Abstract
Nearly every mammalian cell division is accompanied by a mutational event that becomes fixed in a daughter cell. When carried forward to additional cell progeny, a clone of variant cells can emerge. As a result, mammals are complex mosaics of clones that are genetically distinct from one another. Recent high-throughput sequencing studies have revealed that mosaicism is common, clone sizes often increase with age and specific variants can affect tissue function and disease development. Variants that are acquired during early embryogenesis are shared by multiple cell types and can affect numerous tissues. Within tissues, variant clones compete, which can result in their expansion or elimination. Embryonic mosaicism has clinical implications for genetic disease severity and transmission but is likely an under-recognized phenomenon. To better understand its implications for mosaic individuals, it is essential to leverage research tools that can elucidate the mechanisms by which expanded embryonic variants influence development and disease.
This is a preview of subscription content, access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$189.00 per year
only $15.75 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Behjati, S. et al. Genome sequencing of normal cells reveals developmental lineages and mutational processes. Nature 513, 422–425 (2014). This study is one of the first to use colony sequencing from a multicellular organism to reconstruct phylogenies based on shared variants.
Ju, Y. S. et al. Somatic mutations reveal asymmetric cellular dynamics in the early human embryo. Nature 543, 714–718 (2017).
Ye, A. Y. et al. A model for postzygotic mosaicisms quantifies the allele fraction drift, mutation rate, and contribution to de novo mutations. Genome Res. 28, 943–951 (2018).
Spencer Chapman, M. et al. Lineage tracing of human development through somatic mutations. Nature 595, 85–90 (2021).
Coorens, T. H. H. et al. Extensive phylogenies of human development inferred from somatic mutations. Nature 597, 387–392 (2021).
Rockweiler, N. B. et al. The origins and functional effects of postzygotic mutations throughout the human life span. Science 380, eabn7113 (2023). This study demonstrates the potential to use widely available bulk RNA-seq databases for mosaic variant discovery and to reveal insights about embryonic variant acquisition.
Jaiswal, S. et al. Age-related clonal hematopoiesis associated with adverse outcomes. N. Engl. J. Med. 371, 2488–2498 (2014). In this study, the authors provide one of the first demonstrations of the ubiquity of somatic mosaicism in the blood of aged individuals and link it to adverse health outcomes.
Genovese, G. et al. Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N. Engl. J. Med. 371, 2477–2487 (2014).
Coombs, C. C. et al. Therapy-related clonal hematopoiesis in patients with non-hematologic cancers is common and associated with adverse clinical outcomes. Cell Stem Cell 21, 374–382.e4 (2017).
Martincorena, I. et al. Somatic mutant clones colonize the human esophagus with age. Science 362, 911–917 (2018).
Watson, C. J. et al. The evolutionary dynamics and fitness landscape of clonal hematopoiesis. Science 367, 1449–1454 (2020).
Moore, L. et al. The mutational landscape of human somatic and germline cells. Nature 597, 381–386 (2021).
Aluri, J. & Cooper, M. A. Genetic mosaicism as a cause of inborn errors of immunity. J. Clin. Immunol. 41, 718–728 (2021).
Campbell, I. M., Shaw, C. A., Stankiewicz, P. & Lupski, J. R. Somatic mosaicism: implications for disease and transmission genetics. Trends Genet. 31, 382–392 (2015).
Martinez-Glez, V. et al. A six-attribute classification of genetic mosaicism. Genet. Med. 22, 1743–1757 (2020).
Park, S. et al. Clonal dynamics in early human embryogenesis inferred from somatic mutation. Nature 597, 393–397 (2021).
Acuna-Hidalgo, R. et al. Post-zygotic point mutations are an underrecognized source of de novo genomic variation. Am. J. Hum. Genet. 97, 67–74 (2015). This study is one of the earliest to use trio sequencing to demonstrate that a substantial portion of variants presumed to be germline are in fact mosaic.
Cook, C. B. et al. Somatic mosaicism detected by genome-wide sequencing in 500 parent–child trios with suspected genetic disease: clinical and genetic counseling implications. Cold Spring Harb. Mol. Case Stud. 7, a006125 (2021).
Wright, C. F. et al. Clinically-relevant postzygotic mosaicism in parents and children with developmental disorders in trio exome sequencing data. Nat. Commun. 10, 2985 (2019).
Gambin, T. et al. Low-level parental somatic mosaic SNVs in exomes from a large cohort of trios with diverse suspected Mendelian conditions. Genet. Med. 22, 1768–1776 (2020).
Domogala, D. D. et al. Detection of low-level parental somatic mosaicism for clinically relevant SNVs and indels identified in a large exome sequencing dataset. Hum. Genomics 15, 72 (2021).
Sasani, T. A. et al. Large, three-generation human families reveal post-zygotic mosaicism and variability in germline mutation accumulation. eLife 8, e46922 (2019).
Lee, H. et al. Characterization of early postzygotic somatic mutations through multi-organ analysis. J. Hum. Genet. 66, 777–784 (2021).
Rodin, R. E. et al. The landscape of somatic mutation in cerebral cortex of autistic and neurotypical individuals revealed by ultra-deep whole-genome sequencing. Nat. Neurosci. 24, 176–185 (2021).
Gallini, S. et al. Injury prevents Ras mutant cell expansion in mosaic skin. Nature 619, 167–175 (2023).
Thorpe, J., Osei-Owusu, I. A., Avigdor, B. E., Tupler, R. & Pevsner, J. Mosaicism in human health and disease. Annu. Rev. Genet. 54, 487–510 (2020). In this review, the authors discuss the genetic mechanisms of mosaic variant acquisition and details about various detection techniques.
van Echten-Arends, J. et al. Chromosomal mosaicism in human preimplantation embryos: a systematic review. Hum. Reprod. Update 17, 620–627 (2011).
Taylor, T. H. et al. The origin, mechanisms, incidence and clinical consequences of chromosomal mosaicism in humans. Hum. Reprod. Update 20, 571–581 (2014).
Levy, B., Hoffmann, E. R., McCoy, R. C. & Grati, F. R. Chromosomal mosaicism: origins and clinical implications in preimplantation and prenatal diagnosis. Prenat. Diagn. 41, 631–641 (2021).
Vorsanova, S. G., Yurov, Y. B. & Iourov, I. Y. Dynamic nature of somatic chromosomal mosaicism, genetic–environmental interactions and therapeutic opportunities in disease and aging. Mol. Cytogenet. 13, 16 (2020).
Campbell, I. M. et al. Parental somatic mosaicism is underrecognized and influences recurrence risk of genomic disorders. Am. J. Hum. Genet. 95, 173–182 (2014).
Hatton, I. A. et al. The human cell count and size distribution. Proc. Natl Acad. Sci. USA 120, e2303077120 (2023).
Munisha, M. & Schimenti, J. C. Genome maintenance during embryogenesis. DNA Repair. 106, 103195 (2021).
Kermi, C., Aze, A. & Maiorano, D. Preserving genome integrity during the early embryonic DNA replication cycles. Genes 10, 398 (2019).
Bae, T. et al. Different mutational rates and mechanisms in human cells at pregastrulation and neurogenesis. Science 359, 550–555 (2018).
Fasching, L. et al. Early developmental asymmetries in cell lineage trees in living individuals. Science 371, 1245–1248 (2021).
Lee-Six, H. et al. Population dynamics of normal human blood inferred from somatic mutations. Nature 561, 473–478 (2018). This study pioneers the capture–recapture technique to reconstruct phylogenies of human haematopoiesis.
Bizzotto, S. et al. Landmarks of human embryonic development inscribed in somatic mutations. Science 371, 1249–1253 (2021).
Nam, A. S. et al. Somatic mutations and cell identity linked by genotyping of transcriptomes. Nature 571, 355–360 (2019).
Huang, A. Y. et al. Parallel RNA and DNA analysis after deep sequencing (PRDD-seq) reveals cell type-specific lineage patterns in human brain. Proc. Natl Acad. Sci. USA 117, 13886–13895 (2020).
Kim, J. H. et al. Analysis of low-level somatic mosaicism reveals stage and tissue-specific mutational features in human development. PLoS Genet. 18, e1010404 (2022).
Liu, Q. et al. Parental somatic mosaicism for CNV deletions—a need for more sensitive and precise detection methods in clinical diagnostics settings. Genomics 112, 2937–2941 (2020).
Lim, E. T. et al. Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder. Nat. Neurosci. 20, 1217–1224 (2017).
Mensa-Vilaro, A. et al. Unexpected relevant role of gene mosaicism in patients with primary immunodeficiency diseases. J. Allergy Clin. Immunol. 143, 359–368 (2019). In this study, the authors demonstrate that an unexpectedly large number of families with primary immunodeficiency disorders exhibit mosaicism.
Depienne, C. et al. Parental mosaicism can cause recurrent transmission of SCN1A mutations associated with severe myoclonic epilepsy of infancy. Hum. Mutat. 27, 389 (2006).
Xu, X. et al. Amplicon resequencing identified parental mosaicism for approximately 10% of “de novo” SCN1A mutations in children with Dravet syndrome. Hum. Mutat. 36, 861–872 (2015).
Yang, X. et al. Genomic mosaicism in paternal sperm and multiple parental tissues in a Dravet syndrome cohort. Sci. Rep. 7, 15677 (2017).
Nakayama, T. et al. Somatic mosaic deletions involving SCN1A cause Dravet syndrome. Am. J. Med. Genet. A 176, 657–662 (2018).
Aluri, J. et al. Immunodeficiency and bone marrow failure with mosaic and germline TLR8 gain of function. Blood 137, 2450–2462 (2021).
Klonowska, K. et al. Comprehensive genetic and phenotype analysis of 95 individuals with mosaic tuberous sclerosis complex. Am. J. Hum. Genet. 110, 979–988 (2023).
Tovy, A. et al. Tissue-biased expansion of DNMT3A-mutant clones in a mosaic individual is associated with conserved epigenetic erosion. Cell Stem Cell 27, 326–335.e4 (2020).
Williams, N. et al. Life histories of myeloproliferative neoplasms inferred from phylogenies. Nature 602, 162–168 (2022).
Castillo, D. et al. Clonal hematopoiesis and mosaicism revealed by a multi-tissue analysis of constitutional TP53 status. Cancer Epidemiol. Biomark. Prev. 31, 1621–1629 (2022).
Karaman, B. et al. Pallister–Killian syndrome: clinical, cytogenetic and molecular findings in 15 cases. Mol. Cytogenet. 11, 45 (2018).
Holzelova, E. et al. Autoimmune lymphoproliferative syndrome with somatic Fas mutations. N. Engl. J. Med. 351, 1409–1418 (2004).
Beck, D. B. et al. Somatic mutations in UBA1 and severe adult-onset autoinflammatory disease. N. Engl. J. Med. 383, 2628–2638 (2020).
Long, C. et al. Prevention of muscular dystrophy in mice by CRISPR/Cas9-mediated editing of germline DNA. Science 345, 1184–1188 (2014). This study demonstrates that a fraction of cells with a corrected Dmd allele can expand and abrogate the muscular dystrophy phenotype in a mouse model.
Kesari, A. et al. Somatic mosaicism for Duchenne dystrophy: evidence for genetic normalization mitigating muscle symptoms. Am. J. Med. Genet. A 149A, 1499–1503 (2009).
Huisman, S. A., Redeker, E. J., Maas, S. M., Mannens, M. M. & Hennekam, R. C. High rate of mosaicism in individuals with Cornelia de Lange syndrome. J. Med. Genet. 50, 339–344 (2013).
Lindhurst, M. J. et al. A mosaic activating mutation in AKT1 associated with the Proteus syndrome. N. Engl. J. Med. 365, 611–619 (2011).
Donkervoort, S. et al. Mosaicism for dominant collagen 6 mutations as a cause for intrafamilial phenotypic variability. Hum. Mutat. 36, 48–56 (2015).
Li, W. & Baker, N. E. Engulfment is required for cell competition. Cell 129, 1215–1225 (2007).
Claveria, C., Giovinazzo, G., Sierra, R. & Torres, M. Myc-driven endogenous cell competition in the early mammalian embryo. Nature 500, 39–44 (2013).
Ellis, S. J. et al. Distinct modes of cell competition shape mammalian tissue morphogenesis. Nature 569, 497–502 (2019).
Zhang, G. et al. p53 pathway is involved in cell competition during mouse embryogenesis. Proc. Natl Acad. Sci. USA 114, 498–503 (2017).
Lima, A. et al. Cell competition acts as a purifying selection to eliminate cells with mitochondrial defects during early mouse development. Nat. Metab. 3, 1091–1108 (2021).
Challen, G. A. et al. Dnmt3a is essential for hematopoietic stem cell differentiation. Nat. Genet. 44, 23–31 (2011).
Hsu, J. I. et al. PPM1D mutations drive clonal hematopoiesis in response to cytotoxic chemotherapy. Cell Stem Cell 23, 700–713.e6 (2018).
Revy, P., Kannengiesser, C. & Fischer, A. Somatic genetic rescue in Mendelian haematopoietic diseases. Nat. Rev. Genet. 20, 582–598 (2019). In this review, the authors describe in detail mosaic reversion events occurring in the hematopoietic system, where they have been most commonly described.
Jongmans, M. C. et al. Revertant somatic mosaicism by mitotic recombination in dyskeratosis congenita. Am. J. Hum. Genet. 90, 426–433 (2012).
Catto, L. F. B. et al. Somatic genetic rescue in hematopoietic cells in GATA2 deficiency. Blood 136, 1002–1005 (2020).
Bar, D. Z. et al. A novel somatic mutation achieves partial rescue in a child with Hutchinson–Gilford progeria syndrome. J. Med. Genet. 54, 212–216 (2017).
Narumi, S. et al. SAMD9 mutations cause a novel multisystem disorder, MIRAGE syndrome, and are associated with loss of chromosome 7. Nat. Genet. 48, 792–797 (2016).
Buonocore, F. et al. Somatic mutations and progressive monosomy modify SAMD9-related phenotypes in humans. J. Clin. Invest. 127, 1700–1713 (2017).
Veitia, R. A. MIRAGE syndrome: phenotypic rescue by somatic mutation and selection. Trends Mol. Med. 25, 937–940 (2019).
Shirley, M. D. et al. Sturge–Weber syndrome and port-wine stains caused by somatic mutation in GNAQ. N. Engl. J. Med. 368, 1971–1979 (2013).
Weinstein, L. S. et al. Activating mutations of the stimulatory G protein in the McCune–Albright syndrome. N. Engl. J. Med. 325, 1688–1695 (1991).
Lim, J. S. et al. Brain somatic mutations in MTOR cause focal cortical dysplasia type II leading to intractable epilepsy. Nat. Med. 21, 395–400 (2015).
Eskin-Schwartz, M. et al. Somatic mosaicism for a “lethal” GJB2 mutation results in a patterned form of spiny hyperkeratosis without eccrine involvement. Pediatr. Dermatol. 33, 322–326 (2016).
Campbell, I. M. et al. Parent of origin, mosaicism, and recurrence risk: probabilistic modeling explains the broken symmetry of transmission genetics. Am. J. Hum. Genet. 95, 345–359 (2014). This study demonstrates that recurrence risk in offspring varies based on the presence of parental mosaicism and the sex of the mosaic parent.
Jonsson, H. et al. Multiple transmissions of de novo mutations in families. Nat. Genet. 50, 1674–1680 (2018).
Jamuar, S. S. et al. Somatic mutations in cerebral cortical malformations. N. Engl. J. Med. 371, 733–743 (2014).
Koboldt, D. C. Best practices for variant calling in clinical sequencing. Genome Med. 12, 91 (2020).
Yan, Y. H. et al. Confirming putative variants at ≤5% allele frequency using allele enrichment and Sanger sequencing. Sci. Rep. 11, 11640 (2021).
Doan, R. N. et al. MIPP-Seq: ultra-sensitive rapid detection and validation of low-frequency mosaic mutations. BMC Med. Genomics 14, 47 (2021).
Zhou, B. et al. Detection and quantification of mosaic genomic DNA variation in primary somatic tissues using ddPCR: analysis of mosaic transposable-element insertions, copy-number variants, and single-nucleotide variants. Methods Mol. Biol. 1768, 173–190 (2018).
Ha, Y. J. et al. Comprehensive benchmarking and guidelines of mosaic variant calling strategies. Nat. Methods 20, 2058–2067 (2023).
Dou, Y. et al. Accurate detection of mosaic variants in sequencing data without matched controls. Nat. Biotechnol. 38, 314–319 (2020).
Huang, A. Y. & Lee, E. A. Identification of somatic mutations from bulk and single-cell sequencing data. Front. Aging 2, 800380 (2021).
Glessner, J. T. et al. MONTAGE: a new tool for high-throughput detection of mosaic copy number variation. BMC Genomics 22, 133 (2021).
Muyas, F. et al. De novo detection of somatic mutations in high-throughput single-cell profiling data sets. Nat. Biotechnol. https://doi.org/10.1038/s41587-023-01863-z (2023).
Salk, J. J., Schmitt, M. W. & Loeb, L. A. Enhancing the accuracy of next-generation sequencing for detecting rare and subclonal mutations. Nat. Rev. Genet. 19, 269–285 (2018).
King, D. A. et al. Detection of structural mosaicism from targeted and whole-genome sequencing data. Genome Res. 27, 1704–1714 (2017).
Chen, D. et al. Human primordial germ cells are specified from lineage-primed progenitors. Cell Rep. 29, 4568–4582.e5 (2019).
Yang, X. et al. Developmental and temporal characteristics of clonal sperm mosaicism. Cell 184, 4772–4783.e15 (2021).
Jonsson, H. et al. Differences between germline genomes of monozygotic twins. Nat. Genet. 53, 27–34 (2021).
Breuss, M. W. et al. Autism risk in offspring can be assessed through quantification of male sperm mosaicism. Nat. Med. 26, 143–150 (2020).
Moller, R. S. et al. Parental mosaicism in epilepsies due to alleged de novo variants. Epilepsia 60, e63–e66 (2019).
Goriely, A. et al. Gain-of-function amino acid substitutions drive positive selection of FGFR2 mutations in human spermatogonia. Proc. Natl Acad. Sci. USA 102, 6051–6056 (2005).
Shinde, D. N. et al. New evidence for positive selection helps explain the paternal age effect observed in achondroplasia. Hum. Mol. Genet. 22, 4117–4126 (2013).
Yoon, S. R. et al. Age-dependent germline mosaicism of the most common noonan syndrome mutation shows the signature of germline selection. Am. J. Hum. Genet. 92, 917–926 (2013).
Choi, S. K., Yoon, S. R., Calabrese, P. & Arnheim, N. Positive selection for new disease mutations in the human germline: evidence from the heritable cancer syndrome multiple endocrine neoplasia type 2B. PLoS Genet. 8, e1002420 (2012).
Maher, G. J. et al. Selfish mutations dysregulating RAS–MAPK signaling are pervasive in aged human testes. Genome Res. 28, 1779–1790 (2018).
Lim, J. et al. Selfish spermatogonial selection: evidence from an immunohistochemical screen in testes of elderly men. PLoS ONE 7, e42382 (2012).
Fu, X. J. et al. Somatic mosaicism and variant frequency detected by next-generation sequencing in X-linked Alport syndrome. Eur. J. Hum. Genet. 24, 387–391 (2016).
Schirwani, S. et al. Mosaicism in ASXL3-related syndrome: description of five patients from three families. Eur. J. Med. Genet. 63, 103925 (2020).
Baker, S. W. et al. Improved molecular detection of mosaicism in Beckwith–Wiedemann syndrome. J. Med. Genet. 58, 178–184 (2021).
Weksberg, R. et al. Discordant KCNQ1OT1 imprinting in sets of monozygotic twins discordant for Beckwith–Wiedemann syndrome. Hum. Mol. Genet. 11, 1317–1325 (2002).
Cohen, J. L. et al. Diagnosis and management of the phenotypic spectrum of twins with Beckwith–Wiedemann syndrome. Am. J. Med. Genet. A 179, 1139–1147 (2019).
Urraca, N. et al. A rare inherited 15q11.2-q13.1 interstitial duplication with maternal somatic mosaicism, renal carcinoma, and autism. Front. Genet. 7, 205 (2016).
Ansari, M. et al. Genetic heterogeneity in Cornelia de Lange syndrome (CdLS) and CdLS-like phenotypes with observed and predicted levels of mosaicism. J. Med. Genet. 51, 659–668 (2014).
Stosser, M. B. et al. High frequency of mosaic pathogenic variants in genes causing epilepsy-related neurodevelopmental disorders. Genet. Med. 20, 403–410 (2018).
Terracciano, A. et al. Somatic mosaicism of PCDH19 mutation in a family with low-penetrance EFMR. Neurogenetics 13, 341–345 (2012).
Hague, J. et al. Molecularly proven mosaicism in phenotypically normal parent of a girl with Freeman–Sheldon syndrome caused by a pathogenic MYH3 mutation. Am. J. Med. Genet. A 170, 1608–1612 (2016).
Alcantara-Montiel, J. C. et al. Somatic mosaicism in B cells of a patient with autosomal dominant hyper IgE syndrome. Eur. J. Immunol. 46, 2438–2443 (2016).
Hsu, A. P. et al. Intermediate phenotypes in patients with autosomal dominant hyper-IgE syndrome caused by somatic mosaicism. J. Allergy Clin. Immunol. 131, 1586–1593 (2013).
Hildebrand, M. S. et al. Mutations of the sonic hedgehog pathway underlie hypothalamic hamartoma with gelastic epilepsy. Am. J. Hum. Genet. 99, 423–429 (2016).
Green, T. E. et al. Sporadic hypothalamic hamartoma is a ciliopathy with somatic and bi-allelic contributions. Hum. Mol. Genet. 31, 2307–2316 (2022).
Green, T. E. et al. Brain mosaicism of hedgehog signalling and other cilia genes in hypothalamic hamartoma. Neurobiol. Dis. 185, 106261 (2023).
Prochazkova, K. et al. Somatic TP53 mutation mosaicism in a patient with Li–Fraumeni syndrome. Am. J. Med. Genet. A 149A, 206–211 (2009).
Consoli, C. et al. Gonosomal mosaicism for a nonsense mutation (R1947X) in the NF1 gene in segmental neurofibromatosis type 1. J. Invest. Dermatol. 125, 463–466 (2005).
Friedman, D. P. Segmental neurofibromatosis (NF-5): a rare form of neurofibromatosis. AJNR Am. J. Neuroradiol. 12, 971–972 (1991).
Ruggieri, M. & Polizzi, A. Segmental neurofibromatosis. J. Neurosurg. 93, 530–532 (2000).
Boyd, K. P., Korf, B. R. & Theos, A. Neurofibromatosis type 1. J. Am. Acad. Dermatol. 61, 1–14 (2009).
Kluwe, L. & Mautner, V. F. Mosaicism in sporadic neurofibromatosis 2 patients. Hum. Mol. Genet. 7, 2051–2055 (1998).
Evans, D. G. et al. Incidence of mosaicism in 1055 de novo NF2 cases: much higher than previous estimates with high utility of next-generation sequencing. Genet. Med. 22, 53–59 (2020).
Kim, H. J., Song, M. J., Lee, K. O., Kim, S. H. & Kim, H. J. Paternal somatic mosaicism of a novel frameshift mutation in ELANE causing severe congenital neutropenia. Pediatr. Blood Cancer 62, 2229–2231 (2015).
Bartsch, O. et al. Inheritance and variable expression in Rubinstein–Taybi syndrome. Am. J. Med. Genet. A 152A, 2254–2261 (2010).
Kamien, B. et al. Somatic-gonadal mosaicism causing Sotos syndrome. Am. J. Med. Genet. A 170, 3360–3362 (2016).
Spiegel, R. et al. Severe infantile male encephalopathy is a result of early post-zygotic WDR45 somatic mutation. Clin. Genet. 90, 560–562 (2016).
Nakashima, M. et al. WDR45 mutations in three male patients with West syndrome. J. Hum. Genet. 61, 653–661 (2016).
Cooley Coleman, J. A. et al. Mosaicism of common pathogenic MECP2 variants identified in two males with a clinical diagnosis of Rett syndrome. Am. J. Med. Genet. A 188, 2988–2998 (2022).
Xin, B. et al. Novel DNMT3A germline mutations are associated with inherited Tatton–Brown–Rahman syndrome. Clin. Genet. 91, 623–628 (2017).
Hyland, V. J. et al. Somatic and germline mosaicism for a R248C missense mutation in FGFR3, resulting in a skeletal dysplasia distinct from thanatophoric dysplasia. Am. J. Med. Genet. A 120A, 157–168 (2003).
Takagi, M., Kaneko-Schmitt, S., Suzumori, N., Nishimura, G. & Hasegawa, T. Atypical achondroplasia due to somatic mosaicism for the common thanatophoric dysplasia mutation R248C. Am. J. Med. Genet. A 158A, 247–250 (2012).
Tyburczy, M. E. et al. Mosaic and intronic mutations in TSC1/TSC2 explain the majority of TSC patients with no mutation identified by conventional testing. PLoS Genet. 11, e1005637 (2015).
Venot, Q. et al. Targeted therapy in patients with PIK3CA-related overgrowth syndrome. Nature 558, 540–546 (2018).
Bennett, J. T. et al. Mosaic activating mutations in FGFR1 cause encephalocraniocutaneous lipomatosis. Am. J. Hum. Genet. 98, 579–587 (2016).
Baldassari, S. et al. Dissecting the genetic basis of focal cortical dysplasia: a large cohort study. Acta Neuropathol. 138, 885–900 (2019).
Kobow, K. et al. Mosaic trisomy of chromosome 1q in human brain tissue associates with unilateral polymicrogyria, very early-onset focal epilepsy, and severe developmental delay. Acta Neuropathol. 140, 881–891 (2020).
Miller, K. E. et al. Post-zygotic rescue of meiotic errors causes brain mosaicism and focal epilepsy. Nat. Genet. 55, 1920–1928 (2023).
Prokopchuk, O. et al. Maffucci syndrome and neoplasms: a case report and review of the literature. BMC Res. Notes 9, 126 (2016).
Zhuang, Z. et al. Somatic HIF2A gain-of-function mutations in paraganglioma with polycythemia. N. Engl. J. Med. 367, 922–930 (2012).
Wang, H., Zhuang, Z., Rosenblum, J. S. & Pacak, K. Somatic mosaicism of EPAS1 mutations in Pacak–Zhuang syndrome. Endocr. Pract. 28, 734–735 (2022).
Groesser, L. et al. Postzygotic HRAS and KRAS mutations cause nevus sebaceous and Schimmelpenning syndrome. Nat. Genet. 44, 783–787 (2012).
Greco, E., Minasi, M. G. & Fiorentino, F. Healthy babies after intrauterine transfer of mosaic aneuploid blastocysts. N. Engl. J. Med. 373, 2089–2090 (2015).
Capalbo, A. et al. Mosaic human preimplantation embryos and their developmental potential in a prospective, non-selection clinical trial. Am. J. Hum. Genet. 108, 2238–2247 (2021).
Zhang, Y. X. et al. The pregnancy outcome of mosaic embryo transfer: a prospective multicenter study and meta-analysis. Genes 11, 973 (2020).
Essers, R. et al. Prevalence of chromosomal alterations in first-trimester spontaneous pregnancy loss. Nat. Med. 29, 3233–3242 (2023).
Currie, C. E. et al. The first mitotic division of human embryos is highly error prone. Nat. Commun. 13, 6755 (2022).
Debo, B., Van Loocke, M., De Groote, K., De Leenheer, E. & Cools, M. Multidisciplinary approach to the child with sex chromosomal mosaicism including a Y-containing cell line. Int. J. Environ. Res. Public Health 18, 917 (2021).
Huang, A. C., Olson, S. B. & Maslen, C. L. A review of recent developments in Turner syndrome research. J. Cardiovasc. Dev. Dis. 8, 138 (2021).
Posey, J. E. et al. Triploidy mosaicism (45,X/68,XX) in an infant presenting with failure to thrive. Am. J. Med. Genet. A 170, 694–698 (2016).
Balbeur, S. et al. Trisomy rescue mechanism: the case of concomitant mosaic trisomy 14 and maternal uniparental disomy 14 in a 15-year-old girl. Clin. Case Rep. 4, 265–271 (2016).
Coorens, T. H. H. et al. Inherent mosaicism and extensive mutation of human placentas. Nature 592, 80–85 (2021).
Yang, M. et al. Depletion of aneuploid cells in human embryos and gastruloids. Nat. Cell Biol. 23, 314–321 (2021).
Singla, S., Iwamoto-Stohl, L. K., Zhu, M. & Zernicka-Goetz, M. Autophagy-mediated apoptosis eliminates aneuploid cells in a mouse model of chromosome mosaicism. Nat. Commun. 11, 2958 (2020).
Price, C. J. et al. Genetically variant human pluripotent stem cells selectively eliminate wild-type counterparts through YAP-mediated cell competition. Dev. Cell 56, 2455–2470.e10 (2021).
Zhang, F., Gu, W., Hurles, M. E. & Lupski, J. R. Copy number variation in human health, disease, and evolution. Annu. Rev. Genomics Hum. Genet. 10, 451–481 (2009).
Pham, J. et al. Somatic mosaicism detected by exon-targeted, high-resolution aCGH in 10,362 consecutive cases. Eur. J. Hum. Genet. 22, 969–978 (2014).
Ballif, B. C. et al. Detection of low-level mosaicism by array CGH in routine diagnostic specimens. Am. J. Med. Genet. A 140, 2757–2767 (2006).
Messiaen, L. et al. Mosaic type-1 NF1 microdeletions as a cause of both generalized and segmental neurofibromatosis type-1 (NF1). Hum. Mutat. 32, 213–219 (2011).
Allen, S. E. et al. Versatile CRISPR/Cas9-mediated mosaic analysis by gRNA-induced crossing-over for unmodified genomes. PLoS Biol. 19, e3001061 (2021).
Zong, H., Espinosa, J. S., Su, H. H., Muzumdar, M. D. & Luo, L. Mosaic analysis with double markers in mice. Cell 121, 479–492 (2005).
Henner, A., Ventura, P. B., Jiang, Y. & Zong, H. MADM-ML, a mouse genetic mosaic system with increased clonal efficiency. PLoS ONE 8, e77672 (2013).
Livet, J. et al. Transgenic strategies for combinatorial expression of fluorescent proteins in the nervous system. Nature 450, 56–62 (2007).
Mintz, B. & Silvers, W. K. “Intrinsic” immunological tolerance in allophenic mice. 1967. J. Immunol. 178, 4007–4010 (2007).
Sakaue, M. et al. DNA methylation is dispensable for the growth and survival of the extraembryonic lineages. Curr. Biol. 20, 1452–1457 (2010).
Ueno, H. & Weissman, I. L. Clonal analysis of mouse development reveals a polyclonal origin for yolk sac blood islands. Dev. Cell 11, 519–533 (2006).
Kinoshita, M. et al. Disabling de novo DNA methylation in embryonic stem cells allows an illegitimate fate trajectory. Proc. Natl Acad. Sci. USA 118, e2109475118 (2021).
Wang, L. et al. CRISPR–Cas9-mediated genome editing in one blastomere of two-cell embryos reveals a novel Tet3 function in regulating neocortical development. Cell Res. 27, 815–829 (2017).
Nakamura, S., Watanabe, S., Ando, N., Ishihara, M. & Sato, M. Transplacental gene delivery (TPGD) as a noninvasive tool for fetal gene manipulation in mice. Int. J. Mol. Sci. 20, 5926 (2019).
Lipshutz, G. S. et al. In utero delivery of adeno-associated viral vectors: intraperitoneal gene transfer produces long-term expression. Mol. Ther. 3, 284–292 (2001).
Wang, Z. et al. Positive selection of somatically mutated clones identifies adaptive pathways in metabolic liver disease. Cell 186, 1968–1984.e20 (2023).
Acknowledgements
The authors acknowledge funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) F30HD111129 (S.M.W.), the Robert and Janice McNair Foundation M.D./Ph.D. Scholars programme (S.M.W.) and Baylor Research Advocates for Student Scientists (S.M.W.). The Goodell laboratory is supported by CA183252, CA237291, DK092883, AG036695 and CA265748. J.E.P is supported by a McGregor Foundation grant.
Author information
Authors and Affiliations
Contributions
S.M.W. and J.E.P researched the literature. The authors contributed equally to all other aspects of the manuscript.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing interests.
Peer review
Peer review information
Nature Reviews Genetics thanks Donald F. Conrad, Naomichi Matsumoto and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Glossary
- Amplicon sequencing
-
Extremely deep sequencing of a short PCR product (amplicon) that lowers the limit of detection for variants in the specific region of interest.
- Aneuploidy
-
A number of chromosomes that is either greater than or lower than a complete diploid set (for example, in humans, a number of chromosomes that does not equal 46).
- Clonal haematopoiesis
-
A condition in which a haematopoietic stem cell acquires a variant that confers a selective advantage, leading to the outgrowth of the variant cell population in the bone marrow and blood over time. Clonal haematopoiesis is associated with an increased risk of various adverse health outcomes, including cancer, cardiovascular disease and all-cause mortality.
- de novo
-
A term to denote a variant that is not inherited from a parent but, instead, appears spontaneously in the proband (the patient or individual under study).
- Digital droplet PCR
-
An alternative to quantitative PCR that provides absolute rather than relative quantification of a DNA sequence of interest, such as a variant sequence.
- dN/dS ratio
-
The ratio of non-synonymous to synonymous variants in a protein-coding gene. Non-synonymous variants change the amino acid codon and are more likely to be deleterious. This ratio serves as a measure of natural selection, with a ratio >1 indicating positive selection and a ratio <1 indicating negative selection against the cell(s) bearing the variant.
- Exome sequencing
-
A type of next-generation sequencing that focuses on the exons (including exon–intron boundaries), or protein-coding regions, of the genome to achieve higher depth at lower cost.
- Gastrulation
-
The process of embryonic development during which the three germ layers (ectoderm, mesoderm and endoderm) are specified. Each germ layer will later give rise to specific groups of organs.
- Genetic variant
-
The specific genetic sequence that differs from the reference sequence found in the majority of a population.
- Genome sequencing
-
A type of next-generation sequencing that covers both protein-coding and non-coding regions of the genome, including intragenic, regulatory and intronic regions.
- Mutant
-
A pathogenic or benign variant in the context of a non-human animal model or a cell culture system.
- Mutational events
-
The biochemical processes of variant acquisition that alter the DNA sequence.
- Mutations
-
Any permanent alterations in the DNA sequence of an organism.
- Obligate mosaicism
-
A condition in which some cells of an organism carry a variant that is lethal when present in all cells.
- Primordial germ cells
-
A group of stem cells in the embryo that differentiate to form sperm or eggs.
- Proband
-
In genetics, the affected patient who initially presents for evaluation.
- Variant allele frequency
-
(VAF). The percentage of sequencing reads that are composed of the variant sequence. A germline heterozygous variant has a VAF of 50%, whereas a homozygous variant has a VAF of 100%.
- Zygote
-
The first cell of a vertebrate embryo, formed when an egg is fertilized by a sperm.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Waldvogel, S.M., Posey, J.E. & Goodell, M.A. Human embryonic genetic mosaicism and its effects on development and disease. Nat Rev Genet (2024). https://doi.org/10.1038/s41576-024-00715-z
Accepted:
Published:
DOI: https://doi.org/10.1038/s41576-024-00715-z
