Abstract

Improvement of variant calling in next-generation sequence data requires a comprehensive, genome-wide catalog of high-confidence variants called in a set of genomes for use as a benchmark. We generated deep, whole-genome sequence data of 17 individuals in a three-generation pedigree and called variants in each genome using a range of currently available algorithms. We used haplotype transmission information to create a phased "Platinum" variant catalog of 4.7 million single-nucleotide variants (SNVs) plus 0.7 million small (1-50 bp) insertions and deletions (indels) that are consistent with the pattern of inheritance in the parents and 11 children of this pedigree. Platinum genotypes are highly concordant with the current catalog of the National Institute of Standards and Technology for both SNVs (>99.99%) and indels (99.92%) and add a validated truth catalog that has 26% more SNVs and 45% more indels. Analysis of 334,652 SNVs that were consistent between informatics pipelines yet inconsistent with haplotype transmission ("nonplatinum") revealed that the majority of these variants are de novo and cell-line mutations or reside within previously unidentified duplications and deletions. The reference materials from this study are a resource for objective assessment of the accuracy of variant calls throughout genomes.

The 'hybrid' truthsets were generated by merging Genome in a Bottle high confidence calls (hg001, v3.3.2) with those from the Platinum Genomes truthset for the same sample (NA12878, v2017-1.0). Merged records were validated by performing a k-mer test on alignments from the lower pedigree CEPH 1463 (11 children). Records with k-mer support via haplotype inheritance were added to the hybrid truthset.

Data Access

The VCF files for this track can be obtained from the download server: https://hgdownload.soe.ucsc.edu/gbdb/hg38/platinumGenomes/.
These files were obtained from the Platinum genomes source archive: https://s3.eu-central-1.amazonaws.com/platinum-genomes/2017-1.0/ReleaseNotes.txt.

Reference

Eberle MA, Fritzilas E, Krusche P, Källberg M, Moore BL, Bekritsky MA, Iqbal Z, Chuang HY, Humphray SJ, Halpern AL et al. A reference data set of 5.4 million phased human variants validated by genetic inheritance from sequencing a three-generation 17-member pedigree. Genome Res. 2017 Jan;27(1):157-164. PMID: 27903644; PMC: PMC5204340