|Van Gogh, Farmhouse in a Wheat Field, public domain|
Essential personalized medicine means predicting your eventual disease-related phenotypes from your inherited genotype (and here, we'll extend that beyond just DNA sequence, to epigenetic aspects of DNA modification, assuming that will eventually be identifiable from appropriate cells).
If breeders had been finding that once seed with desired traits had been identified, genome-spanning genetic markers (polymorphic sites along the genome) pointed to a small number of locations with big effects, then we would quickly be able to find, and perhaps use the actual genes diagnostically. This seems to be true for some plants with small genomes, for traits that seem to be due to the action of variants in one or only a few genes. This is just what we find for the 'simple' human diseases, or the subset of complex diseases that segregates in families in a way that follows Mendel's principles of inheritance. There are many examples.
But for many traits, including most complex, delayed onset, life-style related, common disorders that are the main target of the GWAS-ification of medicine in the Collins era of NIH funding, what is being found is quite different. Mapping is finding hundreds of genes, almost all of which have either very small individual effects, or if larger effects, that are so rare that they are of minimal public health importance (even if very important to those who carry the dangerous allele). For these, the question is what to do with the countless, variable regions of the genome that make up the bulk of the inherited risk.
This is the same situation as faced in the agricultural breeding arena, for many of the traits, like water- or drought- or pest-tolerance, nutrient yield, or other characteristics desired for large scale farming. The traits are genomically complex. Even with large samples and controlled and uniform conditions--very unlike the human biomedical situation--it is not practicable or practical to try to improve the trait by individual gene identification. Nor is it likely that introducing single exotic transgenes will do the trick (as many agribusinesses are acknowledging).
Instead, molecular breeding takes advantage of the plant's own natural variation to select those variants that do what is desired simply by choosing the plants that transmit those variants, and without attempting to engineer or even to identify what they are. We do not know how reliable the prediction of phenotype from genotype in these circumstances typically is, but the idea is if that you keep selecting plants with the desired regions of the genome that mapping identifies, and breeding them for example with strains that you like for other reasons, you can reduce reliance on individual prediction because eventually every individual will be alike, for the traits you were interested in.
Once that is the case, regardless of the genes or regulatory regions that are involved, you have your desired plants, at least under the conditions of nutrients, climate, and so on, in which the strain was developed.
Clearly this experience is relevant for human genetics, and for evolutionary genetics of the same traits, a topic to which we will turn in our final post in this series.....