Identifying pathogenicity of human variants via paralog-based yeast complementation

To better understand the health implications of personal genomes, we now face a largely unmet challenge to identify functional variants within disease-associated genes. Functional variants can be identified by trans-species complementation, e.g., by failure to rescue a yeast strain bearing a mutation in an orthologous human gene. Although orthologous complementation assays are powerful predictors of pathogenic variation, they are available for only a few percent of human disease genes. Here we systematically examine the question of whether complementation assays based on paralogy relationships can expand the number of human disease genes with functional variant detection assays. We tested over 1,000 paralogous human-yeast gene pairs for complementation, yielding 34 complementation relationships, of which 33 (97%) were novel. We found that paralog-based assays identified disease variants with success on par with that of orthology-based assays. Combining all homology-based assay results, ...

为深入解析个人基因组的健康效应，当前我们仍面临一项尚未得到广泛解决的关键挑战：在疾病相关基因中识别功能变异体（functional variants）。功能变异体可通过跨物种互补实验（trans-species complementation）进行识别，例如通过无法互补拯救携带直系同源人类基因（orthologous human gene）突变的酵母菌株来实现。尽管直系同源互补实验（orthologous complementation assays）可有效预测致病变异（pathogenic variation），但目前仅约百分之几的人类疾病基因可开展此类实验。本研究系统探讨了基于旁系同源关系（paralogy relationships）的互补实验能否扩充可开展功能变异检测实验的人类疾病基因的数量。我们针对超过1000组人-酵母旁系同源基因对（paralogous human-yeast gene pairs）开展了互补实验验证，共获得34组互补关系，其中33组（占比97%）为全新发现。研究结果表明，基于旁系同源关系的实验对疾病变异的识别成功率与基于直系同源关系的实验不相上下。综合所有基于同源性的实验（homology-based assay）结果，……