Review
Somatic gene mutation and human disease other than cancer: An update

https://doi.org/10.1016/j.mrrev.2010.04.002Get rights and content

Abstract

Somatic mosaicism is well known in disorders where the manifestations are readily seen, e.g. the skin in neurofibromatosis I. In single gene disorders of higher frequency, especially X-linked ones, the frequency of combined germ-line and somatic mosaicism is increasingly being appreciated, e.g. Duchenne Muscular Dystrophy. Cell separation techniques; such as the fluorescence-activated cell sorter (FACS) also detect much somatic mosaicism among blood cells in disorders such as paroxysmal nocturnal hemoglobinuria. Depending on the disorder and the class of mutation, in genes for which there are sufficient numbers of patients studied, 6–20% of cases are due to somatic mutation. This update of my previous review is stimulated by the rapid application of new technologies for the study of DNA variation in disease. The results of these studies implicate somatic mutation in a greater variety of genetic diseases and a wider spectrum of tissues than have previously been shown, including heart and kidney. The classes of mutation have also expanded beyond base pair changes, insertions/deletion (indels), and short tandem repeat mutations to include copy number variants and transposon-mediated mutations. I also briefly discuss previously well-known mosaicism for chromosomal mutations. Genomic sequencing, performed on DNA from blood, shows many mutations which are conclusively somatic in origin. It is still too early to see if there is a different pattern of somatic mutation compared to germ-line mutation. Though the parameters to allow careful quantification are not yet available, it seems that the frequency of gene mutation in embryonic cells is not markedly different than that in the germ line.

Introduction

Mosaicism refers to a mixture of cells of different genetic composition in one individual. When the cells have different ancestry, e.g. fertilization of the egg and second polar body by two different sperm, it is usually termed “chimerism”. When the genotype of one zygote is altered by chromosomal mis-segregation or DNA mutation in a detectable number of cells, it is usually called “mosaicism”. It is the latter kind of change which I review, excluding the much studied and much reviewed genetic mosaicism of cancer. Previously, most of the examples I provided involved skin, where changes are easily seen, or blood cells, where separation techniques allow easy identification of unique variants [1]. In the interim, advances in molecular genetic techniques have expanded the tissues in which somatic mosaicism has been detected as well as the kind of mutations being found, e.g. copy number variants (CNVs). The results of complete sequencing of human genomes and exomes (exons only) on blood DNA which find homozygosity for “lethal” mutations and heterozygosity for many potentially harmful mutations, suggest a high frequency of somatic mosaicism. In what follows, I briefly update disorders previously covered [1] and emphasize new examples.

This review follows a somewhat different organization than the earlier review [1]. Previously, most of the examples of somatic mutation were point mutations or insertions/deletions (indels). Now it is important to consider copy number variant mutations, short tandem repeat changes, and transposable element variations in addition to single base pair changes. Somatic chromosomal mutations are now briefly considered. Also the tissues/organs involved in the study of somatic mutations have greatly expanded. As mentioned, most of the previous examples involved the skin and blood, now the central nervous system and other organs, such as the kidney, provide examples.

As I have said before [1], the logarithmic increase in cells during early embryonic development means that only early mutations, maintained in progeny cells, can make a significant contribution to the fetus. Given that only a few cells from the blastocyst eventually contribute to the embryo, an early mutation is likely to affect either all of the organism, including its germ plasm, or none of it. Later, with exponential division rates, there are soon so many cells that a somatic mutation would give rise to a very small clone of mutant cells in the adult organism, Fig. 1. Thus, the time during development for a mutation to create a sufficiently large enough clone to be visible and yet be unlikely to contribute to the germ plasm is short. As a result, there are many examples of germ-line mosaicism, mostly with somatic mosaicism, and many of these will be mentioned.

Section snippets

What does genomic sequencing tell us about somatic mosaicism?

The recent, rapid advances in DNA sequencing usually referred to as “massively parallel sequencing” allow new insights into somatic mosaicism. Massively parallel DNA sequencing refers to a number of new methodologies which share rapidity (up to gigabasepairs in 1 or a few days) in creating short sequence reads (usually about 70 basepairs). Only the availability of gigantic computer power allows the assembly of these sequences into a genomic sequence (which is dependent on the Human Genome

Neurofibromatosis 1 and 2

As previously discussed [1] those dominant disorders with pleiotrophic manifestations (including the skin), not infrequently present as somatic mosaics. At the time, it was apparent that from 3 to 10% of cases of neurofibromatosis one (NF1) was considered to be somatic mosaics. In the interval since the previous review, a number of new reports of segmental NF1 have occurred (Table 1). These range in descriptions of from 1 through 43 cases (Table 1) and provide better characterization of the

Combined germ-line and somatic mosaicism

At the time of my previous review [1], germ-line and somatic mosaicism was a relatively new phenomenon and the number of examples provided included congenital contractural arachnodactyly (fibrillin 2, FBN2); Duchenne muscular dystrophy (dystrophin, DMD); hemophilia A (factor VIII, F8) and B (factor IX, F9); Hunter's syndrome (iduronate 2-sulfatase deficiency, IDS); neurofibromatosis 2 (neurofibromin, merlin, NF2), osteogenesis imperfecta II (COL1A1 and COL1A2); and retinoblastoma (RB). Since

Disorders where somatic mosaicism is likely

The previous review discussed Proteus, Klippel-Trenaunay, and Maffuci syndromes (those with overgrowths of vascular, including lymphatic, soft and or bone tissues) as disorders likely to be due to somatic mutations with germ-line mutations being lethal [1]. There have been many advances in the study of Proteus syndrome but the clear identification of somatic mosaicism is not one of them. In the past, the literature has frequently talked about “Proteus-like” syndromes. Germ-line mutations in PTEN

Revertant mosaicism

As previously stated [1], revertant mosaicism is expected to be less common than “forward” somatic mosaicism since most new secondary mutations are not expected to correct the genetic deficiency. The skin disorder epidermolysis bullosa continues to provide examples for several of the causative genes: the alpha 1 chain of collagen 17 (COL17A1) [104], keratin 14 (KRT14) [105] and laminin beta 3 (LAMB3) [106]. A recent summary by Jonkman and Pasmooij [107] indicates that about one third of

Chromosomal mosaicism

In the previous review [1], this class of somatic mutations was quite neglected—perhaps because it is such a large topic. Given the expansion in the current update to include more than “point” mutations, it seems important to discuss in brief somatic mosaicism for chromosomal mutations.

Human meiosis seems especially error-prone, with two-thirds to three-fourths of all conceptions lost, of which about half are due to chromosomal aneuploidy [118], [119]. It is well known that all monosomies are

Future directions

The application of new technologies, such as comparative genomic hybridization to detect CNVs and massively parallel DNA sequencing (see Section 2.1), to compare germ line with somatic tissues will lead to more accurate estimates of the frequency and types of somatic mutations. The availability of massively parallel DNA sequencing has already allowed such analyses in many cancers. One can anticipate such approaches to detect potential somatic mosaicism in disorders with peripheral abnormalities

Summary

Somatic mutation, both to and from disease-causing mutations, is increasingly being found in human disease. Such mutations cause mosaicism which frequently includes the germ-line. For many disorders, mosaicism with germ-line involvement leads to ready identification when an unaffected individual has multiple affected offspring whom have a disease due to a dominant mutation. The disease-causing somatic mutations show a full spectrum of base changes, indels, short tandem repeat expansions, copy

Conflict of interest

None.

Acknowledgements

This work was supported by the Holsclaw Family Professorship in Human Genetics and Inherited Diseases. I thank Ivan Borbon for administrative assistance and F John Meaney and Katherine Thome for comments on the manuscript.

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