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9.7Mutations and Polymorphisms

Genetic information exists as the DNA base sequence. A range of chemical substances and radiation can alter bases and may further cause errors in DNA replication. Changes in genetic information are termed mutations. Genetic mutations are of many types, ranging from a single base substitution to the deletion of a large region containing multiple genes. To say nothing of the case of a deletion, the protein encoded by highly mutated genes will usually be disadvantageous to survival because of reduction or even loss of function. A homozygote, in which two genes are both mutated in a diploid cell, is often lethal. Individuals with such mutations (mutants) are generally rare within a population, even as a heterozygote. A difference in the sequence that is observed in less than 1% of the population is termed a mutation. Mutations known to cause genetic diseases are generally observed at extremely low frequency. In contrast, if this difference is observed in more than 1% of the population, then it is termed polymorphism.

When a single base of a gene is substituted, it may result in no change in the amino acids comprising the protein (silent mutation); it may result in a change of one amino acid to another (missense mutation), or it may result in a termination codon (nonsense mutation). Proteins encoded by genes with silent and missense mutations are usually not dysfunctional or are slightly dysfunctional. Therefore, these changes do not have a major positive or negative effect on survival. (In some cases, large changes in function are also observed.) Thus, many individuals within populations of living organisms may have altered sequences. This type of mutation is called single nucleotide polymorphism (SNP, see section 5 of Chapter24). If two types of sequences are each observed in a 50% ratio in the population, we refer to them as polymorphisms, without being able to determine the mutated form. Differences between the ABO blood groups are polymorphisms (see Column Selection 4 of Chapter 6). DNA of any two random humans has approximately 1,000,000 single base differences. Some individuals have genetic constitutions that make them susceptible to obesity, diabetes, and hypertension, and recent studies suggested that gene clusters related to these conditions have specific SNPs. Researches focusing on the versatility of SNPs, such as SNPs in characteristic gene clusters in the genealogy of long-lived people and SNPs in enzyme genes related to medicine effectiveness, has drawn attention in various fields as the cornerstone of personalized medicine (therapeutics based on each individual’s characteristics or tailor-made medicine).

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