special subjects
DNA Variants and Mutations
Mutations and polymorphisms
Variations in DNA can occur spontaneously or in response to cellular insults (eg, radiation, mutagenic drugs, viruses). Some variations are repaired by the cell’s DNA error correction mechanisms. Other variations are not and can be passed on to subsequently replicated cells; in such cases, the variation is termed a mutation. However, offspring can inherit the mutation only if germ cells are affected. Mutations may be unique to an individual or family. Most mutations are rare. Polymorphismsbegin as mutations. They are variations in DNA that have become common in a population (prevalence of ≥ 1%) through sufficient propagation or other mechanisms. Most polymorphisms are stable and do not noticeably change phenotype. A common example is human blood groups (A, B, AB, and O). (including polymorphisms) involve random changes in DNA. Many mutations have little effect on cell function. Some mutations change cell function, often in a detrimental way, and some are lethal to the cell. Examples of detrimental changes in cell function are mutations that cause cancer by creating or activating oncogenes or altering tumor suppressor genes (see Molecular Abnormalities ). Rarely, a change in cell function confers a survival advantage. These mutations are more likely to be propagated. The mutation causing sickle cell disease confers resistance to malaria. This resistance conferred a survival advantage in areas where malaria was endemic and often fatal. However, by causing symptoms and complications of sickle cell disease, the mutation also has harmful effects usually when present in the homozygous state. When and in what cell type mutations occur can explain certain abnormalities in inheritance patterns. Typically, an autosomal dominant disorder is expected to be present in one or both parents of an affected person. However, some disorders with autosomal dominant inheritance can appear de novo (in people whose parents have a normal phenotype). For example, about 80% of people with Osteochondrodysplasias (Osteochondrodysplastic Dwarfism) have no family history of dwarfism and thus represent new (de novo) mutations. In many of these people, the mechanism is a spontaneous mutation occurring early in their embryonic life. Thus, other offspring have no increased risk of the disorder. However, in some of them, the disorder develops because of a germ cell mutation in their parents (eg, an autosomal dominant gene in a phenotypically normal parent). If so, other offspring have an increased risk of inheriting the mutation. 