Landmarks of human embryonic development inscribed in somatic mutations

Bizzotto, Sara; Dou, Yanmei; Ganz, Javier; Doan, Ryan; Kwon, Minseok; Bohrson, Craig L.; Kim, Sonia N.; Bae, Taejeong; Abyzov, Alexej; Park, Peter J.; Walsh, Christopher A.

doi:10.1126/science.abe1544

Cited by 85 publications

(91 citation statements)

References 41 publications

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“…The cancer field commonly uses the presence or absence of somatic mutations in clonal populations to track the evolutionary history of a tumor 24,25 . Recent studies have expanded on this approach to use somatic mutations as endogenous barcodes to track embryonic development 26 . Using this same approach, we infer that the DVA was the first lesion to develop and that the associated CCM is derived from cells of the DVA following a somatic mutation in MAP3K3.…”

Section: Resultsmentioning

confidence: 99%

Developmental Venous Anomalies are a Genetic Primer for Cerebral Cavernous Malformations

Snellings

Girard

Lightle

et al. 2021

Preprint

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Cerebral cavernous malformations (CCM) are a neurovascular anomaly that may occur sporadically in otherwise healthy individuals, or be inherited by autosomal dominant mutations in the genes that encode the proteins of the CCM signaling complex (KRIT1, CCM2, or PDCD10). CCMs have long been known to follow a genetic two-hit model where lesion formation is initiated by somatic mutations resulting in biallelic loss of a CCM complex gene. Recent studies have shown that somatic mutations in MAP3K3 and PIK3CA also contribute to CCM pathogenesis; however, it remains unclear how these mutations contribute to sporadic versus familial cases. Here we show that somatic mutations in MAP3K3 are mutually exclusive with mutations in CCM complex genes and that mutations in MAP3K3 contribute to sporadic, but not familial CCM. Using single-nucleus DNA sequencing, we show that co-occurring MAP3K3 and PIK3CA mutations are present within the same clonal population of cells. Furthermore, we identify PIK3CA mutations in CCM-associated developmental venous anomalies (DVA). It has long been known that sporadic CCM often develop in the vicinity of a DVA. However, the underlying cause of this association is unknown. In this first report of the molecular pathology of CCM-associated DVA, we find that the identical PIKC3A mutation is found in both the DVA and its associated CCM, but that an activating MAP3K3 mutation appears only in the CCM. These results support a mechanism where DVA develop as the result of a PIK3CA mutation, creating a region of the brain vasculature that functions as a genetic primer for CCM development following acquisition of an additional somatic mutation.

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Section: Resultsmentioning

confidence: 99%

Developmental Venous Anomalies are a Genetic Primer for Cerebral Cavernous Malformations

Snellings

Girard

Lightle

et al. 2021

Preprint

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“…The researchers performed high-depth whole-genome sequencing (WGS) in different human tissues to identify large numbers of somatic single-nucleotide variants (sSNVs). Based on the use of these variants as barcodes, both studies reconstructed an early embryonic development lineage and revealed that there was an asymmetric partitioning of early progenitors, and a subset of effective progenitor pools made contributions during blastula formation, gastrulation, and organogenesis [ 47 ].…”

Section: New Single-cell Techniques Address Hsc Generation At Spatial and Temporal Resolutionsmentioning

confidence: 99%

Single-Cell Approaches to Deconvolute the Development of HSCs

Xiang

Sugimura

2021

Cells

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Hematopoietic stem cells (HSCs) play a core role in blood development. The ability to efficiently produce HSCs from various pluripotent stem cell sources is the Holy Grail in the hematology field. However, in vitro or in vivo HSC production remains low, which may be attributable to the lack of understanding of hematopoiesis. Here, we review the recent progress in this area and introduce advanced technologies, such as single-cell RNA-seq, spatial transcriptomics, and molecular barcoding, which may help to acquire missing information about HSC generation. We finally discuss unresolved questions, the answers to which may be conducive to HSC production, providing a promising path toward HSC-based immunotherapies.

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“…Synthetic lineage barcoding, which relies on gene editing technologies to induce mutations, has been implemented in a variety of model systems including the zebrafish [4][5][6][7], fruit fly [8], and mouse [9][10][11]. Natural lineage barcoding, which relies on naturally-accumulating somatic mutations, has been primarily used in humans [12][13][14][15]. And while the mechanism, timing, and extent of mutagenesis differ between various implementations, the functional outcome remains the same: genomic barcodes that can retrospectively inform cell phylogeny within one organism at a single-cell resolution.…”

Section: Introductionmentioning

confidence: 99%

Quantitative fate mapping: Reconstructing progenitor field dynamics via retrospective lineage barcoding

Fang

Bell

Sapirstein

et al. 2022

Preprint

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Natural and induced somatic mutations that accumulate in the genome during development record the phylogenetic relationships of cells; however, whether these lineage barcodes can capture the dynamics of complex progenitor fields remains unclear. Here, we introduce quantitative fate mapping, an approach to simultaneously map the fate and quantify the commitment time, commitment bias, and population size of multiple progenitor groups during development based on a time-scaled phylogeny of their descendants. To reconstruct time-scaled phylogenies from lineage barcodes, we introduce Phylotime, a scalable maximum likelihood clustering approach based on a generalizable barcoding mutagenesis model. We validate these approaches using realistically-simulated barcoding results as well as experimental results from a barcoding stem cell line. We further establish criteria for the minimum number of cells that must be analyzed for robust quantitative fate mapping. Overall, this work demonstrates how lineage barcodes, natural or synthetic, can be used to obtain quantitative fate maps, thus enabling analysis of progenitor dynamics long after embryonic development in any organism.

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Landmarks of human embryonic development inscribed in somatic mutations

Cited by 85 publications

References 41 publications

Developmental Venous Anomalies are a Genetic Primer for Cerebral Cavernous Malformations

Developmental Venous Anomalies are a Genetic Primer for Cerebral Cavernous Malformations

Single-Cell Approaches to Deconvolute the Development of HSCs

Quantitative fate mapping: Reconstructing progenitor field dynamics via retrospective lineage barcoding

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