Different mutational rates and mechanisms in human cells at pregastrulation and neurogenesis

Bae, Taejeong; Tomasini, Livia; Mariani, Jessica; Zhou, Bo; Roychowdhury, Tanmoy; Franjic, Daniel; Pletikos, Mihovil; Pattni, Reenal; Chen, Bo Juen; Venturini, Elisa; Riley-Gillis, Bridget; Šestan, Nenad; Urban, Alexander; Abyzov, Alexej; Vaccarino, Flora M.

doi:10.1126/science.aan8690

Cited by 222 publications

(267 citation statements)

References 42 publications

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“…It does face intrinsic limitations, including low throughput, high failure rates of SCNT, low rates of mitotic growth of the newly created cells, incompatibility with humans in requiring the use of laboratory mice, and in some cases a need to generate cloned mice, a process that likely excludes interrogation of cells with highly altered genomes (e.g., aneuploid neurons). Nevertheless, these results demonstrated that individual mitral neurons contain hundreds of unique SNVs, and considering the relatively shorter lifespan of mice vs. humans, the numbers of SNVs in mice are generally consistent with the thousands observed in older human neurons in which SNVs appear to increase with age (Bae et al, ; Lodato et al, ), albeit based upon very few neurons assessed with all of these techniques.…”

Section: Introductionsupporting

confidence: 71%

“…Also proposed to occur during neurogenesis, mosaic LINE1 insertions, as discussed in a previous section, are theoretically capable of generating GM during the cell cycle (Packer et al, ; Muotri et al, ; Shi et al, ; Singer et al, ; Viollet et al, ; Mita et al, ). By contrast, many neural somatic SNVs have been associated with damage due to transcriptional activity (Lodato et al, ), consistent with increased SNV rates in aged brains (Bae et al, ; Lodato et al, ), suggesting this form of GM is generated in postmitotic neurons. It is entirely possible that other mechanisms could contribute to neural GM, including hypothesized gene recombination, which awaits further investigation.…”

Section: Introductionmentioning

confidence: 75%

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Genomic mosaicism in the developing and adult brain

Rohrback

Siddoway

Liu

et al. 2018

Developmental Neurobiology

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Since the discovery of DNA, the normal developing and functioning brain has been assumed to be composed of cells with identical genomes, which remains the dominant view even today. However, this pervasive assumption is incorrect, as proven by increasing numbers of reports within the last 20 years that have identified multiple forms of somatically produced genomic mosaicism (GM), wherein brain cells – especially neurons – from a single individual show diverse alterations in DNA, distinct from the germline. Critically, these changes alter the actual DNA nucleotide sequences – in contrast to epigenetic mechanisms – and almost certainly contribute to the remarkably diverse phenotypes of single brain cells, including single-cell transcriptomic profiles. Here we review the history of GM within the normal brain, including its major forms, initiating mechanisms, and possible functions. GM forms include aneuploidies and aneusomies, smaller copy number variations (CNVs), long interspersed nuclear element type 1 (LINE1) repeat elements, and single nucleotide variations (SNVs), as well as DNA content variation (DCV) that reflects all forms of GM with greatest coverage of large, brain cell populations. In addition, technical considerations are examined, along with relationships amongst GM forms and multiple brain diseases. GM affecting genes and loci within the brain contrast with current neural discovery approaches that rely on sequencing non-brain DNA (e.g., genome-wide association studies (GWAS)). Increasing knowledge of neural GM has implications for mechanisms of development, diversity, and function, as well as understanding diseases, particularly the overwhelming prevalence of sporadic brain GM unlinked to germline mutations.

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Section: Introductionsupporting

confidence: 71%

Section: Introductionmentioning

confidence: 75%

Genomic mosaicism in the developing and adult brain

Rohrback

Siddoway

Liu

et al. 2018

Developmental Neurobiology

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“…A very recent study of clonally expanded human foetal forebrain cells has shown 200‐400 SNVs in each. The mutation rate during neurogenesis was estimated at 5.1 per day per progenitor, and was higher than in the first few cell divisions .…”

Section: Note Addedmentioning

confidence: 94%

Review: Somatic mutations in neurodegeneration

Leija‐Salazar

Piette

Proukakis

2018

Neuropathology Appl Neurobio

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Somatic mutations are postzygotic mutations which may lead to mosaicism, the presence of cells with genetic differences in an organism. Their role in cancer is well established, but detailed investigation in health and other diseases has only been recently possible. This has been empowered by the improvements of sequencing techniques, including single‐cell sequencing, which can still be error‐prone but is rapidly improving. Mosaicism appears relatively common in the human body, including the normal brain, probably arising in early development, but also potentially during ageing. In this review, we first discuss theoretical considerations and current evidence relevant to somatic mutations in the brain. We present a framework to explain how they may be integrated with current views on neurodegeneration, focusing mainly on sporadic late‐onset neurodegenerative diseases (Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis). We review the relevant studies so far, with the first evidence emerging in Alzheimer's in particular. We also discuss the role of mosaicism in inherited neurodegenerative disorders, particularly somatic instability of tandem repeats. We summarize existing views and data to present a model whereby the time of origin and spatial distribution of relevant somatic mutations, combined with any additional risk factors, may partly determine the development and onset age of sporadic neurodegenerative diseases.

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“…We tested RetroSom in several independent WGS datasets. Data from clonally expanded fetal brain cells 24 confirmed that ≥ 2 supporting reads are necessary for high precision (L1: 99.97%; Alu: 99.99%) with adequate sensitivity (L1: 49.5%; Alu: 82.52%) ( Fig. 2A and Supplementary Note 1).…”

Section: Performance Evaluation On Three Independent Datasetsmentioning

confidence: 71%

Machine learning reveals bilateral distribution of somatic L1 insertions in human neurons and glia

Zhu

Zhou

Pattni

et al. 2019

Preprint

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Active retrotransposons in the human genome (L1, Alu and SVA elements) can create genomic mobile element insertions (MEIs) in both germline and somatic tissue 1 . Specific somatic MEIs have been detected at high levels in human cancers 2 , and at lower to medium levels in human brains 3 . Dysregulation of somatic retrotransposition in the human brain has been hypothesized to contribute to neuropsychiatric diseases 4,5 . However, individual somatic MEIs are present in small proportions of cells at a given anatomical location, and thus standard whole-genome sequencing (WGS) presents a difficult signal-tonoise problem, while single-cell approaches suffer from limited scalability and experimental artifacts introduced by enzymatic whole-genome amplification 6 . Previous studies produced widely differing estimates for the somatic retrotransposition rates in human brain 3,6-8 . Here, we present a highly precise machine learning method (RetroSom) to directly identify somatic L1 and Alu insertions in <1% cells from 200× deep WGS, which allows circumventing the restrictions of whole-genome amplification. Using RetroSom we confirmed a lower rate of retrotransposition for individual somatic L1 insertions in human neurons. We discovered that anatomical distribution of somatic L1 insertion is as widespread in glia as in neurons, and across both hemispheres of the brain, indicating retrotransposition occurs during early embryogenesis. We characterized two of the detected brain-specific L1 insertions in great detail in neurons and glia from a donor with schizophrenia. Both insertions are within introns of genes active in brain (CNNM2, FRMD4A) in regions with multiple genetic associations with neuropsychiatric disorders 9-11 . Gene expression was significantly reduced by both somatic insertions in a reporter assay. Our results provide novel insights into the potential for pathological effects of somatic retrotransposition in the human brain, now including the large glial fraction. RetroSom has broad applicability in all disease states where somatic retrotransposition is expected to play a role, such as autoimmune disorders and cancer. yielded ~59,900 (95% CI: 55,100-64,700) false positive MEI detections ( Fig. 1D and Extended Data Fig. 1A).

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Different mutational rates and mechanisms in human cells at pregastrulation and neurogenesis

Cited by 222 publications

References 42 publications

Genomic mosaicism in the developing and adult brain

Genomic mosaicism in the developing and adult brain

Review: Somatic mutations in neurodegeneration

Machine learning reveals bilateral distribution of somatic L1 insertions in human neurons and glia

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