Somatic mutation

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A somatic mutation is a change in the DNA sequence of a somatic cell of a multicellular organism with dedicated reproductive cells; that is, any mutation that occurs in a cell other than a gamete, germ cell, or gametocyte. Unlike germline mutations, which can be passed on to the descendants of an organism, somatic mutations are not usually transmitted to descendants. This distinction is blurred in plants, which lack a dedicated germline, and in those animals that can reproduce asexually through mechanisms such as budding, as in members of the cnidarian genus Hydra.

Contents

While somatic mutations are not passed down to an organism's offspring, somatic mutations will be present in all descendants of a cell within the same organism. Many cancers are the result of accumulated somatic mutations.

Fraction of cells affected

Mutation inherited, de novo, somatic.png
Somatic mutations that occur earlier in embryonic development are generally present in a larger fraction of body cells. In F), the mutation happened earlier in development than in G), and therefore is present in more of the child's cells.

The term somatic generally refers to the cells of the body, in contrast to the reproductive (germline) cells, which give rise to the egg or sperm. For example, in mammals, somatic cells make up the internal organs, skin, bones, blood, and connective tissue. [1]

In most animals, separation of germ cells from somatic cells (germline development) occurs during early stages of development. Once this segregation has occurred in the embryo, any mutation outside of the germline cells can not be passed down to an organism's offspring.

However, somatic mutations are passed down to all the progeny of a mutated cell within the same organism. A major section of an organism therefore might carry the same mutation, especially if that mutation occurs at earlier stages of development. [2] Somatic mutations that occur later in an organism's life can be hard to detect, as they may affect only a single cell - for instance, a post-mitotic neuron; [3] [4] improvements in single cell sequencing are therefore an important tool for the study of somatic mutation. [5] Both the nuclear DNA and mitochondrial DNA of a cell can accumulate mutations; somatic mitochondrial mutations have been implicated in development of some neurodegenerative diseases. [6]

Exceptions to inheritance

Hydra oligactis with two buds. Reproduction by budding is an exception to the rule that somatic mutations can not be inherited. Hydra oligactis.jpg
Hydra oligactis with two buds. Reproduction by budding is an exception to the rule that somatic mutations can not be inherited.

There are many exceptions to the rule that somatic mutations cannot be inherited by offspring. Many organisms simply do not dedicate a separate germline during early development. Plants and basal animals such as sponges and corals instead generate gametes from pluripotent stem cells in adult somatic tissues. [7] [8] In flowering plants, for example, germ cells can arise from adult somatic cells in the floral meristem. Other animals without a designated germ line include tunicates and flatworms. [9]

Somatic mutations can also be passed down to offspring in organisms that can reproduce asexually, without production of gametes. For instance, animals in the cnidarian genus Hydra can reproduce asexually through the mechanism of budding (they can also reproduce sexually). In hydra, a new bud develops directly from somatic cells of the parent hydra. [10] A mutation present in the tissue that gives rise to the daughter organism would be passed down to that offspring.

Many plants naturally reproduce through vegetative reproduction - growth of a new plant from a fragment of the parent plant - propagating somatic mutations without the step of seed production. Humans artificially induce vegetative reproduction via grafting and stem cuttings.

Causes

UV light can damage DNA by causing pyrimidine dimers. Adjacent bases bond with each other, instead of across the "ladder". The distorted DNA molecule does not function properly. Mutation can result if mistakes occur in DNA repair or replication. DNA UV mutation.svg
UV light can damage DNA by causing pyrimidine dimers. Adjacent bases bond with each other, instead of across the “ladder”. The distorted DNA molecule does not function properly. Mutation can result if mistakes occur in DNA repair or replication.

As with germline mutations, mutations in somatic cells may arise due to endogenous factors, including errors during DNA replication and repair, and exposure to reactive oxygen species produced by normal cellular processes. Mutations can also be induced by contact with mutagens, which can increase the rate of mutation.

Most mutagens act by causing DNA damage - alterations in DNA structure such as pyrimidine dimers, or breakage of one or both DNA strands. DNA repair processes can remove DNA damages that would, otherwise, upon DNA replication, cause mutation. Mutation results from damage when mistakes in the mechanism of DNA repair cause changes in the nucleotide sequence, or if replication occurs before repair is complete.

Mutagens can be physical, such as radiation from UV rays and X-rays, or chemical--molecules that interact directly with DNA--such as metabolites of benzo[a]pyrene, a potent carcinogen found in tobacco smoke. [11] Mutagens associated with cancers are often studied to learn about cancer and its prevention.

Mutation frequency

Research suggests that the frequency of mutations is generally higher in somatic cells than in cells of the germline; [12] furthermore, there are differences in the types of mutation seen in the germ and in the soma. [13] There is variation in mutation frequency between different somatic tissues within the same organism [13] and between species. [2]

Milholland et al. (2017) examined the mutation rate of dermal fibroblasts (a type of somatic cell) and germline cells in humans and in mice. They measured the rate of single nucleotide variants (SNVs), most of which are a consequence of replication error. Both in terms of mutational load (total mutations present in a cell) and mutation rate per cell division (new mutations with each mitosis), somatic mutation rates were more than ten times that of the germline, in humans and in mice.

In humans, mutation load in fibroblasts was over twenty times greater than germline (2.8 × 10−7 compared with 1.2 × 10−8 mutations per base pair). Adjusted for differences in the estimated number of cell divisions, the fibroblast mutation rate was about 80 times greater than the germ (respectively, 2.66 × 10−9 vs. 3.3 × 10−11 mutations per base pair per mitosis). [2]

The disparity in mutation rate between the germline and somatic tissues likely reflects the greater importance of genetic integrity in the germline than in the soma. [12] Variation in mutation frequency may be due to differences in rates of DNA damage or to differences in the DNA repair process as a result of elevated levels of DNA repair enzymes. [13]

In April 2022 it has been reported that most mammals have about the same number of mutations by the time they reach the end of their lifespan, so those that have similar lifespan will have similar somatic mutation rates and those who live less/more will have a higher/lower rate of somatic mutations respectively. [14] [15]

Neurons

Post-mitotic neurons accumulate somatic mutations at a constant rate throughout life, and this rate is roughly similar to the mutation rates of mitotically active tissues. [16] The mutations in neurons may arise as a consequence of endogenous DNA damage and the somewhat inaccurate repair of such damage that occurs all the time in cells. [16]

Somatic hypermutation

As a part of the adaptive immune response, antibody-producing B cells experience a mutation rate many times higher than the normal rate of mutation. The mutation rate in antigen-binding coding sequences of the immunoglobulin genes is up to 1,000,000 times higher than in cell lines outside the lymphoid system. A major step in affinity maturation, somatic hypermutation helps B cells produce antibodies with greater antigen affinity. [17]

Disease

Somatic mutations accumulate within an organism's cells as it ages and with each round of cell division; the role of somatic mutations in the development of cancer is well established, and the accumulation of somatic mutations is implicated in the biology of aging. [4]

Mutations in neuronal stem cells (especially during neurogenesis) [18] and in post-mitotic neurons lead to genomic heterogeneity of neurons - referred to as "somatic brain mosaicism". [3] The accumulation of age-related mutations in neurons may be linked to neurodegenerative diseases, including Alzheimer's disease, but the association is unproven. The majority of central-nervous system cells in the adult are post-mitotic, and adult mutations might affect only a single neuron. Unlike in cancer, where mutations result in clonal proliferation, detrimental somatic mutations might contribute to neurodegenerative disease by cell death. [19] Accurate assessment of somatic mutation burden in neurons therefore remains difficult to assess.

Role in carcinogenesis

If a mutation occurs in a cell of an organism, that mutation will be present in all the descendants of this cell within the same organism. The accumulation of certain mutations over generations of somatic cells is part of the process of malignant transformation, from normal cell to cancer cell.

Cells with heterozygous loss-of-function mutations (one good copy of a gene and one mutated copy) may function normally with the unmutated copy until the good copy has been spontaneously somatically mutated. This kind of mutation happens often in living organisms, but it is difficult to measure the rate. Measuring this rate is important in predicting the rate at which people may develop cancer.

See also

Related Research Articles

Mutagenesis is a process by which the genetic information of an organism is changed by the production of a mutation. It may occur spontaneously in nature, or as a result of exposure to mutagens. It can also be achieved experimentally using laboratory procedures. A mutagen is a mutation-causing agent, be it chemical or physical, which results in an increased rate of mutations in an organism's genetic code. In nature mutagenesis can lead to cancer and various heritable diseases, and it is also a driving force of evolution. Mutagenesis as a science was developed based on work done by Hermann Muller, Charlotte Auerbach and J. M. Robson in the first half of the 20th century.

<span class="mw-page-title-main">Mutation</span> Alteration in the nucleotide sequence of a genome

In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mitosis, or meiosis or other types of damage to DNA, which then may undergo error-prone repair, cause an error during other forms of repair, or cause an error during replication. Mutations may also result from insertion or deletion of segments of DNA due to mobile genetic elements.

<span class="mw-page-title-main">Mutagen</span> Physical or chemical agent that increases the rate of genetic mutation

In genetics, a mutagen is a physical or chemical agent that permanently changes genetic material, usually DNA, in an organism and thus increases the frequency of mutations above the natural background level. As many mutations can cause cancer in animals, such mutagens can therefore be carcinogens, although not all necessarily are. All mutagens have characteristic mutational signatures with some chemicals becoming mutagenic through cellular processes.

In cellular biology, a somatic cell, or vegetal cell, is any biological cell forming the body of a multicellular organism other than a gamete, germ cell, gametocyte or undifferentiated stem cell. Somatic cells compose the body of an organism and divide through mitosis.

In cellular biology, the term somatic is derived from the French somatique which comes from Ancient Greek σωματικός, and σῶμα is often used to refer to the cells of the body, in contrast to the reproductive (germline) cells, which usually give rise to the egg or sperm. These somatic cells are diploid, containing two copies of each chromosome, whereas germ cells are haploid, as they only contain one copy of each chromosome. Although under normal circumstances all somatic cells in an organism contain identical DNA, they develop a variety of tissue-specific characteristics. This process is called differentiation, through epigenetic and regulatory alterations. The grouping of similar cells and tissues creates the foundation for organs.

<span class="mw-page-title-main">Germ cell</span> Gamete-producing cell

A germ cell is any cell that gives rise to the gametes of an organism that reproduces sexually. In many animals, the germ cells originate in the primitive streak and migrate via the gut of an embryo to the developing gonads. There, they undergo meiosis, followed by cellular differentiation into mature gametes, either eggs or sperm. Unlike animals, plants do not have germ cells designated in early development. Instead, germ cells can arise from somatic cells in the adult, such as the floral meristem of flowering plants.

<span class="mw-page-title-main">Germline</span> Population of a multicellular organisms cells that pass on their genetic material to the progeny

In biology and genetics, the germline is the population of a multicellular organism's cells that develop into germ cells. In other words, they are the cells that form gametes, which can come together to form a zygote. They differentiate in the gonads from primordial germ cells into gametogonia, which develop into gametocytes, which develop into the final gametes. This process is known as gametogenesis.

<span class="mw-page-title-main">Mosaic (genetics)</span> Condition in multi-cellular organisms

Mosaicism or genetic mosaicism is a condition in which a multicellular organism possesses more than one genetic line as the result of genetic mutation. This means that various genetic lines resulted from a single fertilized egg. Mosaicism is one of several possible causes of chimerism, wherein a single organism is composed of cells with more than one distinct genotype.

<span class="mw-page-title-main">Germline mutation</span> Inherited genetic variation

A germline mutation, or germinal mutation, is any detectable variation within germ cells. Mutations in these cells are the only mutations that can be passed on to offspring, when either a mutated sperm or oocyte come together to form a zygote. After this fertilization event occurs, germ cells divide rapidly to produce all of the cells in the body, causing this mutation to be present in every somatic and germline cell in the offspring; this is also known as a constitutional mutation. Germline mutation is distinct from somatic mutation.

<span class="mw-page-title-main">Mutation rate</span> Rate at which mutations occur during some unit of time

In genetics, the mutation rate is the frequency of new mutations in a single gene, nucleotide sequence, or organism over time. Mutation rates are not constant and are not limited to a single type of mutation; there are many different types of mutations. Mutation rates are given for specific classes of mutations. Point mutations are a class of mutations which are changes to a single base. Missense and Nonsense mutations are two subtypes of point mutations. The rate of these types of substitutions can be further subdivided into a mutation spectrum which describes the influence of the genetic context on the mutation rate.

A de novo mutation (DNM) is any mutation or alteration in the genome of an individual organism that was not inherited from its parents. This type of mutation spontaneously occurs during the process of DNA replication during cell division. De novo mutations, by definition, are present in the affected individual but absent from both biological parents' genomes. These mutations can occur in any cell of the offspring, but those in the germ line can be passed on to the next generation.

Mutation frequency and mutation rates are highly correlated to each other. Mutation frequencies test are cost effective in laboratories however; these two concepts provide vital information in reference to accounting for the emergence of mutations on any given germ line.

A postzygotic mutation is a change in an organism's genome that is acquired during its lifespan, instead of being inherited from its parent(s) through fusion of two haploid gametes. Mutations that occur after the zygote has formed can be caused by a variety of sources that fall under two classes: spontaneous mutations and induced mutations. How detrimental a mutation is to an organism is dependent on what the mutation is, where it occurred in the genome and when it occurred.

Mitotic recombination is a type of genetic recombination that may occur in somatic cells during their preparation for mitosis in both sexual and asexual organisms. In asexual organisms, the study of mitotic recombination is one way to understand genetic linkage because it is the only source of recombination within an individual. Additionally, mitotic recombination can result in the expression of recessive alleles in an otherwise heterozygous individual. This expression has important implications for the study of tumorigenesis and lethal recessive alleles. Mitotic homologous recombination occurs mainly between sister chromatids subsequent to replication. Inter-sister homologous recombination is ordinarily genetically silent. During mitosis the incidence of recombination between non-sister homologous chromatids is only about 1% of that between sister chromatids.

Enquiry into the evolution of ageing, or aging, aims to explain why a detrimental process such as ageing would evolve, and why there is so much variability in the lifespans of organisms. The classical theories of evolution suggest that environmental factors, such as predation, accidents, disease, and/or starvation, ensure that most organisms living in natural settings will not live until old age, and so there will be very little pressure to conserve genetic changes that increase longevity. Natural selection will instead strongly favor genes which ensure early maturation and rapid reproduction, and the selection for genetic traits which promote molecular and cellular self-maintenance will decline with age for most organisms.

<span class="mw-page-title-main">Antagonistic pleiotropy hypothesis</span> Proposed evolutionary explanation for senescence

The antagonistic pleiotropy hypothesis was first proposed by George C. Williams in 1957 as an evolutionary explanation for senescence. Pleiotropy is the phenomenon where one gene controls more than one phenotypic trait in an organism. A gene is considered to possess antagonistic pleiotropy if it controls more than one trait, where at least one of these traits is beneficial to the organism's fitness early on in life and at least one is detrimental to the organism's fitness later on due to a decline in the force of natural selection. The theme of G. C. William's idea about antagonistic pleiotropy was that if a gene caused both increased reproduction in early life and aging in later life, then senescence would be adaptive in evolution. For example, one study suggests that since follicular depletion in human females causes both more regular cycles in early life and loss of fertility later in life through menopause, it can be selected for by having its early benefits outweigh its late costs.

Germline mosaicism, also called gonadal mosaicism, is a type of genetic mosaicism where more than one set of genetic information is found specifically within the gamete cells; conversely, somatic mosaicism is a type of genetic mosaicism found in somatic cells. Germline mosaicism can be present at the same time as somatic mosaicism or individually, depending on when the conditions occur. Pure germline mosaicism refers to mosaicism found exclusively in the gametes and not in any somatic cells. Germline mosaicism can be caused either by a mutation that occurs after conception, or by epigenetic regulation, alterations to DNA such as methylation that do not involve changes in the DNA coding sequence.

Somatic hypermutation is a cellular mechanism by which the immune system adapts to the new foreign elements that confront it. A major component of the process of affinity maturation, SHM diversifies B cell receptors used to recognize foreign elements (antigens) and allows the immune system to adapt its response to new threats during the lifetime of an organism. Somatic hypermutation involves a programmed process of mutation affecting the variable regions of immunoglobulin genes. Unlike germline mutation, SHM affects only an organism's individual immune cells, and the mutations are not transmitted to the organism's offspring. Because this mechanism is merely selective and not precisely targeted, somatic hypermutation has been strongly implicated in the development of B-cell lymphomas and many other cancers.

Mutational signatures are characteristic combinations of mutation types arising from specific mutagenesis processes such as DNA replication infidelity, exogenous and endogenous genotoxin exposures, defective DNA repair pathways, and DNA enzymatic editing.

Human somatic variations are somatic mutations both at early stages of development and in adult cells. These variations can lead either to pathogenic phenotypes or not, even if their function in healthy conditions is not completely clear yet.

References

  1. ↑ Campbell, Neil A., 1946-2004. (2009). Biology. Reece, Jane B. (8th ed.). San Francisco: Pearson Benjamin Cummings. ISBN   978-0-8053-6844-4. OCLC   174138981.{{cite book}}: CS1 maint: multiple names: authors list (link) CS1 maint: numeric names: authors list (link)
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