Functional SNP allele discovery (fSNPd): an approach to find highly penetrant, environmental-triggered genotypes underlying complex human phenotypes.
Functional SNP allele discovery (fSNPd): an approach to find highly penetrant, environmental-triggered genotypes underlying complex human phenotypes.
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DOI：
10.1186/s12864-017-4325-y
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发表时间：
2017-12-04
期刊：
影响因子：
4.4
通讯作者：
Geoffrey Woods C
中科院分区：
文献类型：
--
作者：
Stouffer K;Nahorski M;Moreno P;Sarveswaran N;Menon D;Lee M;Geoffrey Woods C
存在显著的人类疾病/表型，其在疾病/表型出现之前需要环境触发事件和遗传易感性，例如具有rs3909184的罕见SNP等位基因的卡马西平引起史蒂文斯约翰逊综合征，和具有rs 267606617的氨基糖苷类引起感觉神经耳聋。只有当正确的环境触发发生时，潜在的基因型才完全渗透，否则它们是沉默和无害的。这些疾病/表型不会出现孟德尔遗传模式，除非环境触发因素非常常见（每个人一生>50%）。已知的致病基因型可能是具有显性/半显性效应的蛋白质改变SNP。我们质疑其他疾病和表型是否有类似的病因。我们编写了fSNPd程序来同时分析来自测试队列的多个外显子组，目的是以与普通人群显著不同的频率鉴定SNP等位基因。在试验队列中测试fSNPd，迭代改进，并在多参数下针对理想化关联研究进行性能建模。我们还评估了所有人类外显子的测序路径，以确定哪些外显子在外显子组中被fSNPd充分测序-通过逐个碱基评估40个外显子组。我们描述了一种简单的方法，用于检测能够引起由环境事件触发的表型的SNP。这使用具有被研究的表型的相对小规模（30-100个个体）的组群，其外显子组，并由此寻找与预期显著不同的SNP等位基因频率，以鉴定潜在临床重要的蛋白质改变SNP等位基因。这种方法发现人类疾病的重要遗传原因的优点和缺点与孟德尔疾病突变检测和关联研究相当。fSNPd方法是另一种方法，并且在需要少得多的个体来检测疾病/表型的发病机制中涉及的基因方面比关联研究具有潜在的显著优势。此外，所鉴定的SNP等位基因改变氨基酸，可能使设计蛋白质功能的功能测定以确定致病性更容易。本文的在线版本（10.1186/s12864-017-4325-y）包含补充材料，可供授权用户使用。
Significant human diseases/phenotypes exist which require both an environmental trigger event and a genetic predisposition before the disease/phenotype emerges, e.g. Carbamazepine with the rare SNP allele of rs3909184 causing Stevens Johnson syndrome, and aminoglycosides with rs267606617 causing sensory neural deafness. The underlying genotypes are fully penetrant only when the correct environmental trigger(s) occur, otherwise they are silent and harmless. Such diseases/phenotypes will not appear to have a Mendelian inheritance pattern, unless the environmental trigger is very common (>50% per lifetime). The known causative genotypes are likely to be protein-altering SNPs with dominant/semi-dominant effect. We questioned whether other diseases and phenotypes could have a similar aetiology. We wrote the fSNPd program to analyse multiple exomes from a test cohort simultaneously with the purpose of identifying SNP alleles at a significantly different frequency to that of the general population. fSNPd was tested on trial cohorts, iteratively improved, and modelled for performance against an idealised association study under mutliple parameters. We also assessed the seqeuncing depath of all human exons to determine which were sufficiently well sequenced in an exome to be sued by fSNPd - by assessing forty exomes base by base. We describe a simple methodology for the detection of SNPs capable of causing a phenotype triggered by an environmental event. This uses cohorts of relatively small size (30–100 individuals) with the phenotype being investigated, their exomes, and thence seeks SNP allele frequencies significantly different from expected to identify potentially clinically important, protein altering SNP alleles. The strengths and weaknesses of this approach for discovering significant genetic causes of human disease are comparable to Mendelian disease mutation detection and Association Studies. The fSNPd methodology is another approach, and has potentially significant advantage over Association studies in needing far fewer individuals, to detect genes involved in the pathogenesis of a diseases/phenotypes. Furthermore, the SNP alleles identified alter amino acids, potentially making it easier to devise functional assays of protein function to determine pathogenicity. The online version of this article (10.1186/s12864-017-4325-y) contains supplementary material, which is available to authorized users.
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