Germline mutation
Germline mutations can be caused by a variety of endogenous (internal) and exogenous (external) factors, and can occur throughout zygote development.
[4] A mutation that arises later in zygote development will be present in a small subset of either somatic or germline cells, but not both.
[3][4] A germline mutation often arises due to endogenous factors, like errors in cellular replication and oxidative damage.
[5] This damage is rarely repaired imperfectly, but due to the high rate of germ cell division, can occur frequently.
This long stasis period has been shown to result in a higher number of chromosomal and large sequence deletions, duplications, insertions, and transversions.
This type of damage is caused by reactive oxygen species that build up in the cell as a by-product of cellular respiration.
[9] In mice and humans the spontaneous mutation rate in the male germ line is significantly lower than in somatic cells.
[14] 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.
[15] Individuals who inherit germline mutations in TP53 are predisposed to certain cancer variants because the protein produced by this gene suppresses tumors.
[22] Cystic fibrosis is an autosomal recessive disorder that causes a variety of symptoms and complications, the most common of which is a thick mucous lining in lung epithelial tissue due to improper salt exchange, but can also affect the pancreas, intestines, liver, and kidneys.
[25] If both parents have a mutated CFTR (cystic fibrosis transmembrane conductance regulator) protein, then their children have a 25% of inheriting the disease.
[26] Many Mendelian disorders stem from dominant point mutations within genes, including cystic fibrosis, beta-thalassemia, sickle-cell anemia, and Tay–Sachs disease.
[27] This system has shown a higher specificity than TALENs or ZFNs due to the Cas9 protein containing homologous (complementary) sequences to the sections of DNA surrounding the site to be cleaved.
[27] This method has been used in both human and animal models (Drosophila, Mus musculus, and Arabidopsis), and current research is being focused on making this system more specific to minimize off-target cleavage sites.
[27] Similar to TALENs, zinc finger nucleases (ZFNs) are used to create a double stranded break in the DNA at a specific locus in the genome.
[31] The ZFN editing complex consists of a zinc finger protein (ZFP) and a restriction enzyme cleavage domain.
[33] Compared to CRISPR/Cas9, the therapeutic applications of this technology are limited, due to the extensive engineering required to make each ZFN specific to the desired sequence.
