Germline mutation

A germline mutation, or germinal mutation, is any detectable variation within germ cells (cells that, when fully developed, become sperm and ovum). 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. A germline mutation, or germinal mutation, is any detectable variation within germ cells (cells that, when fully developed, become sperm and ovum). 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. Germline mutations can be caused by a variety of endogenous (internal) and exogenous (external) factors, and can occur throughout zygote development. A mutation that arises only in germ cells can result in offspring with a genetic condition that is not present in either parent; this is because the mutation is not present in the rest of the parents' body, only the germline. Due to many severe diseases stemming from de novo germline mutations, different gene editing techniques can be used to induce DNA breaks and repair the mutation. Germline mutations can occur before fertilization and during various stages of zygote development. When the mutation arises will determine the effect it has on offspring. If the mutation arises in either the sperm or the oocyte before development, then the mutation will be present in every cell in the individual's body. A mutation that arises soon after fertilization, but before germline and somatic cells are determined, then the mutation will be present in a large proportion of the individual's cell with no bias towards germline or somatic cells, this is also called a gonosomal mutation. A mutation that arises later in zygote development will be present in a small subset of either somatic or germline cells, but not both. A germline mutation often arises due to endogenous factors, like errors in cellular replication and oxidative damage. This damage is rarely repaired imperfectly, but due to the high rate of germ cell division, can occur frequently. Endogenous mutations are more prominent in sperm than in ova. This is because spermatocytes go through a larger number of cell divisions throughout a male’s life, resulting in more replication cycles that could result in a DNA mutation. Errors in maternal ovum also occur, but at a lower rate than in paternal sperm. The types of mutations that occur also tend to vary between the sexes. A mothers’ eggs, after production, remain in stasis until each is utilized in ovulation. This long stasis period has been shown to result in a higher number of chromosomal and large sequence deletions, duplications, insertions, and transversions. The father’s sperm, on the other hand, undergoes continuous replication throughout his lifetime, resulting in many small point mutations that result from errors in replication. These mutations include single base pair deletions, insertions, duplications, and amino acid changes. Oxidative damage is another endogenous factor that can cause germline mutations. This type of damage is caused by reactive oxygen species that build up in the cell as a by-product of cellular respiration. These reactive oxygen species are missing an electron, and because they are highly electronegative (have a strong electron pull) they will rip an electron away from another molecule. This can initiate DNA damage because it causes the nucleic acid guanine to shift to 8-oxoguanine (8-oxoG). This 8-oxoG molecule is then mistaken for a thymine by DNA polymerase during replication, causing a G>T transversion on one DNA strand, and a C>A transversion on the other. A germline mutation can also occur due to exogenous factors. Similar to somatic mutations, germline mutations can be caused by exposure to harmful substances, which damage the DNA of germ cells. This damage can then either be repaired perfectly, and no mutations will be present, or repaired imperfectly, resulting in a variety of mutations. Exogenous mutagens include harmful chemicals and ionizing radiation; the major difference between germline mutations and somatic mutations is that germ cells are not exposed to UV radiation, and thus not often directly mutated in this manner. Different germline mutations can affect an individual differently depending on the rest of their genome. A dominant mutation only requires 1 mutated gene to produce the disease phenotype, while a recessive mutation requires both alleles to be mutated to produce the disease phenotype. For example, if the embryo inherits an already mutated allele from the father, and the same allele from the mother underwent an endogenous mutation, then the child will display the disease related to that mutated gene, even though only 1 parent carries the mutant allele. This is only one example of how a child can display a recessive disease while a mutant gene is only carried by one parent. Detection of chromosomal abnormalities can be found in utero for certain diseases by means of blood samples or ultrasound, as well as invasive procedures such as an amniocentesis. Later detection can be found by genome screening. Mutations in tumour suppressor genes or proto-oncogenes can predispose an individual to developing tumours. It is estimated that genetic mutations are involved in 5-10% of cancers. These mutations make a person susceptible to tumour development if the other copy of the oncogene is randomly mutated. These mutations can occur in germ cells, allowing them to be heritable. Individuals who inherit germline mutations in TP53 are predisposed to certain cancer variants because the protein produced by this gene suppresses tumors. Patients with this mutation are also at a risk for Li-Fraumeni syndrome. Other examples include mutations in the BRCA1 and BRCA2 genes which predispose to breast and ovarian cancer, or mutations in MLH1 which predispose to hereditary non-polyposis colorectal cancer.