Bioinformatics Research and Development Laboratory, Genomic Sciences and Precision Medicine Center, Milwaukee, WI 53226, USA.
Precision Medicine Simulation Unit, Genomic Sciences and Precision Medicine Center, Milwaukee, WI 53226, USA.
Bioinformatics. 2021 Jun 16;37(10):1367-1375. doi: 10.1093/bioinformatics/btaa972.
Protein-coding genetic alterations are frequently observed in Clinical Genetics, but the high yield of variants of uncertain significance remains a limitation in decision making. RAS-family GTPases are cancer drivers, but only 54 variants, across all family members, fall within well-known hotspots. However, extensive sequencing has identified 881 non-hotspot variants for which significance remains to be investigated.
Here, we evaluate 935 missense variants from seven RAS genes, observed in cancer, RASopathies and the healthy adult population. We characterized hotspot variants, previously studied experimentally, using 63 sequence- and 3D structure-based scores, chosen by their breadth of biophysical properties. Applying scores that display best correlation with experimental measures, we report new valuable mechanistic inferences for both hot-spot and non-hotspot variants. Moreover, we demonstrate that 3D scores have little-to-no correlation with those based on DNA sequence, which are commonly used in Clinical Genetics. Thus, combined, these new knowledge bear significant relevance.
All genomic and 3D scores, and markdown for generating figures, are provided in our supplemental data.
Supplementary data are available at Bioinformatics online.
蛋白质编码基因突变在临床遗传学中经常被观察到，但不确定意义的变异的高产量仍然是决策制定的一个限制。RAS 家族 GTPases 是癌症驱动因素，但只有 54 个变体，跨越所有家族成员，属于已知的热点。然而，广泛的测序已经确定了 881 个非热点变体，其意义仍有待研究。
在这里，我们评估了来自七个 RAS 基因的 935 个错义变体，这些变体在癌症、RAS 病和健康成年人中被观察到。我们用 63 个序列和 3D 结构的评分来描述以前在实验中研究过的热点变体，这些评分是根据其广泛的生物物理特性选择的。应用与实验测量相关性最好的评分，我们报告了新的有价值的热点和非热点变体的机制推断。此外，我们证明 3D 评分与临床遗传学中常用的基于 DNA 序列的评分几乎没有相关性。因此，这些新知识的综合具有重要意义。
所有的基因组和 3D 评分，以及生成图形的标记，都在我们的补充数据中提供。
补充数据可在生物信息学在线获得。
