Heredity is particulate, but development is unitary.  Everything in the organism is the result of the interactions of all genes, subject to the environment to which they are exposed.

T. Dobzhansky 1961, p. 111

The chief analytical ultimacy in the new life sciences enterprise is represented by the capability of shifting scientific reduction to the smallest relevant molecular level for understanding life.

R. D. Alexander, 2008

I have no doubt that in reality the future will be vastly more surprising than anything I can imagine. Now my own suspicion is that the universe is not only queerer than we suppose, but queerer than we can suppose.

J. B. S. Haldane, 1927, p. 286

Kenneth Weiss, in his deeply-scholarly review of recent progress in the genetics of diseases mediated by effects from many genes, suggests that researchers are stalking ever-smaller, more elusive genetic prey – variants slightly increasing risk of disease – with ever-more powerful technological and analytic weapons.  He reminds us that population-genetic theory from nearly a century ago predicted just such a multitude of infinitesimal, variable effects as we are now observing, and that more research efforts might be better deployed other places than genome scans with more genetic markers, cases and controls.

I agree, and suggest that we try spending more money and research effort on true evolutionary disease genetics.   True, in that we must draw tightly together, for the first time, two disparate fields: (1) the study of the molecular and phenotypic selective pressures that have given rise to modern humans, (2) the study of the genetic and environmental underpinnings of polygenic disease. Disease risk, like our other traits, has evolved, but you would hardly know it from reading the pages of American Journal of Medical Genetics, Molecular Psychiatry, or other disease-genetic journals whose authors either ignore evolutionary principles or view them with deep suspicion as untestable speculation. Positive selection, antagonistic pleiotropy, and intragenomic conflicts are all expected to generate pervasive effects on disease risk but are virtually unexplored – as are, we must admit, the workings of the genome itself.  The genome’s machinations will surely turn out to be queerer than we can now imagine, but we must still try to reduce their vast complexities, by attacking with not just more nucleotide data at the bottom, but also with evolutionary concepts and methods across all levels from DNA to development, physiology, morphology and cognition.  A Darwin’s Dulcinea can be seen to embody love of this evolutionary venture, to understand our evolved selves, and our malaises, from single nucleotide polymorphism to brain.  Is this quest hopeless? If so, ultimately, nothing will make sense.

Alexander, R. D.  (2008) On ultimacy in the life sciences.  Unpublished Essay.

Dobzhansky, T. (1961) In: J. S. Kennedy (Ed.). Insect Polymorphism. London: Royal Entomological Society.

Haldane, J. B. S. (1927) Possible Worlds and Other Papers.

Chatto and Windus: London, 1932, reprint.