The evolution of gene discovery and the revelation of truth

Abstract

c a g g i Almost 40 years ago, Michael Brown and Joseph Goldstein established a revolutionary approach to the research of human disease. By studying homozygous familial hypercholesterolemia, a rare genetic disease affecting 1 in 1 million individuals, these Nobel laureates established the genetic basis of the condition. The question commonly eard, even in our current era of genetics research, quickly ollowed: How can finding a culprit gene for a rare familial ondition benefit patients with more common forms of the isease? In the years that followed, the clinical pundits received heir answer. Brown and Goldstein’s discovery of the lowensity lipoprotein (LDL) receptor’s role in cholesterol meabolism led to their description of the LDL receptor athway and the critical role of the 3-hydroxy-3-methylgluaryl-coenzyme A (HMG CoA) reductase enzyme in choesterol synthesis. The recognition of statins as potent inhibitors of this enzyme followed, and over 30 million ndividuals around the world now consume this class of rugs on a daily basis to reduce their risk of heart disease. his number is profound, considering that a genetic discovry affecting 1 in 1 million individuals has reaped benefit in hose who do not suffer from the specific disease of hoozygous familial hypercholesterolemia. And so the paraigm was born: understanding molecular pathways relevant o a disease, based on gene discovery, may lead to targeted rug development and a common benefit to patients who ay not carry the specific genetic defect. Research in the field of human genetics and gene disovery was pursued with a feverish pitch through 1980s and 990s, and reached a peak with the discovery of more than ,600 genes associated with human disease (http://www. cbi.nlm.nih.gov/omim). This rapid expansion of genetic nowledge related mainly to familial, single-gene diseases, nd utilized the then-novel and statistically robust method f linkage analysis. In linkage analysis, hundreds of known enetic markers with variable DNA sequences are anayzed in affected and unaffected family members and a andidate gene is localized based on the finding of spe-