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erates variation in mechanism within individuals, and it is fundamental in the etiology of cancer and a few other diseases, probably including cognitive aging, and may have much greater importance than has yet been documented (Weiss, 2005a, 2005b). Somatic mutation in p53 affects individual cells that can transform to found a clone of cells that constitute a life-threatening cancer. Some somatic changes can in various ways affect gene expression rather than gene sequence itself, and these are known as “epigenetic” effects. A number of epigenetic mechanisms are known and new ones are rapidly being discovered.

The “genetic architecture” of a biological trait refers to the number of genes that contribute to it, the way those genes interact with each other and with the environment, their relative contribution to the trait, and the role of their variation on the trait. It involves all three aspects of genetics. The genetic architecture of traits in multicellular organisms, including human traits of any complexity, is far from completely known. Indeed, “complex” is in the eye of the beholder, and even “simple” traits turn out not to be so simple on close inspection (Scriver and Waters, 1999). Most human genetic epidemiology is largely black-box genetics that searches for statistical correlation between inheritance and trait, initially without knowing (or at the discovery stage even caring) about its mechanism. The situation is made more complex by the expanding definition of “gene” to recognize many functions beyond protein-coding, and these are still being discovered.

The genetic architecture of any trait is the product of its evolution. Evolution is the population-historic process that generates the genomes that construct or affect phenotypes. Evolution involves population size, mating patterns, chance, migration, geographic and social distribution, differential reproduction, and the like. The variation that results depends on mutation rates, the size of the mutation target (number and length of relevant genetic units in the genome), and the effects of reproductive fitness (natural selection). These factors are mediated through demographic history. Evolution helps account for and predict the general trait patterns that we see today, and because humans are a globally distributed species, it is especially useful in explaining the amount and geographic distribution of genetic variation affecting human traits.

The 20th century began with the recognition of Mendel’s work on the particulate (discrete-factor) nature of inheritance. Discretely varying (e.g., presence/absence) traits initially seemed inconsistent with the more prevalent quantitative variation (e.g., height, weight) seen in nature and that seemed to be the working material for evolution. But early in the 20th century it was realized that the combined action of many independently segregating particulate genes could, through combinatorial contributions, lead to a quantitative phenotype (to which environmental variation con-



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