Interrogating the Human Diplome: Computational Methods, Emerging Applications, and Challenges.
Interrogating the Human Diplome: Computational Methods, Emerging Applications, and Challenges.
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DOI：
10.1007/978-1-0716-2819-5_1
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发表时间：
2023-01-01
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影响因子：
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通讯作者：
Schork, Nicholas J
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文献类型：
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作者：
Chan, Agnes P;Choi, Yongwook;Schork, Nicholas J
人类DNA测序方案已经彻底改变了人类生物学、生物医学科学和临床实践，但仍然存在非常重要的局限性。其中一个局限是，大多数方案不会分离或组装（即“定相”）构成22对常染色体以及性染色体假常染色体区域的染色体对中来自母本和父本的每条染色体同源物的核苷酸内容。这导致相关研究匮乏，进而使得许多对基础和临床基因组科学具有根本重要性的现象未得到充分重视。我们讨论了一些获取定相信息的方案及其局限性，包括那些可用于肿瘤定相环境的方案。然后，我们描述了一些需要定相信息的生物学和临床现象。这些现象包括需要精确了解生殖细胞或体细胞染色体片段中核苷酸序列的情况，比如DNA结合事件，以及深入了解独特的顺式与反式作用且具有功能影响的变异组合——例如，与复合杂合性所控制的表型有关的变异。此外，我们还评论了对于可靠且基于共识的二倍体背景下变异识别计算流程的需求，以及对于验证变异组合顺式与反式效应的基于实验室的功能验证策略的需求。我们还简要描述了可用资源、示例研究以及进一步研究的领域，并最终提出，人类二倍体研究背后的科学，被称为“二倍体组学”，它将通过定相基因组的核苷酸水平分辨率得以实现，是人类基因组生物学分析中合乎逻辑的下一步。
Human DNA sequencing protocols have revolutionized human biology, biomedical science, and clinical practice, but still have very important limitations. One limitation is that most protocols do not separate or assemble (i.e., "phase") the nucleotide content of each of the maternally and paternally derived chromosomal homologs making up the 22 autosomal pairs and the chromosomal pair making up the pseudo-autosomal region of the sex chromosomes. This has led to a dearth of studies and a consequent underappreciation of many phenomena of fundamental importance to basic and clinical genomic science. We discuss a few protocols for obtaining phase information as well as their limitations, including those that could be used in tumor phasing settings. We then describe a number of biological and clinical phenomena that require phase information. These include phenomena that require precise knowledge of the nucleotide sequence in a chromosomal segment from germline or somatic cells, such as DNA binding events, and insight into unique cis vs. trans-acting functionally impactful variant combinations-for example, variants implicated in a phenotype governed by compound heterozygosity. In addition, we also comment on the need for reliable and consensus-based diploid-context computational workflows for variant identification as well as the need for laboratory-based functional verification strategies for validating cis vs. trans effects of variant combinations. We also briefly describe available resources, example studies, as well as areas of further research, and ultimately argue that the science behind the study of human diploidy, referred to as "diplomics," which will be enabled by nucleotide-level resolution of phased genomes, is a logical next step in the analysis of human genome biology.