While two randomly selected humans are identical for about 99.5% of their genome sequences, the size of the human genome ensures a remarkable diversity between individuals and population groups. Variations range from common single base pair alterations with no discernible effect on genome structure or function (SNPs) to whole-scale gain or loss of chromosomes (e.g., trisomy 21). Much genome variation is benign; for example, SNPs occur on average about every 1000 base pairs. Separating benign variation from that associated with disease has been a goal of human genetics research since the field’s inception. One approach is to start with groups of affected and “normal” individuals and look for non-random associations between presence of disease and specific variations. Classically, such studies have begun with individuals severely affected by single gene disorders and their families, yielding variations with very high risk of disease (high effect size). These mutations have provided insights into disease pathogenesis, potential treatments, and, sometimes, immediate utility in diagnosis and carrier status detection.
