Somatic mosaicism: implications for disease and transmission genetics

Abstract

Nearly all of the genetic material among cells within an organism is identical. However, single-nucleotide variants (SNVs), small insertions/deletions (indels), copy-number variants (CNVs), and other structural variants (SVs) continually accumulate as cells divide during development. This process results in an organism composed of countless cells, each with its own unique personal genome. Thus, every human is undoubtedly mosaic. Mosaic mutations can go unnoticed, underlie genetic disease or normal human variation, and may be transmitted to the next generation as constitutional variants. We review the influence of the developmental timing of mutations, the mechanisms by which they arise, methods for detecting mosaic variants, and the risk of passing these mutations on to the next generation.

Keywords: mosaicism; postzygotic mutation; recurrence risk; somatic mosaicism; transmission genetics.

Figure I

Use of stochastic process models to study mosaicism. A) A simple exponential model of the emergence of mutations. All cells divide into exactly two cells during each of a predetermined number of mitoses. Mutations are equally likely to occur during each division. B) Galton-Watson model. Cells may divide, give rise to one mutant and one wildtype or expire without dividing during each of a predetermined number of divisions. Fitness can vary with genotype and mutation rate can vary over the process of development. Two or more such models can be combined to model sexual dimorphisms. C) Continuous time branching process model. Cells undergo mitoses after a time determined by a distribution. Thus any two cells may have experienced varying numbers of divisions.

Figure 1

The timing of post-zygotic mutation influences the distribution of mutant cells in the individual. A) Mutations that occur during the first mitosis result in approximately half of the individual being affected. Individuals with CHILD have been observed with this striking pattern (see Figure 2A). B) Mutations that occur before left-right determination can affect both sides of the individual, including one or both gonads. C) Mutations that arise after the determination of the two sides of the embryo can be confined to only one side of the individual. Only one gonad is likely to be effected. D) Mutations that occur after differentiation of primordial germ cells (PGCs) will be absence from somatic tissues. Thus, molecular investigations to detect such gonadal mosaicism must involve direct observation of germ cells. For males, this process is relatively straight forward, but for females it involves invasive biopsy of potentially both ovaries.

Figure 2

Phenotypic manifestations of mosaic mutations. A) Inflammatory nevus affecting the left side of the body of a 1-month-old individual with CHILD syndrome. Note the striking demarcation at the midline. Reproduced with permission from Chander et al. [7] B) Cerebriform connective tissue nevus on the plantar surface of the foot in an 11-year-old individual with Proteus syndrome. Reproduced with permission from Beachkofsky et al. [104]. C) Axial T2-weighted image showing markedly enlarged left cerebral hemisphere in a newborn with hemimegalencephaly. Reproduced with permission from Lang et al.[105]. D) Hyperpigmentation following lines of Blashko in an individual with linear and whorled nevoid hypermelanosis. Reproduced with permission from Molho-Pessach and Schaffer [106].

Figure 3

Personalized assays for detection of mosaicism. A) Structural variants including deletions, duplications and inversions result in two genomic loci that are normally located far apart coming close proximity. B) Researchers can design PCR primers that are capable of amplifying across the breakpoint of the SV. Genomic DNA from individuals harboring only normal alleles do not amplify the breakpoint junction. Meanwhile, individuals with mosaicism for the SV produce the junction because of exponential amplification from the rare allele. C) “Digital” droplet PCR improves detection of mosaicism by segregating wild-type and mutant alleles into individual droplets. Fluorescent probes specific for the mutant allele can anneal and are cleaved by DNA polymerase resulting in a fluorescent droplet. The number of positive fluorescent droplets is then detected by a droplet reader. D) Molecular inversion probes (MIPs) can isolate particular regions of interest for increased scrutiny. Linear probes are developed to anneal upstream and downstream of a target region. Polymerase and ligase fills in the gap to form circular DNA. Exonuclease treatment degrades linear genomic DNA. Further library preparation and massively parallel sequencing then assesses mosaicism.