Early developmental mutations become shared across all somatic cells.
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REFUTED
the evidence says no
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Studies examining human and animal development demonstrate that somatic cells exhibit genetic diversity and somatic mosaicism due to continuous and lineage-specific mutations, refuting the claim that early developmental mutations become shared across all somatic cells.
Somatic mosaicism in normal tissues Somatic cells can accumulate mutations over the course of an individual's lifetime. This generates cells that differ genetically at specific loci within the genome. To explore how this genetic diversity in individuals contributes to disease, Yizhak et al. developed a method to detect mutations from RNA sequencing data (see the Perspective by Tomasetti). Applying this method to Cancer Genome Atlas samples and normal samples from the Genotype-Tissue Expression (GTEx) project generated a tissue-specific study of mutation accumulation. Somatic mutations were detected in nearly all individuals and across many normal human tissues in genomic regions called cancer hotspots and in genes that play a role in cancer. Interestingly, the skin, lung, and esophagus exhibited the most mutations, suggesting that the environment generates many human mutations. Science, this issue p. eaaw0726; see also p. 938 “Normal” skin and other human tissues include macroscopic clonal expansions that contain genes associated with cancer risk. INTRODUCTION Cancer genome studies have contributed to the analysis and discovery of somatic mutations that drive cancer growth. However, studying the genetic makeup of a tumor when it is already fully developed limits our ability to uncover how and which somatic mutations accumulate in normal tissues in the stages preceding cancer initiation. To address this challenge, recent studies performed deep sequencing in a limited number of tissue types and a small number of individuals, identifying a large number of microscopic clones carrying somatic mutations, some in known cancer genes. These findings emphasize the need to uncover the genomic events that occur in all normal tissues. Although efforts have begun to collect and analyze DNA from normal tissues, we still lack a comprehensive catalog of genetic events and clonal properties across a large number of tissues and individuals. By analyzing the information-rich content in RNA now available from recent advances in RNA sequencing methods, we may be able to substantially expand the scope and scale of these studies. RATIONALE Some mutations found in the DNA can be detected in the corresponding RNA, depending on the mutation allele fraction and sequence coverage. We therefore hypothesized that a careful analysis of RNA sequences from normal bulk tissues could uncover somatic mutations reflecting macroscopic clones within the samples. In this work, we used the large collection of RNA sequences from the Genotype–Tissue Expression (GTEx) project, representing more than 6700 samples from ~500 individuals, spanning across 29 different normal tissues. RESULTS We developed a new method, called RNA-MuTect, to identify somatic mutations using a tissue-derived RNA sample and its matched-normal DNA. We validated RNA-MuTect on both tumor-adjacent and cancer samples from The Cancer Genome Atlas (TCGA), wherein DNA and RNA were coextracted from the same samples. Focusing on mutations contained within sufficiently covered sequences, RNA-MuTect achieved high sensitivity and precision, enabling the discovery of most driver events and mutational processes from TCGA tumor RNA data. When applied to the GTEx dataset of normal tissues, multiple somatic mutations were detected in almost all individuals and tissues studied here, including in known cancer genes. The three tissues with the largest number of somatic mutations were sun-exposed skin, esophagus mucosa, and lung; this finding suggests that environmental exposure can promote somatic mosaicism. Both the individuals’ age and tissue-specific proliferation rate were found to be associated with the number of detected mutations. A dN/dS (ratio of nonsynonymous to synonymous substitutions) analysis suggested that some of the mutations identified in cancer genes may confer a selective advantage. In addition, allelic imbalance events at the chromosome arm level were detected in normal tissues. CONCLUSION Geneti
Starting from the zygote, all cells in the human body continuously acquire mutations. Mutations shared between different cells imply a common progenitor and are thus naturally occurring markers for lineage tracing1,2. Here we reconstruct extensive phylogenies of normal tissues from three adult individuals using whole-genome sequencing of 511 laser capture microdissections. Reconstructed embryonic progenitors in the same generation of a phylogeny often contribute to different extents to the adult body. The degree of this asymmetry varies between individuals, with ratios between the two reconstructed daughter cells of the zygote ranging from 60:40 to 93:7. Asymmetries pervade subsequent generations and can differ between tissues in the same individual. The phylogenies resolve the spatial embryonic patterning of tissues, revealing contiguous patches of, on average, 301 crypts in the adult colonic epithelium derived from a most recent embryonic cell and also a spatial effect in brain development. Using data from ten additional men, we investigated the developmental split between soma and germline, with results suggesting an extraembryonic contribution to primordial germ cells. This research demonstrates that, despite reaching the same ultimate tissue patterns, early bottlenecks and lineage commitments lead to substantial variation in embryonic patterns both within and between individuals. Somatic mutations obtained from laser microdissected biopsies of human tissues are used to reconstruct the developmental phylogenies of these tissues back to the zygote.
Somatic cells accumulate genomic alterations with age; however, our understanding of mitochondrial DNA (mtDNA) mosaicism remains limited. Here we investigated the genomes of 2,096 clones derived from three cell types across 31 donors, identifying 6,451 mtDNA variants with heteroplasmy levels of ≳0.3%. While the majority of these variants were unique to individual clones, suggesting stochastic acquisition with age, 409 variants (6%) were shared across multiple embryonic lineages, indicating their origin from heteroplasmy in fertilized eggs. The mutational spectrum exhibited replication-strand bias, implicating mtDNA replication as a major mutational process. We evaluated the mtDNA mutation rate (5.0 × 10−8 per base pair) and a turnover frequency of 10–20 per year, which are fundamental components shaping the landscape of mtDNA mosaicism over a lifetime. The expansion of mtDNA-truncating mutations toward homoplasmy was substantially suppressed. Our findings provide comprehensive insights into the origins, dynamics and functional consequences of mtDNA mosaicism in human somatic cells. Analysis of 2,096 single-cell clones from three tissues of 31 healthy donors characterizes mitochondrial DNA mosaicism and highlights the following two origins of mtDNA variants: heteroplasmy in the fertilized egg and postzygotic mutations.
In many animals, the germline differentiates early in embryogenesis, so only mutations that accumulate in germ cells are inherited by offspring1. Exceptions to this developmental process may indicate that other mechanisms have evolved to limit the effects of deleterious mutation accumulation2. Stony corals are animals that can live for hundreds of years3 and have long been thought to produce gametes from somatic tissue4. To clarify conflicting evidence about germline-soma distinction in corals, we sequenced high coverage, full genomes with technical replicates for parent coral branches and their sperm pools. We identified post-embryonic single nucleotide variants (SNVs) unique to each parent branch, then checked if each SNV was shared by the respective sperm pool: 26% of post-embryonic SNVs were shared by the sperm but 74% were not. We also identified germline SNVs, those that were present in the sperm but not in the parent. These data suggest that self-renewing stem cells in corals differentiate into germ and soma throughout the adult life of the colony, with SNV rates and patterns differing markedly in stem, soma, and germ lineages. In addition to informing the important place in the evolutionary spectrum from non-Weismannian to Weismmanian animals that corals occupy, these insights inform how corals may generate adaptive diversity necessary in the face of global climate change.
The revolution in genome sequencing technologies has enabled the comprehensive detection of genomic variations in human cells, including inherited germline polymorphisms, de novo mutations, and postzygotic mutations. When these technologies are combined with techniques for isolating and expanding single-cell DNA, the landscape of somatic mosaicism in an individual body can be systematically revealed at a single-cell resolution. Here, we summarize three strategies (whole-genome amplification, microdissection of clonal patches in the tissue, and in vitro clonal expansion of single cells) that are currently applied for single-cell mutational analyses. Among these approaches, in vitro clonal expansion, particularly via adult stem cell-derived organoid culture technologies, yields the most sensitive and precise catalog of somatic mutations in single cells. Moreover, because it produces living mutant cells, downstream validation experiments and multiomics profiling are possible. Through the synergistic combination of organoid culture and genome sequencing, researchers can track genome changes at a single-cell resolution, which will lead to new discoveries that were previously impossible.
De novo mutations accumulate with zygotic cell divisions. However, the occurrence of these mutations and the way they are inherited by somatic cells and germ cells remain unclear. Here, we present a novel method to reconstruct cell lineages. We identified mosaic mutations in mice using deep whole-genome sequencing and reconstructed embryonic cell lineages based on the variant allele frequencies of the mutations. The reconstructed trees were confirmed using nuclear transfer experiments and the genotyping of approximately 50 offspring of each tree. The most detailed tree had 32 terminal nodes and showed cell divisions from the fertilized egg to germ cell– and somatic cell–specific lineages, indicating at least five independent cell lineages that would be selected as founders of the primordial germ cells. The contributions of each lineage to germ cells and offspring varied widely. At the emergence of the germ cell–specific lineages, 10–15 embryonic mutations had accumulated, suggesting that the pregastrulation mutation rate is 1.0 mutation per mitosis. Subsequent mutation rates were 0.7 for germ cells and 13.2 for tail fibroblasts. Our results show a new framework to assess embryonic lineages; further, we suggest an evolutionary strategy for preserving heterogeneity owing to postzygotic mutations in offspring.
Segmental vitiligo (SV) is a distinct clinical subtype of vitiligo characterized by unilateral, sharply demarcated depigmentation, rapid progression and early stabilization, and frequent leukotrichia. Compared with non-segmental vitiligo (NSV), SV is generally less strongly associated with systemic autoimmunity, suggesting potential differences in pathogenic mechanisms, although overlap phenotypes and mixed presentations have been reported. Accumulating clinical, epidemiological, and mechanistic evidence supports the concept that SV arises from somatic mosaicism, in which post-zygotic genetic or epigenetic alterations occur during embryogenesis and give rise to a clonally distinct melanocyte population distributed along developmental territories. Embryologic studies indicate that melanoblast migration from the neural crest, coupled with high proliferative activity during early development, creates a permissive context for mosaic mutation accumulation. The resulting melanocyte clones align with Blaschko's lines or other embryonic patterning units, accounting for the segmental distribution of SV. Beyond melanocytes, segment-restricted abnormalities in neural and vascular structures have also been reported, raising the possibility of broader neurocutaneous mosaicism, although whether these changes are primary or secondary to localized immune injury remains unresolved. Recognizing SV as a mosaic disorder has important clinical implications, particularly for early intervention, recurrence risk assessment, and the prominent role of autologous surgical therapies. Future advances will depend on multi-omics approaches to identify causal mosaic mutations, refined disease models, and long-term registries to translate developmental insights into precision management strategies.
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