Department of Genetics and Center for Epigenomics, Albert Einstein College of Medicine, New York, New York 10461, USA.
Department of Pediatrics, New York Medical College, Valhalla, New York 10595, USA.
Genome Res. 2018 Jul;28(7):1039-1052. doi: 10.1101/gr.226282.117. Epub 2018 May 17.
Current approaches to detect and characterize mosaic chromosomal aneuploidy are limited by sensitivity, efficiency, cost, or the need to culture cells. We describe the mosaic aneuploidy detection by massively parallel sequencing (MAD-seq) capture assay and the analytical approach that allow low (<10%) levels of mosaicism for chromosomal aneuploidy or regional loss of heterozygosity to be detected, assigned to a meiotic or mitotic origin, and quantified as a proportion of the cells in the sample. We show results from a multi-ethnic MAD-seq (meMAD-seq) capture design that works equally well in populations of diverse racial and ethnic origins and how the analytical approach can be applied to exome or whole-genome sequencing data, revealing previously unrecognized aneuploidy or copy number neutral loss of heterozygosity in samples studied by the 1000 Genomes Project, cell lines from public repositories, and one of the Illumina Platinum Genomes samples. We have made the meMAD-seq capture design and analytical software open for unrestricted use, with the goal that they can be applied in clinical samples to allow new insights into the unrecognized prevalence of mosaic chromosomal aneuploidy in humans and its phenotypic associations.
目前用于检测和表征嵌合体染色体非整倍体的方法在灵敏度、效率、成本或需要培养细胞方面受到限制。我们描述了通过大规模平行测序(MAD-seq)捕获分析来检测嵌合体非整倍体的方法,以及一种分析方法,该方法可以检测到染色体非整倍体或杂合性区域缺失的低水平(<10%)嵌合体,并将其分配到减数分裂或有丝分裂的起源,并以样本中细胞的比例进行定量。我们展示了来自多民族 MAD-seq(meMAD-seq)捕获设计的结果,该设计在不同种族和民族起源的人群中同样有效,以及如何将分析方法应用于外显子组或全基因组测序数据,揭示了先前在 1000 基因组计划、公共存储库中的细胞系以及 Illumina 铂金基因组样本之一中研究的样本中未被识别的非整倍体或拷贝数中性杂合性缺失。我们已经开放了 meMAD-seq 捕获设计和分析软件供无限制使用,目的是将其应用于临床样本中,以深入了解人类中未被识别的嵌合体染色体非整倍体的流行程度及其表型相关性。