Leveraging the T2T assembly to resolve rare and pathogenic inversions in reference genome gaps

IF 6.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Genome research Pub Date : 2024-11-01 DOI:10.1101/gr.279346.124
Kristine Bilgrav Saether, Jesper Eisfeldt, Jesse D. Bengtsson, Ming Yin Lun, Christopher M. Grochowski, Medhat Mahmoud, Hsiao-Tuan Chao, Jill A. Rosenfeld, Pengfei Liu, Marlene Ek, Jakob Schuy, Adam Ameur, Hongzheng Dai, Undiagnosed Diseases Network, James Paul Hwang, Fritz J. Sedlazeck, Weimin Bi, Ronit Marom, Josephine Wincent, Ann Nordgren, Claudia M.B. Carvalho, Anna Lindstrand
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Abstract

Chromosomal inversions (INVs) are particularly challenging to detect due to their copy-number neutral state and association with repetitive regions. Inversions represent about 1/20 of all balanced structural chromosome aberrations and can lead to disease by gene disruption or altering regulatory regions of dosage-sensitive genes in cis. Short-read genome sequencing (srGS) can only resolve ∼70% of cytogenetically visible inversions referred to clinical diagnostic laboratories, likely due to breakpoints in repetitive regions. Here, we study 12 inversions by long-read genome sequencing (lrGS) (n = 9) or srGS (n = 3) and resolve nine of them. In four cases, the inversion breakpoint region was missing from at least one of the human reference genomes (GRCh37, GRCh38, T2T-CHM13) and a reference agnostic analysis was needed. One of these cases, an INV9 mappable only in de novo assembled lrGS data using T2T-CHM13 disrupts EHMT1 consistent with a Mendelian diagnosis (Kleefstra syndrome 1; MIM#610253). Next, by pairwise comparison between T2T-CHM13, GRCh37, and GRCh38, as well as the chimpanzee and bonobo, we show that hundreds of megabases of sequence are missing from at least one human reference, highlighting that primate genomes contribute to genomic diversity. Aligning population genomic data to these regions indicated that these regions are variable between individuals. Our analysis emphasizes that T2T-CHM13 is necessary to maximize the value of lrGS for optimal inversion detection in clinical diagnostics. These results highlight the importance of leveraging diverse and comprehensive reference genomes to resolve unsolved molecular cases in rare diseases.
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利用 T2T 组装解决参考基因组间隙中的罕见和致病倒位问题
染色体倒位(INVs)由于其拷贝数中性状态和与重复区的关联,检测起来特别具有挑战性。倒位约占所有平衡染色体结构畸变的 1/20,可通过基因中断或改变顺式剂量敏感基因的调控区而导致疾病。短读基因组测序(srGS)只能解决临床诊断实验室转来的70%细胞遗传学上可见的倒位,这可能是由于重复区域的断点造成的。在这里,我们通过长线程基因组测序(lrGS)(n = 9)或 srGS(n = 3)研究了 12 例倒位,并解决了其中的 9 例。在四个案例中,反转断点区域在至少一个人类参考基因组(GRCh37、GRCh38、T2T-CHM13)中缺失,因此需要进行参考不可知分析。在这些病例中,有一个 INV9 仅在使用 T2T-CHM13 的从头组装 lrGS 数据中可映射,它破坏了 EHMT1,与孟德尔诊断一致(Kleefstra 综合征 1;MIM#610253)。接下来,通过对 T2T-CHM13、GRCh37 和 GRCh38 以及黑猩猩和倭黑猩猩进行配对比较,我们发现至少有一个人类参考文献缺失了数百兆字节的序列,这突出表明灵长类动物基因组对基因组多样性做出了贡献。将群体基因组数据与这些区域进行比对表明,这些区域在不同个体之间存在差异。我们的分析强调,T2T-CHM13 对临床诊断中的最佳反转检测来说,是最大化 lrGS 价值的必要条件。这些结果突显了利用多样化和全面的参考基因组解决罕见病未解决的分子病例的重要性。
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来源期刊
Genome research
Genome research 生物-生化与分子生物学
CiteScore
12.40
自引率
1.40%
发文量
140
审稿时长
6 months
期刊介绍: Launched in 1995, Genome Research is an international, continuously published, peer-reviewed journal that focuses on research that provides novel insights into the genome biology of all organisms, including advances in genomic medicine. Among the topics considered by the journal are genome structure and function, comparative genomics, molecular evolution, genome-scale quantitative and population genetics, proteomics, epigenomics, and systems biology. The journal also features exciting gene discoveries and reports of cutting-edge computational biology and high-throughput methodologies. New data in these areas are published as research papers, or methods and resource reports that provide novel information on technologies or tools that will be of interest to a broad readership. Complete data sets are presented electronically on the journal''s web site where appropriate. The journal also provides Reviews, Perspectives, and Insight/Outlook articles, which present commentary on the latest advances published both here and elsewhere, placing such progress in its broader biological context.
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