Those issues are important in diseases that are associated with single-gene disorders, specifically autosomal dominant and sometimes autosomal recessive diseases. Penetrance is the probability that a person who has the variant will express a phenotypic difference expressivity is the magnitude of the phenotypic difference ( Nussbaum et al., 2016). The degree to which a given genetic variant has consequences for a particular person's phenotype reflects the qualities of penetrance and expressivity. In addition to affecting protein function, variants can disrupt parts of DNA that control the regulation of gene expression-time, place, and so on ( Guttmacher and Collins, 2002). In some rare cases, variants can reduce the risk of disease an example is a frameshift mutation in the CCR5 gene that results in resistance to HIV type 1 infection (although the beneficial effect may be accompanied by a more subtle deleterious effect). Sometimes, the function of a mutant protein changes in such a way that it acquires a new toxic role, in some cases even antagonizing the normal protein. Most common is the loss of function of a protein. Health effects are caused by such changes in protein function. Some variants that call for different amino acids might affect the function of the protein only slightly, and others might cause major changes in protein function the effect would depend on the nature of the specific amino acid change and its position in the protein. However, although one might not think that a given variant would directly change an encoded amino acid sequence, it might change pre-mRNA splicing (processing of the RNA that carries protein sequence information from the DNA) and thereby indirectly have profound effects on the encoded amino acid sequence-and it is not always easy to predict whether or how splicing will be changed. A variant in the protein-coding region that does not change the specific amino acid sequence specified is not expected to have a phenotypic effect. Variants can have several effects on function. Variants found in germline cells are inherited because gametes are derived from those cells. A frameshift mutation is caused by insertions or deletions of a number of nucleotides not divisible by 3 and changes the reading frame of the gene in such a way that the original amino acid sequence of the protein is lost from the mutation onward ( Guttmacher and Collins, 2002). A nonsense mutation changes one base of a three-base codon for an amino acid to a premature stop codon and results in a truncated and usually nonfunctional protein. A missense mutation is the replacement of one base with another that can cause disease if the variant results in the substitution of a different amino acid in the resulting protein and a consequent change in function. The change can be a missense, nonsense, or frameshift mutation. A single-base modification is a change in a single DNA base-a single-nucleotide polymorphism-and is the most common kind of variant. Several types of variants can cause disease. Variants range in size they can affect anywhere from a single DNA building block (base pair) to a large segment of a chromosome that includes multiple genes. A sequence variant 1 can be a permanent alteration in the DNA sequence that makes up a gene in such a way that the sequence differs from what is found in most people.
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