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Somatic mutation

Somatic mutation refers to any alteration in the DNA sequence occurring in non-reproductive (somatic) cells after fertilization or conception, distinguishing it from germline mutations that can be inherited by offspring.^[1] These changes affect only the individual in whom they arise and do not pass to future generations, as they occur in body cells rather than sperm or egg cells.^[2] Somatic mutations can arise spontaneously during DNA replication or repair, or be induced by environmental factors such as ionizing radiation, chemical mutagens, or reactive oxygen species.^[1] The mechanisms of somatic mutations include point mutations (single nucleotide changes), insertions or deletions (indels), and larger structural variations like copy number variants or chromosomal rearrangements, leading to genetic mosaicism where different cells within the same organism carry distinct genomes.^[3] Such mutations accumulate over time due to imperfect DNA repair processes, with rates increasing in rapidly dividing cells or under mutagenic stress, such as exposure to tobacco smoke containing over 70 known carcinogens.^[1] While many somatic mutations are neutral or deleterious, causing cell death or dysfunction, some confer selective advantages, particularly in oncogenesis, where alterations in proto-oncogenes or tumor suppressor genes promote uncontrolled cell growth.^[3] Somatic mutations play a pivotal role in various diseases, most notably cancer, where they drive tumorigenesis through a "mutator phenotype" that elevates mutation rates by more than 200-fold compared to normal cells in many tumors, including those of colorectal and lung cancers.^[4] They also contribute to aging by accumulating in tissues like epithelial cells and lymphocytes, correlating with exponential increases in mutation burden that impair cellular function and organ homeostasis.^[5] In neurodegeneration, somatic mutations, including mitochondrial DNA deletions, exacerbate oxidative stress and neuronal loss in conditions such as Alzheimer's and Parkinson's diseases.^[5] Specific syndromes illustrate their impact, such as McCune-Albright syndrome caused by activating mutations in the GNAS gene, leading to endocrine and skeletal abnormalities.^[1] Overall, the study of somatic mutations has advanced fields like personalized medicine, enabling targeted therapies based on tumor-specific genetic profiles.^[6]

Definition and Fundamentals

Definition and Characteristics

Somatic mutations are alterations in the DNA sequence that occur in non-reproductive somatic cells following fertilization, distinguishing them from any embryonic mutations present at conception.^[1] These postzygotic changes arise in body cells and contribute to genetic diversity within an individual by affecting only specific cell lineages.^[7] Key characteristics of somatic mutations include their accumulation over an individual's lifetime in healthy tissues, where they progressively build up in cellular genomes.^[8] Each mutation impacts the affected cell and its progeny, resulting in somatic mosaicism—a state in which an organism contains a mixture of cells with differing genetic compositions derived from the same zygote.^[7] They encompass a range of types, such as point mutations that substitute a single nucleotide, small insertions or deletions (indels), and larger structural variants including inversions, translocations, and copy number changes.^[9] The majority of these mutations are neutral, exerting no notable effect on cellular physiology or organismal fitness.^[10] The recognition of somatic mutations dates to the early 20th century, when Calvin Bridges described mosaic phenotypes in Drosophila melanogaster through his 1919 studies, providing early evidence for postzygotic genetic changes in somatic tissues.^[11] A prominent example of somatic mutations is pigmentary mosaicism in human skin, where postzygotic genetic alterations lead to heterogeneous patterns of hypo- or hyperpigmentation across cellular populations.^[12] Unlike germline mutations, which affect reproductive cells and can be transmitted to offspring, somatic mutations remain confined to the individual's body.^[1]

Distinction from Germline Mutations

Somatic mutations occur in non-reproductive cells of the body, affecting only the individual in which they arise and not being transmitted to offspring, in contrast to germline mutations, which take place in reproductive cells such as eggs or sperm and are heritable across generations.^[13]^[1] This fundamental distinction means that while germline mutations contribute to the genetic makeup passed from parents to children, somatic mutations remain confined to the somatic cell lineages of the affected person, influencing only their phenotype without altering the germline genome.^[14] An exception to this non-heritable nature arises in rare cases of gonadal mosaicism (also known as germline mosaicism), where a postzygotic mutation occurs in a subset of germ cells within the gonads, potentially allowing transmission to offspring despite the parent showing no systemic symptoms.^[15]^[16] In such instances, the mutation is present in a subset of germ cells but not in the parent's somatic tissues, leading to a risk of affected children even in families without prior hereditary patterns.^[17] The implications of this distinction are significant: somatic mutations drive intra-individual variability, such as through mosaicism that can result in tissue-specific traits or adaptations within the organism, but they do not directly contribute to evolutionary inheritance, which relies on germline changes propagated across populations.^[18]^[7]

Aspect	Somatic Mutations	Germline Mutations
Location	Non-reproductive (somatic) cells	Reproductive (germ) cells
Heritability	Not passed to offspring	Passed to offspring
Detection	Tissue-specific analysis required	Detectable in blood or embryonic cells

^[1]^[13]^[7]

Mechanisms of Occurrence

Types of Somatic Mutations

Somatic mutations encompass a diverse array of genetic alterations that occur in non-germline cells, broadly classified into point mutations, insertions and deletions (indels), copy number variations (CNVs), and chromosomal rearrangements. These categories reflect the molecular scale and impact of the changes on the genome. Point mutations, also known as single nucleotide variants (SNVs), involve the substitution of a single base pair, such as transitions (purine to purine or pyrimidine to pyrimidine) or transversions (purine to pyrimidine or vice versa).^[19] Indels refer to small insertions or deletions of nucleotides, typically ranging from 1 to 50 base pairs, which can disrupt coding sequences or regulatory elements by causing frameshifts or altering protein length.^[19] Copy number variations (CNVs) involve gains or losses of larger DNA segments, often spanning kilobases to megabases, leading to duplications or deletions that alter gene dosage.^[19] Chromosomal rearrangements encompass structural variants such as translocations (exchange of segments between non-homologous chromosomes), inversions (reversal of a segment within a chromosome), and other gross chromosomal rearrangements (GCRs) that can juxtapose genes or regulatory elements in novel configurations.^[19] In somatic contexts, these mutations often arise mosaically within tissues, where only a subset of cells carries the alteration, distinguishing them from uniform germline changes. A key somatic-specific feature is clonal expansion, wherein cells harboring a particular mutation proliferate preferentially, amplifying its prevalence within the tissue population over time.^[19] For instance, in epithelial cells of the small intestine, APOBEC-induced mutations—characterized by C-to-T transitions at TC dinucleotides—occur frequently and can drive localized clonal expansions in normal tissue.^[20] Such patterns highlight how somatic mutations propagate through cellular division without transmission to offspring. Detecting somatic mutations presents unique challenges due to their low frequency in heterogeneous tissues, necessitating deep sequencing approaches with high coverage (often >100x) to reliably distinguish them from germline variants and sequencing artifacts.^[19] Bulk tissue sequencing may dilute signals from minor clones, while single-cell methods, though informative, introduce amplification biases that complicate indel and CNV identification.^[19]

Primary Causes and Triggers

Somatic mutations arise from a variety of endogenous and exogenous factors that disrupt DNA integrity at the molecular level. Endogenous causes primarily stem from intrinsic cellular processes. During DNA replication, errors occur due to the infidelity of DNA polymerases, which incorporate incorrect nucleotides at a rate of approximately $10^{-9} per base pair per replication cycle, even after proofreading. The overall mutation rate \mu is influenced by this error rate \epsilon \approx 10^{-9}, adjusted by repair efficiency \eta, such that \mu \approx \epsilon \times (1 - \eta).^[21] Spontaneous deamination of bases, particularly 5-methylcytosine to thymine, generates mismatched pairs that, if unrepaired, lead to C>T transitions, a common endogenous signature observed across tissues.^[22] Additionally, reactive oxygen species (ROS) produced as metabolic byproducts cause oxidative damage, such as 8-oxoguanine lesions that pair erroneously with adenine, contributing to G>C transversions, especially in proliferative tissues like the liver and brain.^[22] Exogenous triggers introduce external DNA-damaging agents that induce mutations through distinct mechanisms. Ultraviolet (UV) radiation from sunlight primarily affects skin cells, forming cyclobutane pyrimidine dimers and 6-4 photoproducts that, upon replication or repair, result in C>T and CC>TT mutations at dipyrimidine sites.^[22] Ionizing radiation, from sources like X-rays or cosmic rays, generates reactive species and direct strand breaks, leading to clustered mutations including deletions and complex rearrangements.^[23] Chemical mutagens, such as polycyclic aromatic hydrocarbons in tobacco smoke, form bulky DNA adducts that distort the helix and cause G>T transversions during replication, a hallmark in lung and other exposed tissues.^[24] Viral integrations, exemplified by human papillomavirus (HPV) in cervical cells, disrupt host DNA at integration sites, inducing local deletions, insertions, and chromosomal instability that promote oncogenic mutations.^[25] Failures in DNA repair mechanisms amplify mutation accumulation from both endogenous and exogenous sources. Defects in mismatch repair (MMR) pathways, often arising somatically through biallelic inactivation of genes like MLH1 or MSH2, impair the correction of replication errors and slippage in repetitive sequences, resulting in microsatellite instability (MSI) characterized by expanded or contracted microsatellites and a hypermutator phenotype with thousands of additional insertions/deletions and base substitutions.^[26] This instability is prevalent in certain cancers and accelerates the overall somatic mutation burden.

Frequency and Variation

Baseline Mutation Rates

Somatic mutations accumulate in human cells at a baseline rate of approximately 10 to 20 single nucleotide variants (SNVs) per cell per year in most adult tissues, with rates varying modestly across different organs due to inherent differences in cellular turnover and exposure to endogenous damage.^[27] This accumulation is notably higher in stem cells, which undergo more frequent divisions and thus incur additional replication-associated errors, often reaching 20 to 50 mutations per cell per year in proliferative compartments like those in the intestine or skin.^[28] These rates reflect the steady-state balance between DNA damage from spontaneous chemical processes and repair mechanisms, establishing a foundational level of genetic variation that increases predictably over time without external stressors.^[22] A key factor influencing baseline rates is the age-related increase driven by clock-like mutational processes, particularly the spontaneous deamination of 5-methylcytosine at CpG dinucleotides, which generates the predominant COSMIC Signature 1.^[29] This endogenous process operates at a near-constant pace, leading to a linear or slightly accelerated accumulation in many tissues, with total mutations often scaling as M = a \times \text{[age](/page/Age)}^b, where a and b are tissue-specific parameters (typically b \approx 1 for linear clocks but higher in stress-exposed organs).^[30] For instance, in the liver, stem cells accrue about 11 SNVs per cell per year, resulting in roughly 700 to 1,000 mutations per cell by age 70, underscoring the cumulative burden over a lifespan.^[31] These baseline rates are quantified through whole-genome sequencing (WGS) of clonally expanded cells from normal tissues, which distinguishes somatic variants from germline ones by comparing multiple samples per individual and leveraging ultra-deep coverage to detect low-frequency clones.^[32] Somatic mutation clocks, calibrated against chronological age using signatures like SBS1, further enable estimation of accumulated burden and validation of tissue-specific dynamics, providing a molecular timeline independent of phenotypic aging markers.^[29] Such methods have revealed that, absent pathological influences, mutation loads remain orders of magnitude below oncogenic thresholds in healthy adults, yet contribute subtly to cellular heterogeneity over decades.^[33]

Cell-Type Specific Patterns

Somatic mutation frequencies exhibit significant variation across different cell types, influenced by factors such as proliferative activity, environmental exposures, and intrinsic DNA repair mechanisms. In post-mitotic cells like neurons, which persist for decades without division, mutations accumulate primarily from endogenous damage rather than replication errors, leading to higher burdens over time compared to rapidly dividing cells. Conversely, quiescent stem cells maintain lower rates due to reduced opportunities for error-prone processes. These patterns highlight how cellular context shapes genomic stability throughout life.^[33] Neurons display a notably high somatic mutation burden, attributed to their extended lifespan and exposure to oxidative stress from high metabolic demands. Studies using single-nucleus whole-genome sequencing have shown that prefrontal cortex neurons accumulate approximately 2,000-2,500 single-nucleotide variants (SNVs) by age 80, with rates increasing linearly at about 25 SNVs per year. This accumulation is exacerbated by reactive oxygen species generated during neuronal activity, which can induce DNA damage if not fully repaired. In contrast, hematopoietic stem cells (HSCs) exhibit lower mutation rates, largely due to their predominantly quiescent state, which minimizes cell divisions and thus replication-associated errors; estimates indicate only about 14 base substitutions per year in HSCs, with early-life mutations being minimal.^[34] Epithelial cells, particularly in high-turnover tissues like the colon or airways, experience elevated mutation frequencies owing to frequent proliferation, which heightens exposure to exogenous mutagens and replication stress. For instance, colonic epithelial stem cells can accumulate dozens of driver mutations over decades, driven by their rapid renewal cycles that amplify opportunities for error fixation. These differences underscore a general trend where proliferative cells face higher mutational loads from division, while long-lived, non-dividing cells accrue damage from chronic stressors.^[35]^[36] Brain mosaicism emerges as a key pattern, arising from somatic mutations incurred during early embryonic development, which propagate to create genetically diverse neuronal populations. Single-cell sequencing has revealed that such early mutations, often occurring in neural progenitors around the 8- to 16-cell stage, result in widespread mosaicism detectable in adult cortex, contributing to inter-individual brain variability. Additionally, retrotransposon activity, particularly LINE-1 (L1) insertions, is elevated in germinal matrix cells during neurogenesis, with studies identifying approximately 10-15 somatic L1 insertions per hippocampal neuron genome, though recent estimates suggest fewer (around 1-2).^[37] This activity peaks in precursor cells of the developing hippocampus and cortex, potentially influencing neuronal diversification. Recent advances in single-cell sequencing, post-2020, have illuminated how neuronal mosaicism interfaces with neurodevelopment, showing that somatic variants in genes like ARID1B or CHD8 create mosaic neuronal subsets that alter circuit formation and synaptic connectivity. For example, low-level mosaic mutations in autism-associated genes have been linked to subtle disruptions in cortical layering during fetal stages, detectable via droplet-based single-nucleus genomics. As of 2025, Human Cell Atlas initiatives have refined these patterns, confirming brain-specific rates and emphasizing mosaicism's role in generating functional diversity in the healthy brain, beyond pathological contexts.^[38]^[39]

Somatic Hypermutation in Immunity

Somatic hypermutation (SHM) is a specialized process that occurs in germinal center B cells during the adaptive immune response, enabling the diversification of immunoglobulin (Ig) genes to generate high-affinity antibodies. In this process, activation-induced deaminase (AID), expressed specifically in germinal center B cells, targets the variable regions of Ig genes by deaminating cytosine bases to uracil, creating U:G mismatches that lead to point mutations upon replication or repair.^[40] This AID-mediated deamination is transcription-dependent, occurring primarily on single-stranded DNA exposed during Ig gene transcription in germinal centers following antigen stimulation.^[41] The mutations introduced by SHM are processed through error-prone DNA repair pathways, notably involving translesion synthesis polymerases such as polymerase eta (Pol η), which preferentially introduces errors at A:T base pairs, contributing to the biased mutation spectrum observed in SHM.^[42] This error-prone repair, including mismatch repair and base excision repair, transforms the initial U:G lesions into transitions and transversions, with Pol η playing a key role in generating A:T mutations essential for antibody diversification. The overall mutation rate in SHM reaches approximately 10^{-3} mutations per base pair per generation, which is about 10^6-fold higher than the baseline somatic mutation rate in non-Ig genes.^[43] This elevated rate facilitates rapid accumulation of mutations, allowing for the selection of B cells producing antibodies with enhanced antigen-binding affinity, a process known as affinity maturation.^[42] Regulation of SHM ensures mutations are largely confined to the Ig variable (V) regions, spanning about 1-2 kb downstream of the promoter, to minimize off-target effects on the genome while maximizing diversity in antigen-binding sites. This targeting is achieved through specific cis-regulatory elements, such as Ig enhancers and promoters, which direct AID activity and limit mutations to transcriptionally active Ig loci.^[41] By restricting hypermutation to these regions, the process supports precise immune adaptation without compromising B cell viability or genomic stability.^[40]

Biological Roles

In Immune System Adaptation

Somatic mutations play a pivotal role in the adaptive immune system through V(D)J recombination, a process that generates immense diversity in T-cell receptors (TCRs) and B-cell immunoglobulins by rearranging variable (V), diversity (D), and joining (J) gene segments.^[44] This site-specific recombination, mediated by the RAG1 and RAG2 endonucleases, introduces programmed double-strand breaks and subsequent repairs that create junctional diversity through nucleotide additions and deletions, enabling the recognition of a vast array of antigens. In T cells, V(D)J recombination assembles TCR genes to produce receptors capable of detecting peptide-MHC complexes, while in B cells, it forms the variable regions of antibodies, fundamentally shaping the immune repertoire.^[45] These somatic rearrangements confer adaptive advantages by allowing the immune system to respond to novel pathogens that have not been encountered in an individual's lifetime. The generated diversity ensures that rare clones with receptors matching a specific antigen can be rapidly expanded through clonal selection, where antigen binding triggers proliferation and differentiation of those lymphocytes, amplifying effective immune responses.^[46] This mechanism not only enhances pathogen clearance but also supports immunological memory, as selected clones persist as memory cells for faster secondary responses. Somatic hypermutation further refines this diversity post-recombination, but V(D)J primarily establishes the initial variability.^[44] Dysregulation of somatic mutations in TCR genes exemplifies their double-edged nature, contributing to autoimmunity risk when self-reactive clones escape tolerance mechanisms. For instance, aberrant V(D)J junctional modifications can generate TCRs with heightened affinity for self-antigens, leading to conditions like autoimmune disorders if regulatory checkpoints fail.^[47] Studies of expanded T-cell clones have identified somatic variants in TCR signaling genes that promote survival and auto-reactivity, underscoring the need for precise control in recombination fidelity.^[46] The V(D)J recombination system is evolutionarily conserved across jawed vertebrates (gnathostomes), highlighting its fundamental importance for adaptive immunity. From cartilaginous fish to mammals, this mechanism has persisted for over 500 million years, co-opted from ancient transposon elements like RAG, to enable antigen receptor assembly in all species possessing lymphocytes.00152-8) Variations in gene segment numbers across species, such as greater TCRα diversity in some lineages, reflect adaptive refinements, yet the core recombinatorial process remains a defining feature of vertebrate immunity.^[48]

In Development and Cellular Diversity

Somatic mutations occurring after zygote formation lead to mosaicism, where genetically distinct cell populations arise within an individual, contributing to cellular diversity during development. These post-zygotic changes introduce genetic heterogeneity in tissues, allowing for varied cellular responses and adaptations in embryonic and fetal stages.^[49] In humans, such mosaicism can manifest as a spectrum of cell types with differing mutation burdens, influencing tissue formation and function without affecting the germline.30756-X) While X-inactivation represents a key epigenetic mechanism of somatic variation that silences one X chromosome in female mammals to balance gene dosage, true genetic somatic mutations provide an additional layer of diversity through sequence alterations. In certain species, somatic mutations play a critical role in organogenesis and regeneration, enabling adaptive cellular reprogramming. For instance, in planarians like Schmidtea mediterranea, which possess neoblasts as pluripotent stem cells, somatic mutations accumulate during regeneration processes, supporting the reconstruction of complex organs after injury and maintaining anatomical homeostasis over extended asexual reproduction cycles.^[50] These mutations, often de novo and distinct from baseline somatic changes, facilitate tissue patterning and stem cell proliferation, highlighting their necessity for developmental plasticity in regenerative models.^[51] In humans, early somatic mutations during embryogenesis are typically linked to congenital anomalies rather than normal development; for example, mosaic mutations arising in the first few cell divisions can result in developmental disorders if they disrupt essential pathways. A prominent example of mosaicism's impact is seen in somatic mutations of the TP53 gene, which can produce Li-Fraumeni-like syndromes in mosaic forms. These mutations, present in a subset of cells, confer increased susceptibility to tumors and developmental irregularities without full germline involvement, as documented in cases where codon-specific alterations like p.R282W were detected somatically.^[52] Such mosaicism underscores how partial genetic heterogeneity can mimic hereditary syndromes while originating post-zygotically.^[53] Recent advances in spatial transcriptomics have illuminated how somatic mutations drive cell fate decisions in development. Techniques integrating single-cell sequencing with spatial mapping have traced mutation lineages in human embryonic tissues, revealing that somatic variants influence neuronal divergence and cortical layering by altering gene expression patterns in specific locales.^[54] Studies from 2023 onward, including lineage tracing in placentas and brain tissues, demonstrate that these mutations inscribe developmental landmarks, enabling precise reconstruction of cell trajectories and highlighting their role in generating tissue diversity.^[55] This approach has expanded understanding of mosaicism's contributions to normal embryogenesis, as seen in analyses of postzygotic events shaping organ formation.00130-6)

Implications in Disease and Aging

Contribution to Cancer

Somatic mutations play a central role in cancer development by providing the genetic variation that enables neoplastic transformation. These mutations can be classified as driver mutations, which confer a selective growth advantage to cells, or passenger mutations, which arise incidentally without impacting fitness. The accumulation of driver mutations disrupts key cellular pathways, leading to uncontrolled proliferation, evasion of cell death, and other hallmarks of cancer. For instance, activating mutations in oncogenes like KRAS promote constitutive signaling through the RAS-MAPK pathway, enhancing cell survival and division, as observed in approximately 90% of pancreatic ductal adenocarcinomas. Similarly, inactivating mutations in tumor suppressor genes, such as loss-of-function alterations in TP53, impair DNA damage response and apoptosis, occurring in over 50% of all human cancers. Clonal evolution in tumors follows a Darwinian process, where somatic mutations generate diversity, and natural selection favors clones with enhanced fitness, leading to tumor progression and heterogeneity. This involves the sequential acquisition of mutations, often requiring multiple hits to fully inactivate tumor suppressors or activate oncogenes. Alfred Knudson's two-hit hypothesis, proposed based on retinoblastoma incidence patterns, posits that both alleles of a tumor suppressor gene must be inactivated—typically one germline and one somatic mutation in hereditary cases, or two somatic mutations in sporadic cases—for tumorigenesis to occur. In retinoblastoma, biallelic inactivation of the RB1 gene exemplifies this model, with the first hit often being a point mutation and the second a loss of heterozygosity via chromosomal deletion. Mutational signatures provide insights into the exogenous and endogenous processes driving somatic mutations in cancer, cataloged in the COSMIC database. These signatures represent patterns of base substitutions, insertions, and deletions reflective of specific mutagenic mechanisms. For example, COSMIC Signature 4 (SBS4) is characterized by a high frequency of C>A transversions at CpCpA trinucleotides and is strongly associated with tobacco smoking due to exposure to polycyclic aromatic hydrocarbons like benzopyrene, predominantly in lung and head-and-neck squamous cell carcinomas. Most cancers are initiated and progressed by a small number of driver mutations, typically 2 to 8 per tumor, with seminal analyses indicating that around 3 sequential driver events suffice for malignancy in common epithelial cancers like colorectal and lung adenocarcinomas. In evolutionary terms, the fitness of a mutant clone can be modeled simply as its growth rate equaling the baseline rate of wild-type cells plus the selective advantage conferred by the mutation, often denoted as r = r_0 + s, where r_0 is the baseline growth rate and s is the advantage (typically 0.01 to 0.1 in early stages). This framework underscores how even modest selective benefits accumulate over time to drive clonal dominance in the tumor microenvironment.

Associations with Non-Cancerous Conditions

Somatic mutations have been implicated in various non-cancerous conditions, particularly those involving tissue-specific mosaicism that disrupts normal cellular function without oncogenic transformation. In neurological disorders, these mutations can arise postzyotically in neuronal progenitors, leading to mosaic populations of affected cells that contribute to disease phenotypes. For instance, somatic mosaic deletions in the SCN1A gene, which encodes a voltage-gated sodium channel, have been identified in patients with Dravet syndrome, a severe epilepsy characterized by focal and generalized seizures beginning in infancy. Similarly, ultra-deep sequencing of postmortem brain tissue from individuals with autism spectrum disorder (ASD) reveals an excess of somatic single-nucleotide variants in neural enhancer sequences compared to neurotypical controls, suggesting that neuronal mosaicism in these regulatory regions may impair gene expression critical for synaptic development and contribute to ASD risk.^[56] In autoimmune diseases, somatic variants in immune-related genes can promote aberrant immune responses and disease exacerbations. For example, somatic mutations in B-cell lymphoma-associated genes, such as those detected in expanded B-cell clones, have been observed in subsets of patients with systemic lupus erythematosus (SLE), correlating with increased autoantibody production and potentially driving lupus flares through dysregulated humoral immunity. These mutations, often acquired in hematopoietic stem or progenitor cells, enhance B-cell survival and activation, amplifying pathogenic autoimmunity in susceptible individuals. Cardiovascular conditions also show links to somatic mutations in vascular tissues. Genotoxic stress in endothelial cells, leading to somatic mutations, induces endothelial dysfunction—a key initiator of atherosclerosis—by promoting proinflammatory cytokine expression, such as IL-6 and IL-8, and cytogenetic damage like micronuclei formation.^[57] Additionally, somatic JAK2 V617F mutations detected in endothelial cells of patients with myeloproliferative neoplasms have been associated with accelerated vascular pathology, including atherosclerotic plaque formation, through enhanced proliferative signaling. A classic example of somatic mutation-driven non-cancerous disease is McCune-Albright syndrome (MAS), caused by postzygotic mosaic gain-of-function mutations in the GNAS gene, which encodes the Gαs subunit of G-protein-coupled receptors. These mutations result in constitutive activation of adenylyl cyclase, leading to excessive cyclic AMP production in affected tissues and manifesting as fibrous dysplasia of bone, café-au-lait skin pigmentation, and endocrine hyperfunction, such as precocious puberty. The mosaic nature of GNAS alterations explains the variable clinical severity, as the proportion of mutated cells in different lineages determines the extent of tissue involvement.

Influence on Aging Processes

The accumulation of somatic mutations over time imposes a mutational load that progressively erodes tissue function, contributing to the physiological decline observed in aging. This process disrupts cellular homeostasis by altering gene expression, impairing protein function, and promoting cellular senescence, ultimately leading to reduced organ efficiency and systemic frailty. For instance, in skeletal muscle, somatic mutations in mitochondrial DNA (mtDNA) accumulate clonally, causing respiratory chain deficiencies that impair energy production and contribute to sarcopenia and muscle weakness.^[58]^[59] Evidence from large-scale genomic analyses demonstrates that somatic mutation burdens increase linearly with chronological age across multiple tissues, correlating with markers of frailty such as reduced physical resilience and increased vulnerability to stressors. These clock-like mutational signatures, characterized by consistent patterns like C>T transitions at CpG sites, accumulate at predictable rates in normal aging but accelerate dramatically in progeroid syndromes, where defects in DNA repair lead to premature tissue degeneration and shortened lifespan.^[60]^[61]^[62] In progeroid conditions like Hutchinson-Gilford progeria syndrome, these accelerated signatures mimic advanced aging phenotypes, underscoring the causal role of heightened mutational rates in senescence.^[61] Twin studies highlight the quantitative impact of somatic processes on aging variance, estimating that genetic factors explain approximately 20-30% of differences in human longevity, with post-zygotic somatic mutation accumulation accounting for a significant portion of the non-shared environmental influences on age-related decline. Interventions targeting this burden show promise; for example, CRISPR-Cas9 base editing has successfully corrected progerin mutations in progeroid models, restoring cellular function and extending lifespan, suggesting broader potential for mitigating age-associated mutations in somatic tissues.^[63]^[64] Recent studies also indicate that caloric restriction reduces somatic mutation rates by enhancing DNA repair pathways and lowering oxidative stress, as observed in mouse models where it slowed cryptic mtDNA heteroplasmy accumulation by up to 50% compared to ad libitum feeding.^[65] These findings support the feasibility of lifestyle and genetic strategies to attenuate mutational load and delay aging processes.00072-2)

Evolutionary and Research Perspectives

Somatic Evolution

Somatic evolution describes the Darwinian processes occurring within multicellular organisms, where somatic mutations generate genetic variation among cells, and natural selection favors the proliferation of advantageous clones in tissues.^[66] This intra-organismal evolution operates on timescales much shorter than germline evolution, driven by competition for space, nutrients, and survival signals in self-renewing cell populations.^[67] Unlike germline mutations, which contribute to species-level adaptation, somatic evolution shapes tissue-level dynamics, often suppressed by developmental mechanisms to maintain organismal integrity.^[68] In non-disease contexts, competition among mutant clones manifests in adaptive responses to physiological demands. For instance, in liver regeneration, somatic mutations in genes like SERPINA1 confer selective advantages to hepatocytes, enabling their clonal expansion and enhanced regenerative capacity in chronic liver disease.^[69] These examples illustrate how somatic evolution can promote tissue resilience without necessarily leading to pathology, as seen in brief parallels to clonal expansions in cancer.^[70] Recent single-cell studies as of November 2025 in human chondrocytes reveal age-related somatic mutation accumulation at 18 SNVs per cell per year, highlighting tissue-specific evolutionary dynamics.^[71] Theoretical frameworks, such as multilevel selection theory, explain how somatic evolution balances conflicts between cellular and organismal interests. At the cellular level, mutations promoting selfish proliferation are favored, but organismal selection enforces mechanisms like germline-soma separation to prioritize reproductive fitness over intra-somatic competition.^[72] This soma-germline conflict underscores the evolutionary pressures that limit uncontrolled somatic adaptation while allowing beneficial clonal dynamics in specific contexts.^[66] Recent computational models from 2025 have advanced understanding by simulating somatic phylogenies to reconstruct clonal histories and selection pressures. For example, approximate Bayesian computation applied to mouse hematopoiesis generates phylogenetic trees that estimate mutation rates and fitness effects, revealing patterns of neutral and adaptive evolution in blood cell lineages.^[73] These simulations highlight the hierarchical nature of selection, integrating genetic drift, mutation, and environmental factors to model tissue-wide evolutionary trajectories.^[74]

Detection Methods and Recent Advances

Next-generation sequencing (NGS) serves as the cornerstone for detecting somatic mutations, enabling high-throughput analysis of tumor DNA compared to matched normal tissue to identify variants absent in the germline.^[75] Whole-exome sequencing (WES) and whole-genome sequencing (WGS) within NGS frameworks capture over 95% of coding regions and facilitate the detection of single-nucleotide variants (SNVs), insertions/deletions, and copy number alterations with high sensitivity.^[76] Single-cell DNA sequencing (scDNA-seq) extends this capability to resolve heterogeneity at the cellular level, allowing de novo identification of somatic SNVs in individual cells without matched bulk DNA, as exemplified by algorithms like SComatic that achieve precision rates of 0.67–0.87 in scRNA-seq data by modeling error rates and filtering artifacts.^[77] Liquid biopsies, which analyze circulating tumor DNA (ctDNA) from blood, provide a non-invasive alternative for somatic mutation detection, offering 93.8% gene-level concordance with tissue biopsies in non-small cell lung cancer while identifying additional actionable mutations like EGFR alterations missed in solid samples.^[78] Key challenges in somatic mutation detection include distinguishing true somatic variants from germline polymorphisms and technical noise, particularly for low-frequency variants below 5% allele frequency that may arise from clonal hematopoiesis or sequencing errors.^[79] Paired tumor-normal analysis helps filter germline variants by comparing allele frequencies—somatic ones typically show variant allele frequencies under 30%—but limitations arise in hematopoietic samples where blood contamination can confound results, necessitating alternative controls like skin fibroblasts.^[79] Low-depth sequencing in single-cell or ctDNA approaches exacerbates noise from allelic dropout or polymerase chain reaction artifacts, reducing sensitivity for subclonal mutations.^[80] Recent advances have improved accuracy through AI-driven variant calling, with DeepSomatic—a deep learning extension of DeepVariant—achieving up to 98% precision in identifying somatic SNVs and indels across short- and long-read platforms by better handling tumor heterogeneity and sequencing artifacts, as demonstrated in 2025 benchmarks outperforming tools like Mutect2.^[81] Long-read sequencing technologies, such as Oxford Nanopore and PacBio, enhance detection of structural variants (SVs) missed by short-read NGS, with algorithms like SAVANA enabling single-haplotype resolution of somatic SVs and copy number aberrations in repetitive genomic regions, detecting 86% of known SVs plus novel rearrangements in clinical cancer samples at sensitivities exceeding 90%.^[82] These methods also reveal mutation signatures, such as age-related SBS1 and SBS5, at unprecedented resolution.^[39] In population-scale applications, error-corrected approaches like NanoSeq have been applied to UK Biobank cohorts, analyzing somatic mutations in whole blood from over 200,000 individuals to identify clonal hematopoiesis drivers, identifying 17 additional genes under positive selection beyond the 14 previously nominated via the 2023 exome sequencing release.^[83] This has facilitated large-scale studies linking somatic burdens to aging and disease risk, with mutations in oral epithelium accumulating at rates of roughly 18 SNVs per cell per year, achieving error rates below 5 × 10⁻⁹ per base pair even in low-input samples.^[39]

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Germline mutations (that occur in eggs and sperm) can be passed on to offspring, while somatic mutations (that occur in body cells) are not passed on.Point Mutation · Mutación · Deletion
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The effects of mutations - Understanding Evolution
Not all mutations matter for evolution. Somatic mutations occur in non-reproductive cells and so won't be passed on to offspring.
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Definition of gonadal mosaicism - NCI Dictionary of Genetics Terms
This means that a parent may not develop a genetic condition but could pass it on to one or more of their children.Missing: inheritance | Show results with:inheritance
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Mosaicism in Human Health and Disease - PMC - NIH
Somatic mosaicism is a postzygotic mutation that occurs in the soma, and it may occur at any developmental stage or in adult tissues.
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Gonadal Mosaicism as a Rare Inheritance Pattern in Recessive ...
Sep 11, 2024 · Gonadal or germline mosaicism refers to the presence of two distinct cell populations in the gonads, one of which contains a genetic aberration.
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Somatic mutation load and spectra: A record of DNA damage and ...
This review focuses on the current methodologies to measure mutation loads and to determine mutation signatures for evaluating the environmental and endogenous ...
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APOBEC mutagenesis is a common process in normal human small ...
Jan 26, 2023 · APOBEC mutagenesis is found frequently in small intestine epithelium compared to the large intestine epithelium and most other cell types thus ...
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Mutational signatures of ionizing radiation in second malignancies
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Tobacco exposure and somatic mutations in normal human ... - NIH
Jul 29, 2020 · Summary. Tobacco smoking causes lung cancer, driven by the 60+ carcinogens in cigarette smoke that directly damage and mutate DNA.
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The Triggering Role of HPV Integration in Cervical Cancer - MDPI
Somatic Mutations. HPV integration can induce mutations in the host genome through various mechanisms. Typical mechanisms include the following: (1) Direct ...
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Mismatch repair gene defects in sporadic colorectal cancers with ...
These results demonstrate that tumours can acquire somatic mutations that presumably do not directly affect cell growth but result only in genetic instability.
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The Dynamics of Somatic Mutagenesis During Life in Humans
Dec 16, 2021 · Whole genome sequencing studies have revealed that there are significant differences in mutation burden and patterns across tissues, but also ...
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Clock-like mutational processes in human somatic cells - PMC
Based on similarities of mutational signature, the mutational process underlying signature 1 is likely to be deamination of 5-methylcytosine at CpG ...
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Single-cell analysis reveals different age-related somatic mutation ...
Jan 31, 2020 · Accumulating somatic mutations have been implicated in age-related cellular degeneration and death. Because of their random nature and low ...
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Commonalities and differences in the mutational signature and ...
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Dec 24, 2019 · Somatic mutations in healthy tissues contribute to aging, neurodegeneration, and cancer initiation, yet they remain largely uncharacterized.
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Age-related somatic mutation burden in human tissues - Frontiers
Sep 20, 2022 · Somatic mutations also accumulate with age in hematopoietic cells, albeit at a moderate rate of only 14∼25 SNVs/cell/year (Zhang et al., 2019; ...Abstract · Introduction · Tissue-specific somatic... · Functional impact of increased...
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somatic mutation in the brain links age-related decline with disease ...
Somatic single-nucleotide variants (SNVs) increase with age in the human brain, in a somewhat stochastic process that may nonetheless be controlled by ...
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Somatic mutations in chronic lung disease are associated ... - medRxiv
Mar 5, 2023 · This pattern suggests that high turnover cells, such as airway epithelial cells, have higher accumulation of somatic mutations compared to ...
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The human brain through the lens of somatic mosaicism - Frontiers
May 11, 2023 · This review starts with a methodological perspective on the study of somatic mosaicism to then cover the most recent findings in brain development and aging.
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AID AND SOMATIC HYPERMUTATION - PMC - NIH
In response to an assault by foreign organisms, peripheral B cells can change their antibody affinity and isotype by somatically mutating their genomic DNA.
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The generation of antibody diversity through somatic hypermutation and class switch recombination
### Summary of Mutation Rates for SHM and Comparison to Baseline Somatic Mutation Rates
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Diverse mutational landscapes in human lymphocytes - Nature
Aug 10, 2022 · The adaptive immune system depends on programmed somatic mutation to generate antigen receptor diversity. ... V(D)J recombination is mediated by ...
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Somatic generation of antibody diversity - Nature
Apr 14, 1983 · Both somatic recombination and mutation contribute greatly to an increase in the diversity of antibody synthesized by a single organism.
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Somatic mutations associate with clonal expansion of CD8 + T cells
Jun 7, 2024 · Somatic mutations in T cells can cause cancer but also have implications for immunological diseases and cell therapies.
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Somatic mutations in lymphocytes in patients with immune-mediated ...
Mar 30, 2021 · Our results suggest that somatic mutations in T cells are common, associate with clonality, and can alter T-cell phenotype, warranting further investigation.
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Origin and evolutionary malleability of T cell receptor α diversity
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https://www.nature.com/articles/302575a0
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Planarian Regeneration as a Model of Anatomical Homeostasis
How is it possible for the genome to accumulate somatic mutations over hundreds of millions of years and yet maintain perfect anatomical fidelity? This ...
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Mutational profile of the regenerative process and de novo genome ...
Most of these mutations arose during regeneration as they were not detected in the parent, and their spectrum differed from somatic mutations in control animals ...
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Somatic TP53 mutation mosaicism in a patient with Li-Fraumeni ...
However, both tumors were typical for the Li-Fraumeni syndrome (LFS), and the patient met criteria for germline TP53 mutation testing. A mutation in codon 282 ( ...
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Guidelines for the Li–Fraumeni and heritable TP53-related cancer ...
May 26, 2020 · ... somatic TP53 alterations conferring a growth advantage. ... Contribution of de novo and mosaic TP53 mutations to Li-Fraumeni syndrome.
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Spatial transcriptomics reveals human cortical layer and area ...
May 14, 2025 · Cell lineage analysis with somatic mutations reveals late divergence of neuronal cell types and cortical areas in human cerebral cortex.
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Grave-to-cradle: human embryonic lineage tracing from the ... - Nature
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https://pubmed.ncbi.nlm.nih.gov/19012332/
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Induced somatic mutation accumulation during skeletal muscle ...
Aug 20, 2025 · Our study provides experimental evidence that somatic mutation accumulation in post-zygotic cells can contribute to muscle aging phenotypes. It ...
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Somatic mitochondrial DNA mutations in mammalian aging - PubMed
Aging humans have increased levels of somatic mtDNA mutations that tend to undergo clonal expansion to cause mosaic respiratory chain deficiency.
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Somatic mutations in aging and disease - PMC - NIH
By now, numerous studies have documented the accumulation of somatic mutations with age in normal cells and tissues of mice, humans, and other animals, showing ...
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Aging and neurodegeneration are associated with increased ...
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Somatic mutations in human ageing: New insights from DNA ...
While numbers of SNVs detected in most tissues were found in a range of a few hundred to several thousand per genome, these numbers vary from tissue to tissue.
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The genetics of human ageing - PMC - PubMed Central - NIH
Widely cited heritability estimates for human longevity from twin studies range from 20 ... Similar accumulations of somatic mutations with age have been ...
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CRISPR base editor treats premature-aging syndrome - Nature
Apr 16, 2021 · CRISPR-mediated adenine base editor (ABE) to repair mutations of the Hutchinson–Gilford progeria syndrome (HGPS or progeria), attenuate symptoms, and extend ...
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Cryptic mitochondrial DNA mutations coincide with mid-late life and ...
Mar 6, 2025 · These findings suggest that caloric restriction slows the rate of increase of average cryptic heteroplasmy, this mechanism might be an ...
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Struggle within: evolution and ecology of somatic cell populations
In short, some form of somatic “de-Darwinization” or suppression of intra-organism evolution has become recognized as a prerequisite for multicellular ...
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Somatic mutations – Evolution within the individual - ScienceDirect
Apr 1, 2020 · Somatic mutation is an alternation in DNA that occurs after conception. In contrast to germline mutations, somatic mutations are not transmitted to progeny.Somatic Mutations... · 2.5. Transposable Elements... · 2.7. Gene Expressions And...
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Animal Cell Differentiation Patterns Suppress Somatic Evolution - PMC
Somatic evolution is inevitable given the cumulative Darwinian selection that occurs in any self-renewing population of proliferating cells, together with a ...
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Selection for somatic escape variants in SERPINA1 in the liver of ...
Mar 10, 2025 · We show that somatic variants in SERPINA1, the gene encoding A1AT, are strongly selected for in A1AT deficiency, with evidence of convergent evolution.
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Somatic mutations increase hepatic clonal fitness and regeneration ...
Normal tissues accumulate genetic changes with age, but it is unknown if somatic mutations promote clonal expansion of non-malignant cells in the setting of ...
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The Evolutionary Origin of Somatic Cells under the Dirty Work ... - NIH
May 13, 2014 · We analyze the lineages of multicellular organisms that successfully differentiate and discover that they display unforeseen evolutionary ...
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Clonal dynamics and somatic evolution of haematopoiesis in mouse
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Single-cell phylodynamic inference of stem cell differentiation and ...
May 21, 2025 · We introduce scPhyloX, a computational framework modeling structured cell populations by leveraging single-cell phylogenetic trees to infer tissue development ...
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The use of technical replication for detection of low-level somatic ...
Mar 5, 2019 · Next-generation sequencing (NGS) has afforded researchers the means with which to investigate somatic variants with tremendous accuracy. For ...
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Systematic comparison of somatic variant calling performance ...
Feb 26, 2020 · Whole-exome sequencing (WES) is an effective approach to detect genome mutations. It is reported that WES can detect 95% coding regions and >98% ...
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De novo detection of somatic mutations in high-throughput single ...
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Usefulness of Circulating Tumor DNA in Identifying Somatic ... - NIH
Interpretation: ctDNA analysis offers similar usefulness to tissue biopsy analysis in detecting somatic mutations, assessing mutual exclusivity, analyzing ...
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Challenges associated with the identification of germline variants on ...
Although primarily intended to identify somatic mutations, not infrequently, potentially clinically significant germline variants are also identified.
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Somatic variant calling from single-cell DNA sequencing data
This review will focus on the bioinformatic methods developed to identify genomic alterations from scDNA-seq data, particularly single-nucleotide variants ( ...
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New AI tool detects hidden cancer mutations - UC Santa Cruz - News
Oct 16, 2025 · DeepSomatic uses AI to detect cancer-causing variants more accurately across all major DNA sequencing technologies, moving genome sequencing ...
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SAVANA: reliable analysis of somatic structural variants and copy ...
May 28, 2025 · Here we describe SAVANA, an algorithm designed to detect somatic SVs and SCNAs at single-haplotype resolution and estimate tumor purity and ploidy using long- ...Missing: advances | Show results with:advances
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Somatic mutation and selection at population scale - Nature
Oct 8, 2025 · Variants of uncertain significance are germline or somatic variants identified by genetic testing whose clinical relevance is unknown. Evidence ...
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Analysis of somatic mutations in whole blood from 200,618 ... - Nature
May 14, 2024 · Analysis of somatic mutations in whole blood from 200,618 individuals identifies pervasive positive selection and novel drivers of clonal ...