Genetic Variation, Comparative Genomics, and the Diagnosis of Disease

The discovery of mutations associated with human genetic disease is an exercise in comparative genomics (see Glossary). Although thereare many different strategies and approaches, the central premise is that affected persons harbor a significant excess of pathogenic DNA variants as compared with a group of unaffected persons (controls) that is either clinically defined or established by surveying large swaths of the general population.The more exclusive the variant is to the disease, the greater its penetrance, the larger its effect size,and the more relevant it becomes to both disease diagnosis and future therapeutic investigation.

The most popular approach used by researchers in human geneticsis the case–control design, but there are others that can be used to track variants and disease in a family context or that consider the probability of different classesof mutations based on evolutionary patterns of divergence or de novo mutational change. Although the approaches may be straightforward, the discovery of pathogenic variation and its mechanism of action often is less trivial, and decades of research can be required in order to identify the variants underlying both mendelian and complex genetic traits.