Personalized medicine and the genotype-phenotype dilemma.

Important human phenotypes like height or facial appearance run in families—that has been known for millennia. Systematic studies of the way in which crossing pea plants resulted in changes in important pea plant phenotypes such as flower color or leaf number were defined in the mid-nineteenth century by Mendel [1] and the chemical basis for “inherited inborn errors of metabolism” by Garrod [2] at the turn of the twentieth century. Thus, some of the fundamental and familiar rules that we accept in a contemporary understanding of human genetics were laid down decades ago. However, an understanding of the mechanisms whereby genetic information is transmitted from generation to generation and how this information modulates important physiologic or disease susceptibility traits has been more recent. The fundamental discovery was the double-helix structure of DNA, which immediately led to the inference that DNA replication might replicate itself [3]. The last 50 years has seen the development of increasingly robust techniques for sequencing DNA and for using DNA as a laboratory reagent.