Single-cell genome sequencing of human neurons identifies somatic point mutation and indel enrichment in regulatory elements
| Autor: | Lovelace J. Luquette, Michael B. Miller, Zinan Zhou, Craig L. Bohrson, Yifan Zhao, Hu Jin, Doga Gulhan, Javier Ganz, Sara Bizzotto, Samantha Kirkham, Tino Hochepied, Claude Libert, Alon Galor, Junho Kim, Michael A. Lodato, Juan I. Garaycoechea, Charles Gawad, Jay West, Christopher A. Walsh, Peter J. Park |
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| Přispěvatelé: | Hubrecht Institute for Developmental Biology and Stem Cell Research |
| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: |
Neurons
High-Throughput Nucleotide Sequencing/methods Genome Human/genetics INDEL Mutation/genetics Genome Human Nucleotides High-Throughput Nucleotide Sequencing Biology and Life Sciences Polymorphism Single Nucleotide/genetics Polymorphism Single Nucleotide Article INDEL Mutation Genetics Medicine and Health Sciences Genome Human/genetics Humans Point Mutation Polymorphism Single-Cell Analysis Single Nucleotide/genetics SIGNATURES |
| Zdroj: | Nature Genetics, 54(10), 1564-1571. Nature Publishing Group NATURE GENETICS Nat Genet |
| ISSN: | 1061-4036 1546-1718 |
| Popis: | Single-cell DNA sequencing data are generated from human neurons using primary template-directed amplification and analyzed using SCAN2, an improved genotyping tool. Indels are enriched in neuronal regulatory elements and may be deleterious. 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. |
| Databáze: | OpenAIRE |
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