Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA 22903, USA.
Department of Biological Sciences, Clemson University, Clemson, SC 29631, USA.
Nucleic Acids Res. 2024 May 8;52(8):4409-4421. doi: 10.1093/nar/gkae258.
Gene fusions and their chimeric products are commonly linked with cancer. However, recent studies have found chimeric transcripts in non-cancer tissues and cell lines. Large-scale efforts to annotate structural variations have identified gene fusions capable of generating chimeric transcripts even in normal tissues. In this study, we present a bottom-up approach targeting population-specific chimeric RNAs, identifying 58 such instances in the GTEx cohort, including notable cases such as SUZ12P1-CRLF3, TFG-ADGRG7 and TRPM4-PPFIA3, which possess distinct patterns across different ancestry groups. We provide direct evidence for an additional 29 polymorphic chimeric RNAs with associated structural variants, revealing 13 novel rare structural variants. Additionally, we utilize the All of Us dataset and a large cohort of clinical samples to characterize the association of the SUZ12P1-CRLF3-causing variant with patient phenotypes. Our study showcases SUZ12P1-CRLF3 as a representative example, illustrating the identification of elusive structural variants by focusing on those producing population-specific fusion transcripts.
基因融合及其嵌合产物通常与癌症有关。然而，最近的研究在非癌组织和细胞系中发现了嵌合转录本。大规模注释结构变异的努力已经确定了即使在正常组织中也能产生嵌合转录本的基因融合。在这项研究中，我们提出了一种针对人群特异性嵌合 RNA 的自下而上的方法，在 GTEx 队列中鉴定出 58 个这样的实例，包括 SUZ12P1-CRLF3、TFG-ADGRG7 和 TRPM4-PPFIA3 等显著的例子，它们在不同的祖系群体中具有不同的模式。我们提供了另外 29 个具有相关结构变异的多态性嵌合 RNA 的直接证据，揭示了 13 个新的罕见结构变异。此外，我们利用 All of Us 数据集和大量临床样本，描述了导致 SUZ12P1-CRLF3 的变异与患者表型的关联。我们的研究以 SUZ12P1-CRLF3 为例，说明了通过关注产生人群特异性融合转录本的变异来识别难以捉摸的结构变异的方法。
