小柯机器人

美国西奈山伊坎医学院Kristen J. Brennand等研究人员讨论了脑疾病研究中的复杂遗传结构建模。该观点论文于2020年3月23日在线发表在《自然—遗传学》杂志上。

研究人员表示，每个个体的遗传结构均包含共同或罕见的变体，这些变体单独或组合发挥作用，从而产生疾病风险。风险变体与脑疾病存在关联，这些风险变体产生的细胞类型特异性和/或背景依赖性功能后果必须得以解决。

人类诱导型多能干细胞（hiPSC）技术与CRISPR基因组工程的结合可以在遗传背景下对变异体进行精确的等基因比较。尽管功能验证研究通常是一次只对一种变异体以及在一种细胞类型中进行，但复杂的遗传疾病需要多重基因扰动来研究基因的组合并解决生理相关的疾病生物学问题。

研究人员讨论了基因组学、hiPSC和CRISPR交叉领域的进展。更好地了解潜在疾病风险的分子机制将改善遗传诊断、推动表型药物发现并为精准医学铺平道路。

附：英文原文

Title: Modeling the complex genetic architectures of brain disease

Author: Michael B. Fernando, Tim Ahfeldt, Kristen J. Brennand

Issue&Volume: 2020-03-23

Abstract: The genetic architecture of each individual comprises common and rare variants that, acting alone and in combination, confer risk of disease. The cell-type-specific and/or context-dependent functional consequences of the risk variants linked to brain disease must be resolved. Coupling human induced pluripotent stem cell (hiPSC)-based technology with CRISPR-based genome engineering facilitates precise isogenic comparisons of variants across genetic backgrounds. Although functional-validation studies are typically performed on one variant in isolation and in one cell type at a time, complex genetic diseases require multiplexed gene perturbations to interrogate combinations of genes and resolve physiologically relevant disease biology. Our aim is to discuss advances at the intersection of genomics, hiPSCs and CRISPR. A better understanding of the molecular mechanisms underlying disease risk will improve genetic diagnosis, drive phenotypic drug discovery and pave the way toward precision medicine.

DOI: 10.1038/s41588-020-0596-3

Source: https://www.nature.com/articles/s41588-020-0596-3

Nature Genetics：《自然—遗传学》，创刊于1992年。隶属于施普林格·自然出版集团，最新IF：41.307
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