The emergence of human‐evolutionary medical genomics

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.

Functional primate genomics—leveraging the medical potential

“…It is beyond the scope of this article to review these approaches in detail, especially since its impact on medical genomics has just recently been discussed [7]. However, I would like to make a few, rather cautionary, remarks:…”

“…One reason is that genome-wide association studies use statistical tools rooted in population genetic theory, for example to control for population stratification [6]. Another is that genetic variants can reach high frequencies due to selection, and identifying such loci could be medically informative [7]. Genomic comparisons across species have also increasingly become possible, but so far had a relatively limited or at least a not well-recognized impact on medicine.…”

The evolutionary biology of child health

“…Key expectations from life-history theory applied to the human lineage are that evolutionary prolongation of pre-adult stages should engender lifetime-reproductive benefits sufficiently strong to counterbalance increased pre-adult survival costs [7], and that strong selection for survival and growth early in life should, owing to antagonistic pleiotropy, sustain considerable deleterious, more weakly selected effects later in life [2,3,8].…”

Diabetic Embryopathy: A Developmental Perspective from Fertilization to Adulthood

“…In line with this, the long-term consequences (either acquired, or genetic or both) of IUGR in DM may represent the in utero precursor of the 'thrifty' genotype(s) predisposing to DM2. Therefore, in terms of developmental medicine [Crespi, 2011], the long-lasting (i.e. epigenetic) effects of maternal diabetes on gene regulation of the developing embryo, which prospectively become diabetic in (early) adulthood, could act as a selective advantage facilitating diffusion of DM in the past.…”