Population Stratification
The recent, dramatic acceleration in human population growth over the last several millennia has resulted in an excess of rare variants in the human genome, and these variants have not had enough time to be subjected to natural selection [14]. Since the identification of disease-associated variants consists largely of assessing rare variants, one must bear in mind the possibility that a variant of interest could be population-specific and not necessarily disease-causing. This is especially problematic if the patient cohort is not of European or, more specifically, northwestern European descent. Recent public sequencing projects, such as the 1000 Genomes Project and NHLBI Go Exome Sequencing Project, have covered a greater variety of non-European ethnic groups than before, and they report that these groups harbor a greater burden of rare variants as compared to Europeans [14, 16]. For example, indigenous African individuals may carry 2-3 times more rare variants, and East Asian individuals may carry 1.5 times more variants when compared to individuals of European descent. Rare variants specific to the population of study might be easily mistaken as patient-enriched variants; it is thus necessary to screen the presumed variant with carefully matched healthy individuals.