Individual Genetic Variation

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Individual Genetic Variation

"Variety is the spice of life," or so the saying goes. In fact, it is probably more precise to say that variety is the key to life. It is genetic variation that contributes to the diversity in phenotype that provides for richness in human variation, and it is genetic variation that gives evolution the tool that it needs for selection and for trying out different combinations of alleles and genes.

Some variation is directly observable. Some examples of human genetic variants include the widow's-peak hairline, which is dominant to nonwidow's peak; free earlobe, which is dominant to attached earlobe; facial dimples, which are dominant to no facial dimples; and tongue-rolling, which is dominant to non-tongue-rolling. Another example is the ability to taste phenylthio-carbamide (PTC), a bitter-tasting substance. Seven out of ten people can taste the bitterness in PTC paper, and the ability to taste it is dominant to nontasting. Much variation at the genetic level, however, is not observable just by looking at someone. Even these "invisible" traits can nonetheless be scored in the laboratory.

Variation and Alleles

Any locus having two or more alleles (variant forms of particular genes), each with a frequency of at least 1 percent in the general population, is considered to be polymorphic . The difference between two alleles may be as subtle as a single base-pair change, such as the thymine-to-alanine substitution that alters the B chain of hemoglobin A from its wild type to its hemoglobin sickle cell state. These single nucleotide polymorphisms are termed "SNPs" ("snips").

As of March 2002, in the approximately 3.2 billion base pairs of DNA, approximately 3.2 million SNPs have been identified. Some base-pair changes have no deleterious effect on the function of the gene; nevertheless, these functionally neutral changes in the DNA still represent different alleles. Alternatively, allelic differences can be as extensive as large, multi-codon deletions, such as those observed in Duchenne muscular dystrophy.

Genetic variation is transmissible from parent to child through germ cells , and it can occur anew via mutation in either germ cells or in somatic cells. Interestingly, new mutations occur twice as frequently in sperm as in eggs, probably because so many more cell divisions are required to make sperm than eggs.

Scoring Variation in the Lab

Differences in alleles can be scored via laboratory testing. The ability to score allele differences accurately within families, between families, and between laboratories is critically important for linkage analysis in both simple Mendelian and genetically complex common disorders. Linkage analysis traces coinheritance of a disease gene and polymorphic markers such as SNPs to discover where in the chromosomes the disease gene is located.

Allele scoring strategies may be as simple as noting the presence (+) or absence (−) of a deletion or point mutation, or as complicated as assessing the allele size in base pairs of DNA. The latter application is common when highly polymorphic; microsatellite repeat markers are used in linkage analysis.

When genetic counselors talk to patients and families about mutations (a type of genetic variation) that are present in themselves or their children, they are careful to point out that each individual is estimated to carry between five to seven deleterious alleles that, in the right combination with other genes or with specific environmental influences, can lead to disease. Most of us do not know which deleterious genes we carry. Some are recessive and do not influence the genotype unless paired with a second recessive allele. Thus, these alleles will not be noticed without genetic analysis. And, genetic counselors are careful to avoid the term "mutation," because it is potentially stigmatizing. When speaking with patients, they prefer to use the more neutral term "variant."

see also Disease, Genetics of; Genotype and Phenotype.

Marcy C. Speer