Large-scale sequencing efforts in amyotrophic lateral sclerosis (ALS) have implicated novel genes using gene-based collapsing methods. However, pathogenic mutations may be concentrated in specific genic regions. To address this, we developed two collapsing strategies: One focuses rare variation collapsing on homology-based protein domains as the unit for collapsing, and the other is a gene-level approach that, unlike standard methods, leverages existing evidence of purifying selection against missense variation on said domains. The application of these two collapsing methods to 3093 ALS cases and 8186 controls of European ancestry, and also 3239 cases and 11,808 controls of diversified populations, pinpoints risk regions of ALS genes, including SOD1, NEK1, TARDBP, and FUS While not clearly implicating novel ALS genes, the new analyses not only pinpoint risk regions in known genes but also highlight candidate genes as well.

中文翻译：

---

一种在功能蛋白域上折叠罕见变异的新方法涉及 ALS 中的特定基因区域。

肌萎缩性侧索硬化症 (ALS) 的大规模测序工作已经涉及使用基于基因的折叠方法的新基因。然而，致病突变可能集中在特定的基因区域。为了解决这个问题，我们开发了两种折叠策略：一种侧重于将基于同源性的蛋白质结构域折叠为折叠单位的罕见变异，另一种是基因水平的方法，与标准方法不同，它利用现有的证据来纯化选择以防止错义所述域的变化。将这两种折叠方法应用于欧洲血统的 3093 个 ALS 病例和 8186 个对照，以及多样化人群的 3239 个病例和 11,808 个对照，确定了 ALS 基因的风险区域，包括 SOD1、NEK1、TARDBP 和 FUS 虽然没有明确暗示新肌萎缩侧索硬化基因，