Figure 3. Discovery pipeline for mechanism of disease: past and future paradigms.

A. Former strategy to identify disease mechanisms, starting with ascertainment of pedigrees for linkage, disease mapping to a particular chromosomal locus, and candidate gene Sanger sequencing. Once a mutant gene was identified, animal models were created to understand the mechanism. B. The future paradigm bypasses the need for informative pedigrees and disease mapping, instead going directly from patient ascertainment to genome sequencing, then to variant identification and expanded to identification of modifiers and mutational load. In parallel, patient-specific disease modeling using human cells coupled with protein interaction networks and therapeutic drug screening can further uncover disease mechanisms and help develop better treatments.