What's Normal?
SNPs, mutations, and mutants:
a note on terminology & some lessons from history

    The classical genetic picture of the genome was that most organisms, at any given gene locus, are homozygous for a single dominant allele, whose phenotype corresponds to the "wild type" norm for the species, and  which is shared with other typical members of the same species. The occasional, rare phenotypic variant was believed to arise as a mutation, the large majority of which were regarded as recessive and deleterious. For example, most Drosophila have red eyes: the rare white-eyed fly was regarded as a mutant ("changed") that arose as a result of a mutation ("change") in a gene.

    In humans, many easily-recognized single-gene traits result in medical conditions such as albinism (absence of skin pigment), polydactyly (extra digits), achondroplasia (stunted limb growth), etc., all of which we tend to put in the category of "diseases". Thus we tend to think of these rare individuals as "mutants" and therefore "abnormal," in contrast to the majority of the population who are (like ourselves) "normal". We tend to associate genetic variation with disease, and view all "mutation" as negative. These perceptions are inaccurate. Advances in molecular biology since the late 1960s have shown instead an enormous amount of genetic variation in most species, including our own. At the level of DNA sequences, it is likely that almost everyone is heterozygous at most gene loci, and (except for close relatives) is likely to differ from other members of the population. This being the case, the concept of a standard 'wild type' has no meaning. The basis of observed genetic differences are single-nucleotide polymorphisms (SNPs), alternative base pair differences at particular positions in the gene sequence. The variable effect of such SNP variation on phenotypes is one of the topics of this course. It remains the case that many gene variants do lead to medically deleterious conditions, and a great deal of time, money, and research is invested to understand and ameliorate such conditions.

    In modern usage, we avoid the use of 'mutant' to refer to individual humans ("Queen Victoria was a mutant!"), though we may talk about 'mutant flies'. We also restrict the term 'mutation' to describe the molecular process by which gene variants are produced ("PKU results from a mutation of the PAH locus"), or to characterize a newly-arisen sequence variant ("a splice-site mutation"). DNA mutation gives rise to SNP variation within populations, however observed SNP differences between any two individuals likely arose long ago in their ancestors, rather than as a result of mutation in the parental generation. The exceptions are genetic variants observed in close relatives, which can often be traced to a particular mutational event in a common ancestor.

    Conscious or unconscious acceptance of inaccurate attitudes about "What is Normal" with respect to genetic variation have led to misinformed social policy, sometimes with disastrous consequences. The term "eugenics" was introduced in the late 19th century to describe efforts to improve the human species by encouraging breeding of persons with "good genes," as evidenced by superior intelligence, general health, proper social status or skin colour, etc. In the absence of any knowledge of genetics, early "positive eugenic" practices were those of livestock breeding, e.g., persons of 'good stock' should breed with others like themselves and hope for the best.

    With the rediscovery of Mendel's work on inheritance in peas, many scientists assumed that variation for almost any trait could be explained by single-gene Mendelian inheritance. For example, the US Navy in 1919 commissioned a study by the Eugenics Records Office of the genetics of "leadership ability" and "love of the sea" (thallasophilia), so as to provide a means of selecting naval cadets on the basis of their favourable pedigrees. Not surprisingly, 'leadership' was found to be dominant and 'sea lust' recessive and sex-limited, like beard growth (ever see a lady Admiral?). Textbooks showed pedigrees of the JS Bach family to demonstrate inheritance of musical ability, as shown by his multiple talented offspring.  State fairs awarded blue-ribbons to 'fitter families' with sturdy, healthy children, presenting them with ribbons and medals in exactly the same way as superior livestock. Such efforts confuse heredity with familiality, the tendency of family members to resemble each other because of their shared environmental background. For example, boys often follow their fathers into military careers, the Bach children received music lessons from Dad, etc..

    Eugenics unfortunately had its dark side. For example, the massive casualties of World War I were seen in some Western countries as having "negative eugenic" consequences, as officers and soldiers killed tended to be young, physically fit, pre-reproductive males of superior intelligence, leaving behind those unqualified for military service to do the breeding. Studies of certain notorious 'feeble-minded' and/or 'criminal' families (notably, the Kallikaks) concluded that such traits ran in families, again ignoring effects of familial poverty, malnutrition, and social stigmatization ('Kallikak' children were habitually shunned). The popularity of eugenic thinking reinforced post-war anti-immigrant sentiment in the US: low IQ scores of new immigrants were ascribed to their poor genetics, disregarding the fact that the tests were administered in English to non-English-speaking persons. It also led to efforts to discourage or actively interfere with the breeding of persons perceived to have "bad genes".  In the 1920s and '30s, many US states and Canadian provinces passed laws mandating compulsory sterilization for thousands of persons with a variety of conditions considered "hereditary" on the basis of little or no evidence (epilepsy, mental retardation, "congenital" criminality or pauperism, etc). The Nazi regime in Germany adopted these same laws, and extended them to outright murder of institutionalized persons ("Lebensunwertes Leben:" Life unworthy of Life") in its Aktion T4 extermination policy of the 1930s. Technical methods of large-scale execution developed in this program were extended directly to the murder of millions in the Holocaust of the 1940s.

    Recommended books include
        J Cornwell, "Hitler's Scientists: Science, War, and the Devil's Pact"
        C Browning, "The Origin of the Holocaust"
        SJ Gould "The Mismeasure of Man," 2nd ed.

Text material © 2011 by Steven M. Carr