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Review
. 2022 Sep 26:13:983668.
doi: 10.3389/fgene.2022.983668. eCollection 2022.

De novo mutations, genetic mosaicism and human disease

Mohiuddin Mohiuddin  1 , R Frank Kooy  2 , Christopher E Pearson  1   3
Affiliations
Review

De novo mutations, genetic mosaicism and human disease

Mohiuddin Mohiuddin et al. Front Genet. .

Abstract

Mosaicism-the existence of genetically distinct populations of cells in a particular organism-is an important cause of genetic disease. Mosaicism can appear as de novo DNA mutations, epigenetic alterations of DNA, and chromosomal abnormalities. Neurodevelopmental or neuropsychiatric diseases, including autism-often arise by de novo mutations that usually not present in either of the parents. De novo mutations might occur as early as in the parental germline, during embryonic, fetal development, and/or post-natally, through ageing and life. Mutation timing could lead to mutation burden of less than heterozygosity to approaching homozygosity. Developmental timing of somatic mutation attainment will affect the mutation load and distribution throughout the body. In this review, we discuss the timing of de novo mutations, spanning from mutations in the germ lineage (all ages), to post-zygotic, embryonic, fetal, and post-natal events, through aging to death. These factors can determine the tissue specific distribution and load of de novo mutations, which can affect disease. The disease threshold burden of somatic de novo mutations of a particular gene in any tissue will be important to define.

Keywords: autism spectrum disorder; de novo mutation; genetic diseases; germline mutation; mosaicism; repeat instability; somatic mutation; timing of mutation.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Overview of categories of mutations including inherited, de novo, and somatic variation. (A) Inherited mutations are constantly transmitted through the germline, which is detectable in all tissues of the child and their parent. (B) Parental gonosomal mutation is detectable in some tissues of the parents and in all tissues of the child, which is transmitted from a parent with mosaic mutation (combination of somatic and germline mosaicism). (C) Parental germline mosaicism is detectable in gametes of the parent and in all tissues of the child. (D) De novo germline mutation is detectable in all tissues of the child but not detectable in the parent. (E) post-zygote/embryonic but pre-fetal somatic mosaicism occurs in zygote within first few cell divisions such that the mutation presents in all cells that contribute to the embryo, is detectable in all tissues of the child but not detectable in the parent. (F) post-embryonic/fetal/pre-natal somatic mosaicism, which is present in nonbrain and brain tissues, occurs early in post-zygotic development, is detectable in some tissues of the child but not detectable in the parent. (G) early post-natal somatic mosaicism, which is present only in the brain, occurs later in post-zygotic development, is detectable only in brain tissue of the child but not detectable in the parent. (H) late post-natal somatic mosaicism, which occurs very late in post-zygotic development, is detectable only in single cell of the child, which requires single-cell sequencing to detect but not detectable in the parent. In all panels, brown denotes the mutation and darker shades designate increasing degree of mosaicism.
FIGURE 2
FIGURE 2
Germline and somatic DNA metabolic processes in human. (A) Somatic mosaicism in patients with a genetic disease can exhibit both pre-natal and post-natal tissue specific mosaicism. (B) Depending on the timing of mutations during embryonic development, different types of germline mosaicism can arise; star signs indicate different stages at which mutations can arise and the consequential types of mosaicism. Germline mosaic variants, which were apparent within the parents’ blood, were possibly established before mesoderm tissue separation from PGCs within the parents (green stars). One potential explanation for mosaic mutations that are only shared by siblings—were not apparent in the parents’ blood—is that the mutations arose after separation of PGCs from mesoderm in the mosaic parents (red stars). (C) Fertilization and also the steps leading to the two-cell embryo, which includes the development of two pronuclei, the completion of maternal meiosis II, decondensation of the paternal genome, DNA repair, gonomeric DNA replication within two haploid pronuclei, the breakdown of pronuclear envelopes, syngamy and cleavage (Gianaroli, 2000). Gonomeric duplication is that the only haploid DNA replication within the diploid metazoan life cycle. DNA metabolic processes appearing during each developmental stage are denoted by graded shading. Abbreviations: rec-repair - recombination-associated repair; gm-repair - genome maintenance repair; repl. - replication errors and replication associated repair; pb, polar body. Information compiled from previously published studies (Drost and Lee, 1995; Gianaroli, 2000; Zenzes, 2000; Baarends et al., 2001). These processes can differ prominently between different species. Figure adapted from Pearson (2003).
FIGURE 3
FIGURE 3
Reproductive and non-reproductive lineage cells and de novo mutations. Mutations that occur in the reproductive lineage from a fertilized egg to gametes can be defined as reproductive lineage cell mutations and categorized into two groups: pre-germ-cell-stage mutations (gonosomal mutation) and germ-cell-stage mutations. The germ-cell-stage mutations arise in the primordial germ cells (pGCs) and their offspring after the point of divergence from somatic cells, usually being designated as germline mutations. Gonosomal mutations arise before this point of divergence. These mutations can exist in both somatic cells and gametes at the same time. The mutations that arise in the non-reproductive lineage cells, after the stage of divergence from germ lineage cells, are designated as somatic cell mutations and are unable to transmit to the offspring. Figure adapted from Sakumi (2019).
FIGURE 4
FIGURE 4
Timing of de novo mutations: they can happen anytime. (A) Diagram of gastrula—the embryo with three primary germ layers (ectoderm, mesoderm, and endoderm). This diagram is color-coded: ectoderm, blue; mesoderm, orange; endoderm, green; and blastopore, purple. Cells in ectoderm, mesoderm and endoderm differentiate into tissues and embryonic organs. The ectoderm contributes to the nervous system and the epidermis, among other tissues. The mesoderm contributes to the muscle cells and connective tissue in the body. The endoderm contributes to the gut and many internal organs (Pansky, 1982). (B) Human timeline of development features and approximate developmental timing of various tissues. Tissues are arranged depending on the approximate time of development. The single-cell zygote, which proceeds through cleavage divisions and the morula stage to form the blastocyst, is arose by the fertilization of a mature oocyte by a sperm cell. The embryo is originated from the inner cell mass of the blastocyst. During the process of gastrulation, these cells differentiate to form the three germ layers (ectoderm, endoderm, and mesoderm), which differentiate into tissues and embryonic organs. Following birth and sexual maturation, mature sperm and oocytes are produced by the completion of meiosis in adult animals. Schematics prepared using bio-render software.
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