Next generation sequencing and rare genetic variants: from human population studies to medical genetics

The allelic frequency spectrum emerging from several Next Generation Sequencing (NGS) projects is revealing important details about evolutionary and demographic forces that shaped the human genome. Herein, we discuss some of the achievements of the use of low-frequency and rare variants from NGS studies. The majority of variants that affect protein-coding regions are recent and rare. Often, the novel rare variants are enriched for deleterious alleles and are population-specific, making them suitable for the study of disease susceptibility. To investigate this kind of variation and its effects in association studies, very large sample sizes will be necessary to achieve sufficient statistical power. Moreover, as these variants are typically population-specific, the replication of disease associations across populations could be very difficult due to population stratification. Therefore, the design of experiments focusing on the identification of rare variants and their effects should be carefully planned. Although several successes have already been achieved through NGS for genetic epidemiology, pharmacogenetic and clinical purposes, with improvements of the sequencing technology and decreased costs, further advances are expected in the near future.