志上。

研究人员对BAP1进行了详尽的饱和基因组编辑（SGE），BAP1的破坏与肿瘤发生和神经发育改变有关。研究通过实验鉴定了18108个独特变异，发现其中6196个具有异常功能，然后研究人员利用这些数据评估了英国生物库中的表型关联。

研究还表征了利用大量人群确定的肿瘤集合、癌症谱系和ClinVar中的变异，并对癌症相关变异与神经发育表型相关变异进行了比较。该分析表明，种系破坏性BAP1变异与有丝分裂原IGF-1的循环水平升高显著相关，这表明存在一种潜在的病理机制和治疗靶点。

此外，研究还建立了一个灵敏度和特异性均大于98%的变异分类工具，对证据强度进行量化，以帮助精确解读变异。

据悉，人们从父母那里获得的遗传、从头产生或体外获得的许多变异都很罕见，这限制将它们与疾病联系起来的精确度。

附：英文原文

Title: Saturation genome editing of BAP1 functionally classifies somatic and germline variants

Author: Waters, Andrew J., Brendler-Spaeth, Timothy, Smith, Danielle, Offord, Victoria, Tan, Hong Kee, Zhao, Yajie, Obolenski, Sofia, Nielsen, Maartje, van Doorn, Remco, Murphy, Jo-Ellen, Gupta, Prashant, Rowlands, Charlie F., Hanson, Helen, Delage, Erwan, Thomas, Mark, Radford, Elizabeth J., Gerety, Sebastian S., Turnbull, Clare, Perry, John R. B., Hurles, Matthew E., Adams, David J.

Issue&Volume: 2024-07-05

Abstract: Many variants that we inherit from our parents or acquire de novo or somatically are rare, limiting the precision with which we can associate them with disease. We performed exhaustive saturation genome editing (SGE) of BAP1, the disruption of which is linked to tumorigenesis and altered neurodevelopment. We experimentally characterized 18,108 unique variants, of which 6,196 were found to have abnormal functions, and then used these data to evaluate phenotypic associations in the UK Biobank. We also characterized variants in a large population-ascertained tumor collection, in cancer pedigrees and ClinVar, and explored the behavior of cancer-associated variants compared to that of variants linked to neurodevelopmental phenotypes. Our analyses demonstrated that disruptive germline BAP1 variants were significantly associated with higher circulating levels of the mitogen IGF-1, suggesting a possible pathological mechanism and therapeutic target. Furthermore, we built a variant classifier with >98% sensitivity and specificity and quantify evidence strengths to aid precision variant interpretation.

DOI: 10.1038/s41588-024-01799-3

Source: https://www.nature.com/articles/s41588-024-01799-3