hg19K: addressing a significant lacuna in hg19-based variant calling

Area of Science:

• Genomics
• Bioinformatics

Background:

• The hg19 human genome assembly is widely used for variant calling.
• hg19 contains minor alleles, impacting variant call accuracy.
• Standard variant calling methods assume major alleles at all positions.

Purpose of the Study:

• To assess the impact of minor alleles in hg19 on variant calling.
• To develop an improved reference genome for accurate individual genome analysis.

Main Methods:

• Created hg19K by replacing hg19 minor alleles with data from the 1000 Genomes Project phase 3.
• Analyzed and compared variant calls from hg19 and hg19K using five individual genomes.

Main Results:

• Identified 1.9 million positions in hg19 with major alleles not matching the 1000 Genomes Project data.
• ~30% of single nucleotide variants (SNVs) in individuals fall within these 1.9 million positions.
• ~8% of unique SNVs were identified using the hg19K approach.

Conclusions:

• Minor alleles in hg19 cause approximately 8% false negatives and 30% false positives in variant calls.
• hg19K-based methods identify unique SNVs missed by hg19, including potentially deleterious mutations.
• Accurate variant calling requires addressing minor alleles in reference genomes.