A reference data set of 5.4 million phased human variants validated by genetic inheritance from sequencing a three-generation 17-member pedigree

By M. Eberle, Epameinondas Fritzilas, P. Krusche, Morten Källberg, Benjamin L. Moore, M. Bekritsky, Z. Iqbal, Han-Yu Chuang, S. Humphray, A. Halpern and 4 more. bioRxiv, 2016

352 citations recorded by the source corpus.

Improvement of variant calling in next-generation sequence data requires a comprehensive, genome-wide catalogue of high-confidence variants called in a set of genomes for use as a benchmark. We generated deep, whole-genome sequence data of seventeen 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 catalogue of 4.7 million single nucleotide variants (SNVs) plus 0.7 million small (1-50bp) insertions and deletions (indels) that are consistent with the pattern of inheritance in the parents and eleven children of this pedigree. Platinum genotypes are highly concordant with the current catalogue of the National Institute of Standards and Technology for both SNVs (>99.99%) and indels (99.92%), and add a validated truth catalogue 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 (“non-platinum”) 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.

Subfields: Genetics

View Paper: https://www.semanticscholar.org/paper/29f68a9512a16c6db526fb166a6433be72ad005c

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In Genetics

Citations in the corpus

Merqury: reference-free quality, completeness, and phasing assessment for genome assemblies (2020, methodology): “Alternative methods report phasing statistics from small variants (mostly SNPs) called with short-read mapping [8, 20 – 23], or use benchmark genomes that have curated, phased variation call sets [24 – 27].”
De novo assembly of haplotype-resolved genomes with trio binning (2018, neutral): “Dotted vertical lines mark the fraction of heterozygous 21-mers for H. sapiens and the B. taurus F1 cross. a) Counts of structural variants between NA12878 haplotypes across the entire genome as reported by Assemblytics 34 .”
Best practices for variant calling in clinical sequencing (2020, methodology): “The most widely used ones include the Genome in a Bottle (GIAB) [67] and the Platinum Genome [68] datasets for NA12878, a human sample of European ancestry that has been sequenced with various technologies at Table 1 Sequencing strategies for NGS and empirical variant detection sensitivity.”
Detection of long repeat expansions from PCR-free whole-genome sequence data (2016, background): “The values were chosen tomaximize Mendelian consistency of genotype calls in Platinum Genome pedigree samples (Eberle et al. 2017) on an unrelated set of repeats.”
Scaling accurate genetic variant discovery to tens of thousands of samples (2017, background): “The orthogonal Illumina Platinum Genomes evaluation [9] showed a FDR of less than 1 While variant calling accuracy on a single sample is of primary importance in some studies, in nearly all contexts the interpretation of variants requires data derived from many samples.”
Scaling read aligners to hundreds of threads on general-purpose processors (2017, methodology): “Reads We obtained sequencing reads from accessions ERR194147 (Platinum Genomes Project [34]), SRR069520 (1000 Genomes Project [35]) and SRR3947551 (a low coverage whole genome sequencing project [36]).”
High-coverage whole-genome sequencing of the expanded 1000 Genomes Project cohort including 602 trios (2021, neutral): “Platinum Genome NA12878 call set generated by Illumina (Eberle et al., 2017).”