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.2011 Mar;4(2):292-314.
doi: 10.1111/j.1752-4571.2010.00156.x. Epub 2010 Oct 12.

The emergence of human-evolutionary medical genomics

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The emergence of human-evolutionary medical genomics

Bernard J Crespi. Evol Appl.2011 Mar.

Abstract

In this review, I describe how evolutionary genomics is uniquely suited to spearhead advances in understanding human disease risk, owing to the privileged position of genes as fundamental causes of phenotypic variation, and the ability of population genetic and phylogenetic methods to robustly infer processes of natural selection, drift, and mutation from genetic variation at the levels of family, population, species, and clade. I first provide an overview of models for the origins and maintenance of genetically based disease risk in humans. I then discuss how analyses of genetic disease risk can be dovetailed with studies of positive and balancing selection, to evaluate the degree to which the 'genes that make us human' also represent the genes that mediate risk of polygenic disease. Finally, I present four basic principles for the nascent field of human evolutionary medical genomics, each of which represents a process that is nonintuitive from a proximate perspective. Joint consideration of these principles compels novel forms of interdisciplinary analyses, most notably studies that (i) analyze tradeoffs at the level of molecular genetics, and (ii) identify genetic variants that are derived in the human lineage or in specific populations, and then compare individuals with derived versus ancestral alleles.

Keywords: disease risk; evolutionary medicine; genetics; genome-wide; human evolution.

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Figures

Figure 1
Figure 1
Polygenic disease risk for a given individual can be depicted as a combination of risk owing to alleles inherited from parents (inherited polygenic liability), and risk owing to new mutations (de novo germline mutation). Somatic mutation during development is also likely to be important, but has yet to be studied in detail.
Figure 2
Figure 2
The frequency spectrum of human disease risk alleles includes alleles at all frequencies from rare to common, with effect sizes from high to low, with the relative importance in risk of different variants yet to be ascertained. From Manolio et al. (2009).
Figure 3
Figure 3
Storage and expenditure of resources for human growth, maintenance, and reproduction involve tradeoffs at multiple levels, from whole body to organs and tissues (shown here), and ultimately to cells and alleles. Such tradeoffs are expected to structure the evolution, development and expression of polygenic disease risks, just as they structure the evolution of human life history traits. From Wells (2009), with permission.
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