小柯机器人

美国哈佛医学院Peter J. Park和美国波士顿儿童医院Christopher A. Walsh团队共同合作近期取得重要工作成果。他们研究利用人类神经元的单细胞基因组测序识别调控元件中富集的体细胞点突变和插入缺失突变。这一研究成果2022年9月26日在线发表于《自然—遗传学》上。

研究人员使用SCAN2分析了来自52个PTA扩增的单个神经元的全基因组测序数据，SCAN2是他们开发的一种新的基因分型仪，用于利用突变特征和等位基因平衡来识别PTA数据中的体细胞单核苷酸变异（SNVs）和小的片段插入及缺失（indels）。他们的分析证实随着年龄增长，单个神经元中非克隆体细胞突变会增加，但将这种积累的估计速率修正为每年16个SNV。研究人员还识别其他放大方法中的假象。

最重要的是，他们发现体细胞indels每个神经元每年至少增加三个，并且富含基因组的功能区域，例如增强子和启动子。他们的数据表明，基因调控元件中的indels对人类神经元的基因组完整性有相当大的影响。

据介绍，由于扩增相关的假象，从单细胞DNA测序中准确检测体细胞突变是具有挑战性的。为了减少这种假象负担，研究人员引入了一种改进的扩增技术，即初级模板定向扩增（PTA）。

附：英文原文

Title: Single-cell genome sequencing of human neurons identifies somatic point mutation and indel enrichment in regulatory elements

Author: Luquette, Lovelace J., Miller, Michael B., Zhou, Zinan, Bohrson, Craig L., Zhao, Yifan, Jin, Hu, Gulhan, Doga, Ganz, Javier, Bizzotto, Sara, Kirkham, Samantha, Hochepied, Tino, Libert, Claude, Galor, Alon, Kim, Junho, Lodato, Michael A., Garaycoechea, Juan I., Gawad, Charles, West, Jay, Walsh, Christopher A., Park, Peter J.

Issue&Volume: 2022-09-26

Abstract: Accurate somatic mutation detection from single-cell DNA sequencing is challenging due to amplification-related artifacts. To reduce this artifact burden, an improved amplification technique, primary template-directed amplification (PTA), was recently introduced. We analyzed whole-genome sequencing data from 52 PTA-amplified single neurons using SCAN2, a new genotyper we developed to leverage mutation signatures and allele balance in identifying somatic single-nucleotide variants (SNVs) and small insertions and deletions (indels) in PTA data. Our analysis confirms an increase in nonclonal somatic mutation in single neurons with age, but revises the estimated rate of this accumulation to 16 SNVs per year. We also identify artifacts in other amplification methods. Most importantly, we show that somatic indels increase by at least three per year per neuron and are enriched in functional regions of the genome such as enhancers and promoters. Our data suggest that indels in gene-regulatory elements have a considerable effect on genome integrity in human neurons.

DOI: 10.1038/s41588-022-01180-2

Source: https://www.nature.com/articles/s41588-022-01180-2

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
官方网址：https://www.nature.com/ng/
投稿链接：https://mts-ng.nature.com/cgi-bin/main.plex