ABSTRACT
The transition between the last and the present millennium of scientific progress will surely be most noted for the successful definition of the complete DNA sequences of several unique individuals, including even some who pioneered this remarkable accomplishment. To place the event in historical perspective, recall that its origins go back only a bit more than a century to Mendel’s discoveries concerning the inheritance of simple traits affecting his harvest of garden peas. Discovery of the paired double-stranded structure of DNA, now 50 years ago, subsequently provided the basis for explaining how the phenotypes observed by Mendel were transmitted from one generation to another. Since that time, much has been learned about how these same principles help explain human traits such as eye or hair color, and how the ability to read DNA sequences of genes at specific chromosomal loci can provide information on the incidence of many congenital diseases, their segregation within different generations, and how such changes convey a just-emerging dimension of health susceptibility not previously envisioned. Current understanding of how mutations result in functional physiological differences and how single-gene, that is ‘monogenic’, syndromes are characterized by well-defined disease phenotypes that occur in concert with Mendel’s laws, is well advanced. Indeed single gene mutations with high ‘penetrance’, that is they occur in most individuals who inherit the mutation, are now well recognized as the cause of more than 1000 different syndromes,1 and the stories of their discovery represent some of the most exciting pages in medical history. Today, as the details in the newly completed human genome projects are being digested, the task for the next period of discovery would appear to be to understand not just mutations that result in frank ‘congenital’ defects and ‘Mendelian’ diseases, but the full complement of DNA variation, from the less frequent ‘high impact’ events that result in extreme phenotypes, to the more complicated ‘polygenic’ conditions, involving multiple genes and ‘lower impact’ common single base polymorphisms (SNPs), that define more subtle functional differences between a healthy and a diseased individual.
