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.
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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.
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S.M.W. and J.E.P researched the literature. The authors contributed equally to all other aspects of the manuscript.
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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.
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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
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DOI: https://doi.org/10.1038/s41576-024-00715-z