蛋白截断变异（protein-truncating variant，PTV）

蛋白截断变异（protein-truncating variant，PTV）通过引入终止密码子，移码突变或剪接位点，破坏蛋白编码基因[1]。蛋白截断变异的研究对于人类进化（human evolution），基因功能（gene function），疾病相关变异（disease-related variants）和疾病患者变异的临床解读（Clinical interpretation of variants in patients with disease）有着重要作用[2-7]。由于蛋白截断变异普遍为罕见突变，大规模人群的研究十分有必要。过万的样本量才适合有统计学功效（power）的蛋白截断变异研究。目前最大的蛋白截断研究来源于Broad研究所Daniel MacArthur教授的6万人ExAC人类外显子组整合数据库（ExAC Exome Aggregation Consortium）[2]。

 

 

 

 

 

1. Rivas MA, Pirinen M, Conrad DF, et al. Human genomics. Effect of predicted protein-truncating genetic variants on the human transcriptome. Science. 2015;348(6235):666-9.
2. 2. Exome Aggregation Consortium, Lek M, Karczewski KJ, et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature. 2016;536(7616):285-291. doi:10.1038/nature19057.
3. 3. Cassa CA, Weghorn D, Balick DJ, et al. Estimating the selective effects of heterozygous protein-truncating variants from human exome data. Nat Genet. 2017;49(5):806-810.
4. 4. MacArthur DG, Tyler-Smith C. Loss-of-function variants in the genomes of healthy humans. Hum Mol Genet. 2010;19(R2):R125-30.
5. 5. Bartha, I., di Iulio, J., Venter, J. C. & Telenti, A. Human gene essentiality. Nat. Rev. Genet. 19, 51–62 (2018).
6. 6. Ganna, A., Satterstrom, K., Zekavat, S., Das, I., Kurki, M., Churchhouse, C., & Neale, B. (2018). Quantifying the impact of rare and ultra-rare coding variation across the phenotypic spectrum. Am J Hum Genet, 102(6), 1204–1211. 
7. 7. Tarailo-Graovac M, Shyr C, Ross CJ, et al. Exome Sequencing and the Management of Neurometabolic Disorders. N Engl J Med. 2016;374(23):2246-55.