2013 ASHG: Recognition of disease-associated alleles in the reference sequence is critical for accurate risk assessment through genome sequencing

Inaccuracies with the Public Reference

The public reference genome sequence (GRCh37) contains minor alleles at >1 million positions. The presence of minor alleles in the reference impacts the detection of variants in an individual and in many cases negatively affects the genetic and medical interpretation of their results.

An Enhanced Reference Sequence

Leveraging both public and proprietary data sources, we identified medically relevant minor allele positions in GRCh37, where the reference allele is the minor allele by frequency (via 1000 Genomes) in four different HapMap populations. These positions include those variants previously associated with Mendelian disease, pharmacogenomic response, and complex disease.