Massively parallel approaches for characterizing noncoding functional variation in human evolution

IF 3.7 2区 生物学 Q2 CELL BIOLOGY Current Opinion in Genetics & Development Pub Date : 2024-08-31 DOI:10.1016/j.gde.2024.102256
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Abstract

The genetic differences underlying unique phenotypes in humans compared to our closest primate relatives have long remained a mystery. Similarly, the genetic basis of adaptations between human groups during our expansion across the globe is poorly characterized. Uncovering the downstream phenotypic consequences of these genetic variants has been difficult, as a substantial portion lies in noncoding regions, such as cis-regulatory elements (CREs). Here, we review recent high-throughput approaches to measure the functions of CREs and the impact of variation within them. CRISPR screens can directly perturb CREs in the genome to understand downstream impacts on gene expression and phenotypes, while massively parallel reporter assays can decipher the regulatory impact of sequence variants. Machine learning has begun to be able to predict regulatory function from sequence alone, further scaling our ability to characterize genome function. Applying these tools across diverse phenotypes, model systems, and ancestries is beginning to revolutionize our understanding of noncoding variation underlying human evolution.

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用大规模并行方法描述人类进化中的非编码功能变异
与灵长类近亲相比,人类独特表型的遗传差异一直是个谜。同样,在人类向全球扩张的过程中,人类群体之间适应性的遗传基础也没有得到很好的描述。揭示这些遗传变异的下游表型后果一直很困难,因为其中很大一部分位于非编码区,如顺式调控元件(CRE)。在此,我们回顾了最近用于测量 CREs 功能及其变异影响的高通量方法。CRISPR 筛选可以直接扰乱基因组中的 CREs,从而了解其对基因表达和表型的下游影响,而大规模并行报告测定则可以破译序列变异对调控的影响。机器学习已开始能够仅通过序列预测调控功能,进一步提高了我们描述基因组功能的能力。将这些工具应用于不同的表型、模型系统和祖先,正开始彻底改变我们对人类进化背后的非编码变异的理解。
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来源期刊
CiteScore
7.90
自引率
0.00%
发文量
102
审稿时长
1 months
期刊介绍: Current Opinion in Genetics and Development aims to stimulate scientifically grounded, interdisciplinary, multi-scale debate and exchange of ideas. It contains polished, concise and timely reviews and opinions, with particular emphasis on those articles published in the past two years. In addition to describing recent trends, the authors are encouraged to give their subjective opinion of the topics discussed. In Current Opinion in Genetics and Development we help the reader by providing in a systematic manner: 1. The views of experts on current advances in their field in a clear and readable form. 2. Evaluations of the most interesting papers, annotated by experts, from the great wealth of original publications.[...] The subject of Genetics and Development is divided into six themed sections, each of which is reviewed once a year: • Cancer Genomics • Genome Architecture and Expression • Molecular and genetic basis of disease • Developmental mechanisms, patterning and evolution • Cell reprogramming, regeneration and repair • Genetics of Human Origin / Evolutionary genetics (alternate years)
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