what causes somatic mutations

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What is an example of a somatic mutation?

The most common example of somatic mutation is the occurrence of cancer cells in the life of a person. Cancer means excess and uncontrollable growth of the body’s cells and its rapid spread infiltrating and destroying the normal body cells. It can occur at any stage of life in any of the body cells or tissues or organs.

Do somatic mutations get passed on?

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.

Does somatic mutation contribute to evolution?

Somatic mutations can promote the evolution of diploidy, polyploidy, sexual recombination, outcrossing, clonality, and separate sexes, and they may contribute genetic variability in many other traits. The amplification of beneficial mutations via intraorganismal selection may relax selection to reduce the genomic mutation rate or to protect the ...

Is a somatic mutation is always transmitted to the offspring?

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. See also What is the meaning of shoot for the stars aim for the moon?

What is somatic mutation?

A somatic mutation describes any alteration at the cellular level in somatic tissues occurring after fertilization. These mutations do not involve the germline and consequently do not pass on to offspring. Somatic mutations are a normal part of aging and occur throughout an organism’s life cycle either spontaneously as a result of errors in DNA repair mechanisms or a direct response to stress. Mutations occurring early in development can cause mosaicism within the gene line, impacting organism development. The impacts of mosaicism on overall health due to mutations depend on the specific gene the mutation affects.

What are the factors that affect the risk of somatic mutations?

Environmental stressors and errors that occur during cellular replication increase the risk for somatic mutations to occur. Radiation, exposure to certain chemical compounds, and intracellular processes generating free radicals are stressors placed on the cell that can cause cellular damage and mutations within DNA. After a mutation occurs, the newly altered DNA undergoes normal cellular replication and then becomes incorporated into all subsequent prodigy cell lines within the individual.

How do somatic mutations occur?

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. Somatic mutations that occur later in an organisms life can be hard to detect, as they may affect only a single cell - for instance, a post-mitotic neuron; improvements in single cell sequencing are therefore an important tool for the study of somatic mutation. 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.

What is somatic mutation?

A somatic mutation is 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 ...

What is the mutation rate of B cells?

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.

Why is the rate of mutations different between germline and somatic tissues?

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 . 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.

What is the role of somatic evolution in cancer?

Further information: Somatic evolution in cancer. If a mutation occur in a somatic cell of an organism, it will be present in all descendants of this cell within the same organism.

How many times did somatic mutations occur in humans?

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.

Why do somatic cells have mutations?

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.

What are somatic mutations?

Disease-causing mutations can also occur during the mitotic cell divisions that generate the embryo after fertilization and zygote formation. These mutations lead to individuals who are mosaic, with only a subset of their cells harboring the mutation (Fig. 1, E and F). These mutations are de novo in the sense that they are not detectable in the parents of the affected individuals but are more specifically termed somatic mutations. Somatic mutations can give rise to cancer (9), as well as noncancerous diseases. Noncancerous somatic mutations that occur during development may affect cell proliferation, as would be the case in cancer, or they may simply alter cellular function without causing a proliferative effect. There are estimates that the mutation burden in somatic cells is quite high, and estimates based on known mutation rates suggest that every cell division creates some form of genetic variation, which may or may not have an effect on cellular function (10, 11). Several recent studies have even suggested that the brain may harbor widespread somatic mutations, in the form of aneuploidy or retrotransposon insertions, perhaps as part of its “normal” development (12–14). If somatic mutations, especially in brain cells, do play a role in “complex” diseases (that is, diseases with genetic influences that are non-Mendelian), detecting them represents a substantial challenge with current sequencing strategies that mainly analyze blood DNA.

How are somatic mutations inherited?

Genetic mutations causing human disease are conventionally thought to be inherited through the germ line from one’s parents and present in all somatic (body) cells, except for most cancer mutations, which arise somatically. Increasingly, somatic mutations are being identified in diseases other than cancer, including neurodevelopmental diseases. Somatic mutations can arise during the course of prenatal brain development and cause neurological disease—even when present at low levels of mosaicism, for example—resulting in brain malformations associated with epilepsy and intellectual disability. Novel, highly sensitive technologies will allow more accurate evaluation of somatic mutations in neurodevelopmental disorders and during normal brain development.

What is a clonal-appearing brain lesion suspected to be caused by somatic mutation in?

Focal cortical dysplasia: a clonal-appearing brain lesion suspected to be caused by somatic mutation in a progenitor cell

Why are somatic mutations important?

The importance of somatic mutations has long been understood in the context of several dominant conditions in which patients inherit a heterozygous mutation, present in all cells, with somatic second mutations leading to overgrowth of specific tissues because of inactivation of a second allele, according to the “two-hit” model of Knudson (31). For example, neurofibromatosis type 1 (NF1)—which is associated with focal lesions of the skin, optic gliomas, and peripheral nervous system tumors called neurofibromas—is characterized by germline mutations in the gene NF1, with second mutations in the other NF1allele causing the neurofibromas (32). A similar phenomenon occurs in the multisystem disorder tuberous sclerosis complex (TSC), a condition caused by mutations in the genes TSC1and TSC2(33, 34), whose gene products form a protein-protein complex together and regulate the mammalian target of rapamycin (mTOR) pathway; somatic second mutations have been shown in non-nervous system tumors of TSC (35), and “second hits” in the form of posttranslational inactivation of TSC2 have been shown in sub-ependymal giant cell astrocytomas, as well as in the noncancerous cortical tubers in patients with TSC (36). Mutation of the second TSCallele in cortical tubers has been hypothesized to occur as well but has so far been demonstrated for only a single TSC lesion (37). These neurocutaneous syndromes give us a sense of how common somatic mutations really are because the somatic mutations are revealed in the presence of hamartomatous lesions. Remarkably, typical patients with these conditions have dozens of lesions of various tissues, suggesting that deleterious somatic mutations at any single gene occur many times during normal development.

What is the difference between recessive and dominant mutations?

This is because recessive mutations that affect survival or fertility in the homozygous state can persist in the population in a heterozygous state, whereas severe dominant mutations cannot be passed to offspring when present in enough cells to cause severe disease in a parent. From this, we would predict that for any disease caused by a dominant mutation the ratio of sporadic cases caused by de novo mutations to cases caused by inherited mutations as seen in recurrent familial cases should correlate with the severity of the disease’s effect on survival and fertility. The most deleterious mutations that are not compatible with embryonic development might even be found only as somatic mosaic and not as inherited mutations.

What are de novo mutations?

These de novo mutations are typically present in the sperm or egg of one parent and yet are not detectable in blood taken from the parents ; once transmitted to the embryo, they are present in all tissues of the offspring (Fig. 1, C and D). Whole-exome sequencing studies have shown that most individuals have one or two spontaneous mutations in the exome (the part of the genome encoding proteins) that are not present in their parents, but in individuals with neurodevelopmental and neuropsychiatric conditions [such as autism spectrum disorders (ASDs)] these de novo mutations are more likely to be damaging, suggesting that some of these de novo mutations cause disease (1, 4, 5, 8). In fact, mutations that greatly increase the risk of neurodevelopmental or neuropsychiatric disease—even when only one of the two alleles of a gene is affected (heterozygous mutations)—appear to arise de novo most of the time and are inherited relatively rarely. This is not unexpected because individuals with these disorders are less likely to bear offspring, placing the disease-causing mutations under strong negative selection. Because affected people thus rarely transmit the mutation to children, the presence of the disease reflects the ongoing appearance of new mutations.

Can somatic mutations be detected in leukocytes?

Our ability to detect a pathogenic somatic mutation by using current clinical methods depends on how abundant it is in the leukocytes. The examples above suggest that at least some cases of autism, epilepsy, and perhaps other neuropsychiatric conditions such as schizophrenia may show roles for somatic mutations that have been overlooked by the usual paradigm of leukocyte DNA sequencing. Some cases of epilepsy, for example, may be due to somatic mutations affecting a specific cell lineage, such as γ-aminobutyric acid–secreting interneurons. Autism and other disorders that predominantly affect language function may be due to somatic mutations in populations of cells critical for language function in specific regions of the developing cortex. These may have been systematically missed by previous research designs that rarely sequence affected brain tissue and often do not account for the possibility of somatic mutations present at low levels in a mosaic pattern. The possibility of somatic mosaic mutations in some patients with high-functioning ASD is intriguing because it could provide a mechanism for the remarkable preservation of some abilities (“splinter or savant skills”) in some rare autistic patients: Mosaic mutations could result in a brain that is normal in some regions yet abnormal in other regions, which is analogous to HMG, in which gain-of-function mutations in the mTOR pathway result in one hemisphere that is impaired whereas the other hemisphere may functional normally. Nevertheless, studies relying on direct analysis of brain tissue are limited to autopsy studies for patients with autism or epilepsy and studies of human brain tissue removed in epilepsy surgery for patients with medically uncontrollable epilepsy. Such ongoing studies will continue to be informative, but they may or may not be generalizable to the broader group of patients with neuro-developmental disease. Thus, it is difficult to predict to what extent somatic mutation may account for conditions such as autism and epilepsy.

What are the causes of gene mutations?

Mutagens are external factors that can cause alterations to DNA. Examples of potentially harmful environmental factors include toxic chemicals, X-rays and pollution.

What are some examples of mutations in germline cells?

Defective genes on chromosomes are passed on, as well as too many or too few chromosomes per cell when these mutations happen in germline cells. Gene mutation examples include severe genetic disorders, cell overgrowth, tumor formation and heightened risk of breast cancer.

When Do Gene Mutations Occur?

Mutations frequently occur just before the process of mitosis when DNA is being replicated in the cell nucleus. During mitosis or meiosis, mishaps can occur when chromosomes are not lined up correctly or fail to separate properly. Chromosomal mutations in the germ cells can be inherited and passed along to the next generation.

What is frameshift mutation?

Frameshift mutations: These are point mutations that result when a nucleotide pair is added or omitted in a gene sequence that shifts how codons are read. Such mutations often result in different amino acids being added to the protein being synthesized. An example is beta thalassemia, a blood disorder caused by mutations to the HBB gene.

What happens when one nucleotide is replaced with another?

Missense mutation: This happens when one nucleotide is replaced with another. Substitutions of bases can interfere with normal protein syntheses and functioning. For instance, a single point mutation on the hemoglobin beta (HBB) gene causes sickle cell anemia blood disorders.

What causes cancer in cells?

Carcinogens are mutagens that cause cancer such as UV radiation. Various types of spontaneous mutations happen due to mistakes in cell division or reproduction, as well as during DNA replication or transcription.

What is genetic mutation?

Genetic mutations are slight alterations of DNA or RNA nucleotides, genes or chromosomes that may occur during replication or cell division. Random, uncorrected errors may be beneficial or harmful in relationship to evolution. Some effects of gene mutation go unnoticed.

What is a somatic activating mutation?

The most common mutation, causing Gα q p.Gln209Leu, is an activating mutation that leads to increased downstream signaling through the MAPK pathway . The activation of this pathway increases cell proliferation and inhibits apoptosis. 9 A few uveal melanomas have been reported to harbor a somatic mutation in GNAQ encoding p.Arg183Gln, although the functional consequence of this substitution has not been reported. 8 The pathogenesis of uveal melanoma is likely to be very different from the pathogenesis of nonsyndromic port-wine stains and the Sturge–Weber syndrome. Melanomas frequently have several somatic mutations. 22 We found no evidence of accumulating mutations on whole-genome sequencing of our three paired samples (affected and unaffected tissue) from participants with the Sturge–Weber syndrome. In addition, the Sturge–Weber syndrome, nonsyndromic port-wine stains, and melanocytic nevi are thought to originate during fetal development; therefore, the effects of the same GNAQ somatic mutation may be quite different, depending on the cell type and the point in development at which they arise. There are reported cases of uveal melanoma associated with phakomatosis pigmentovascularis, 23 and the coincidence of the blue nevus and port-wine stain phenotypes in a patient with the Sturge–Weber syndrome may indicate an increased risk of uveal melanoma, although such coincidences are rare.

What mutations are in GNAQ?

Two specific mutations, c.548G→A (encoding p.Arg183Gln) and c.626A→T (encoding p.Gln209Leu), were introduced separately into GNAQ with the use of primers for site-directed mutagenesis (Table S4 in the Supplementary Appendix ). Serum response element plasmid (pSRE)–Luc (Agilent Technologies) and pSV40-RL (Roche) were used as reporter plasmids for the luciferase assay.

What are the causes of asymmetric birth defects?

Rudolf Happle first suggested that sporadic asymmetric or scattered birth defects involving the skin are caused by somatic mosaic mutations that would be lethal if they occurred in very early embryonic development. 11 Somatic mosaic activating mutations have been identified in several disorders, including the McCune–Albright syndrome 12 and the Proteus syndrome. 13 In the current study, we found that a specific somatic mosaic activating mutation in GNAQ is associated with both the Sturge–Weber syndrome, a neurocutaneous disorder, and apparently nonsyndromic port-wine stains. GNAQ encodes Gα q, a member of the q class of G-protein alpha subunits that mediates signals between G-protein–coupled receptors and downstream effectors. We have identified somatic mosaic GNAQ encoding p.Arg183Gln amino acid substitutions in skin and brain tissue from patients with the Sturge–Weber syndrome and in skin tissue with nonsyndromic port-wine stains and have shown that this mutation, much like the GNAQ variant encoding p.Gln209Leu, activates downstream MAPK signaling. Gα q Arg183 is conserved in the guanosine triphosphate (GTP) binding pocket of all human Gα subunits, where it plays a critical role in the hydrolysis of GTP, the key step required for inactivation of the protein. Substitution of cysteine at this position results in a reduction in the intrinsic GTPase activity, leading to increased signaling activity. 10,14-18

What causes Sturge-Weber syndrome?

It has been hypothesized that somatic mosaic mutations disrupting vascular development cause both the Sturge–Weber syndrome and port-wine stains, and the severity and extent of presentation are determined by the developmental time point at which the mutations occurred. To date, no such mutation has been identified.

What substitutions overstimulate the SRE?

A different substitution in GNAQ encoding a variant at the same amino acid residue, p.Arg183Cys, was previously shown to overstimulate the serum response element (SRE) in a promoter reporter assay. 10 We investigated whether the p.Arg183Gln substitution had the same stimulatory effect on SRE promoter activity. We transfected HEK 293T cells with pSRE-Luc, pSV40-RL (reporter constructs), and GNAQ, GNAQ p.Arg183Gln, or GNAQ p.Gln209Leu plasmids and measured luciferase activity after 24 hours. Both p.Gln209Leu and p.Arg183Gln showed significantly increased reporter activity as compared with nonmutant GNAQ (P<0.05), confirming that the p.Arg183Gln mutation is a gain-of-function or activating mutation ( Figure 2F ). In this assay, the p.Gln209Leu substitution again showed a stronger effect than did p.Arg183Gln.

Overview

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 asexu…

Fraction of cells affected

Causes

Mutation frequency

Disease

See also