In 1874, when Charles Darwin's younger cousin Francis Galton published English Men of Science: Their Nature and Nurture, Galton was no doubt aware of Shakespeare's priority, for when Prospero spoke of Caliban in 1611, calling him "A devil, a born devil, on whose nature nurture can never stick; ...,"3 one of the most entrenched dialectics in all of biology was born.
The impasse, widened in 1690 by John Locke's now well-worn metaphor of the newborn mind as a tabula rasa,4 a blank slate on which nature had scribbled nothing, became contentious when Galton insisted, to the contrary, that nature had ordained not language itself, but differential capacities for language; not genius, but differential predispositions for the realization of genius. It was as if Galton had supposed that nature had indeed written on Locke's clean slate, but that she had written her messages in invisible ink, and that the slate had to be held over a flame before the messages could be read.
Somewhere between these polarized philosophical views, between the nature uber alles of Galton and the environmental determinism of Locke, an empirical middle ground is currently being excavated, a middle ground that rejects neither view and that successfully incorporates components from each. Nowhere has this become clearer than in the complex interactions of disease agents, disease vectors, and the gene-based responses of their human hosts.
Genetic epidemiology is the study of genetic elements of disease, and is a growing methodology for understanding how those elements function in complex biological systems. Genetic epidemiologists seek to discover and understand the genetic basis of diseases, traits with complex inheritance patterns, and risk factors associated with gene-based diseases within specific environmental contexts (Mai, Young Owl, & Kersting, 2004; Motulsky, 1984).
The conjunction of the terms "genetic" and "epidemiology" at first may seem a forced blend; an attempt to meld two separate approaches that is doomed to chronic marbling rather than complete synthesis. However, some of the recent work of geneticists, epidemiologists, and, indeed, genetic epidemiologists, has blurred the once distinct barrier between these approaches. Classical Mendelian genetics has an increasingly limited utility in terms of understanding the complexity of many diseases and genetic predispositions to cytotoxic agents. The new mechanisms that have only recently become understood are for the most part epigenetic rather than genetic.
This review will address the possibility of an epidemiological transition, and end with a discussion and illustration of "transmissible" (in the epidemiological sense) genetic disease.
The concept of an epidemiological transition as a continuum that can be organized into stages similar to the well-known demographic transition has existed for some time (Corruccini & Kaul, 1983; Lappe, 1994). Such a continuum might extend well back into Miocene primate ecology, and from there forward into the Plio-Pleistocene foraging, scavenging, and hunting behaviors of early hominids. During these millennia, hominids continued to adapt genetically. They brought forward with them not only the genetic markers of prior adaptations, but also a host of commensal and parasitic "heirloom species" (Barnes, Armelagos, & Morreale, 1999). Humans cohabit a parallel evolutionary universe with body lice and enter-obacteria that evolve and speciate in synchrony with us (Hafner & Nadler, 1988; Klassen, 1992). We possess anticarcinogens against most plant-related agents (Ames, 1983; Steinkellner et al., 2001) but fewer against meat-related agents, especially heterocyclic amines (HCAs) in cooked meat (Adamson et al., 1996; Sugimura, 2000). These observations reflect the long, slow process of this epidemiological transition.
The roots of the anatomically modern human epi-demiological transition extend back at least 10 millennia, to a time when humans began to exploit marine environments extensively, and adapted both immunologically and digestively to the consumption of shellfish and other marine organisms (Walter et al., 2000).
The beginning of the human epidemiological transition proper, however, occurred when some human groups shifted from gathering and hunting to primary food production and the domestication of animals (Corruccini & Kaul, 1983; Diamond, 1997, p. 207). A second transition occurred when acute infectious diseases were controlled and the prevalence of chronic, noninfectious, and degenerative diseases increased; a third transition, according to some researchers, is defined by the "re-emergence and emergence of antibiotic-resistant diseases on a global scale" (Barnes et al., 1999; note 1, pp. 229-230).
Genetic diseases such as sickle cell disease (SCD)5 could be considered classic stage one/two "noninfectious" adaptations. "Genetic epidemiology" describes the distribution of gene-based adaptations when driven by an environmental agent, in this case the distribution of the infections agents of malaria, various species of Plasmodium.
Genetic diseases are increasing in prevalence, and perhaps in incidence as well. Some of this change may be an artifact of expertise, as higher resolution diagnostic tools are invented, and as diagnostic skills improve. A substantial proportion, however, is a sequela of improved treatment, and is the consequence of relaxed selection (see the entry Genetic Disease I).
Genetic diseases exhibit focal patterns. Some are as well known as SCD, others are less well understood. Some residual genotypic spatial distributions are thought to reflect past episodes of infection, such as cline of the P allele in Europe that may be due to selection against the IA allele during a smallpox epidemic (Bodmer & Cavalli-Sforza, 1976, p. 404). Other conditions with genetic manifestations will eventually be shown to be congruent with the distributions of nonorganic agents, such as foci of chemical mutagens, regions of high radioactivity, or pools of environmental carcinogens. Age-dependent genetic diseases will be found to cluster where demographically aged populations reside.
Classically, the distribution of some genetic diseases can be attributed a few already well-understood factors. Foremost among these are consanguinity (inbreeding), and the founder effect (drift).
Every genetic entity with significant present-day prevalence can be traced, at least theoretically, back to an ultimate mutation, the single source that was the founder of the modern distributions. Nowhere has this been more obvious than among the closed demes, where many genetic conditions—including breast cancer and Tay-Sachs disease (among the Ashkenazim); autism, lactose persistence, and the A32 mutation in the CCR5 gene (among Icelanders); Polydactyly, dwarfism, and maple syrup urine disease (among the Old Order Amish of Lancaster County, PA); congenital adrenal hyperplasia (among the Yu'pik Eskimos); and achromatopsia (among the Pingelapese people in Micronesia)—have been accounted for by these mechanisms (Lewis, 2001, p. 246).
The geographic removal of closed demes from one region to another is at times the sole mechanism invoked to explain the spatial variation of a genetic disease, known as a founder effect. For example, 30,000 living Afrikaaners (out of 2.5 million) have porphyria variegata. These affected individuals are all descended from a single pair of peripatetic colonizers who emigrated from Holland to South Africa in 1688.
In other cases, the slower dispersion of expanding populations into hominid-empty ecological niches appears to be the simplest explanation. Native Americans, for example, seem by some accounts to have entered
North America from Siberia in three major waves between 33,000 and 5,000 years ago; by other accounts, there was only one continuous dispersion event (Dillehay, 2000, p. 241). The second of these alleged waves, between 15,000 and 12,000 years ago, consisted of founders whose descendants today have high incidences of albinism and the New World syndrome. Any of the well-documented diasporas has left a similar genetic trail (Brown, 1990; Owens & King, 1999).
In any case, most simple monogenic conditions, if they are compatible with life, and if reproduction is possible (or permitted), and if sustained in a population for many generations, can potentially be reconstructed. Most of these reconstructions will resemble a dendritic funnel, with many branches at the open mouth ending in clusters of demes composed of living individuals that carry the inherited alleles. These extend back in time, downward into the throat of the funnel, twigs joined together into branches, branches into limbs, and limbs into a single ancestral trunk representing the family of the individual with the original mutation.
In the absence of other forces, a unique founder will have offspring who will live and die more or less in situ, as will grandchildren and all future heirs of the mutant allele. In this most simple—and most unlikely— of all cases, an undisturbed distribution would, at least in theory, appear as a perfect circle with the greatest density (highest allele frequencies) near the center. Humans are not bacteria, however, and while it may be possible to find such a neat distribution in a Petri dish, most human distributions have been affected dramatically by the contingencies of history: by wars and local catastrophes, by colonization, by economics, by the depletion of regional resources that necessitated out-migrations, by cycles of prey movement, by the ebb and flow of weather patterns. Entire branches of the human tree have been broken off and flung to the winds, some being crushed in the process. Others have withered, while yet others have flourished and increased, pushing smaller demes toward lands with marginal resources.
The reconstruction of the human tree has already commenced. A body of journal articles, books, and computer programs under the general rubric of "genes, people and languages," provides an entrée to the literature that documents this ongoing task (Cavalli-Sforza & Cavalli-Sforza, 1995; Layrisse & Wilbert, 1999).
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