A common technique to understand a locus is to fine map it, or genotype/sequence all variants within the implicated locus. According to the latest findings from the 1000 Genomes Project Consortium, there have been nearly 90 million genetic variants discovered in humans (1000 Genomes Project Consortium, 2015). However, any particular individual differs from the extensively curated human reference genome at only ~5 million sites. The difference between 5 and 90 million lies in the fact that most variants identified to date are rare – the allele not observed on the reference genome only exists in a tiny fraction of individuals and any particular individual only has a small number of these rare alleles distributed throughout their genome. Traditional GWAS studies use a genome-wide array that genotypes a few hundred thousand up to a few million common genetic variants. Imputation methods can now fairly accurately impute variants down to ~0.1% minor allele frequency, the frequency with which the rare allele (often but not always the non-reference allele) is observed. Observing variants with even lower frequency currently requires direct genotyping or genome sequencing techniques.
