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

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

doi:10.1038/s41588-022-01180-2

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

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

Hubrecht Institute

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28 Citaten (Scopus)

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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.

Originele taal-2	Engels
Pagina's (van-tot)	1564-1571
Aantal pagina's	8
Tijdschrift	Nature Genetics
Volume	54
Nummer van het tijdschrift	10
DOI's	https://doi.org/10.1038/s41588-022-01180-2
Status	Gepubliceerd - okt. 2022

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10.1038/s41588-022-01180-2

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Luquette, L. J., Miller, M. B., Zhou, Z., Bohrson, C. L., Zhao, Y., Jin, H., Gulhan, D., Ganz, J., Bizzotto, S., Kirkham, S., Hochepied, T., Libert, C., Galor, A., Kim, J., Lodato, M. A., Garaycoechea, J. I., Gawad, C., West, J., Walsh, C. A., & Park, P. J. (2022). Single-cell genome sequencing of human neurons identifies somatic point mutation and indel enrichment in regulatory elements. Nature Genetics, 54(10), 1564-1571. https://doi.org/10.1038/s41588-022-01180-2

@article{c32b40dbe71945a18319adee9a8a4292,

title = "Single-cell genome sequencing of human neurons identifies somatic point mutation and indel enrichment in regulatory elements",

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.",

keywords = "Genome, Human/genetics, High-Throughput Nucleotide Sequencing/methods, Humans, INDEL Mutation/genetics, Neurons, Nucleotides, Point Mutation, Polymorphism, Single Nucleotide/genetics, Single-Cell Analysis",

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

note = "{\textcopyright} 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2022",

month = oct,

doi = "10.1038/s41588-022-01180-2",

language = "English",

volume = "54",

pages = "1564--1571",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "10",

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Luquette, LJ, Miller, MB, Zhou, Z, Bohrson, CL, Zhao, Y, Jin, H, Gulhan, D, Ganz, J, Bizzotto, S, Kirkham, S, Hochepied, T, Libert, C, Galor, A, Kim, J, Lodato, MA, Garaycoechea, JI, Gawad, C, West, J, Walsh, CA & Park, PJ 2022, 'Single-cell genome sequencing of human neurons identifies somatic point mutation and indel enrichment in regulatory elements', Nature Genetics, vol. 54, nr. 10, blz. 1564-1571. https://doi.org/10.1038/s41588-022-01180-2

Single-cell genome sequencing of human neurons identifies somatic point mutation and indel enrichment in regulatory elements. / Luquette, Lovelace J; Miller, Michael B; Zhou, Zinan et al.
In: Nature Genetics, Vol. 54, Nr. 10, 10.2022, blz. 1564-1571.

Onderzoeksoutput: Bijdrage aan wetenschappelijk tijdschrift/periodieke uitgave › Artikel › Wetenschappelijk › peer review

TY - JOUR

T1 - Single-cell genome sequencing of human neurons identifies somatic point mutation and indel enrichment in regulatory elements

AU - Luquette, Lovelace J

AU - Miller, Michael B

AU - Zhou, Zinan

AU - Bohrson, Craig L

AU - Zhao, Yifan

AU - Jin, Hu

AU - Gulhan, Doga

AU - Ganz, Javier

AU - Bizzotto, Sara

AU - Kirkham, Samantha

AU - Hochepied, Tino

AU - Libert, Claude

AU - Galor, Alon

AU - Kim, Junho

AU - Lodato, Michael A

AU - Garaycoechea, Juan I

AU - Gawad, Charles

AU - West, Jay

AU - Walsh, Christopher A

AU - Park, Peter J

PY - 2022/10

Y1 - 2022/10

N2 - 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.

AB - 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.

KW - Genome, Human/genetics

KW - High-Throughput Nucleotide Sequencing/methods

KW - Humans

KW - INDEL Mutation/genetics

KW - Neurons

KW - Nucleotides

KW - Point Mutation

KW - Polymorphism, Single Nucleotide/genetics

KW - Single-Cell Analysis

U2 - 10.1038/s41588-022-01180-2

DO - 10.1038/s41588-022-01180-2

M3 - Article

C2 - 36163278

SN - 1061-4036

VL - 54

SP - 1564

EP - 1571

JO - Nature Genetics

JF - Nature Genetics

IS - 10

ER -

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

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