Analysis-ready whole-genome (WG) BED files for germline-somatic SNV overlap analyses

Version 2 update

Version 2 replaces the previously deposited HGDP rare-variant whole-genome BED file, which had not undergone linkage-disequilibrium pruning, with the LD-pruned dataset used in the final analyses. This version also adds the LD-pruned common and rare 1KGP BED files used for independent replication of the whole-genome results. The metadata were updated to document the distinct file schemas and the final analytical workflow. Version 1 is retained for provenance but should not be used to reproduce the final analyses.

Dataset description

These files contain autosomal biallelic single-nucleotide variants (SNVs) represented in the GRCh38 human genome assembly. The datasets were generated from the Human Genome Diversity Project (HGDP), the high-coverage 1000 Genomes Project (1KGP), ClinVar, and COSMIC for the investigation of exact-coordinate recurrence across germline and somatic SNV classes.

HGDP served as the primary population reference panel, whereas the high-coverage 1KGP dataset was used as an independent replication panel. Linkage-disequilibrium pruning was applied to both population-based datasets before classification into common and rare SNVs.

The primary whole-genome analyses compared HGDP common and rare SNVs with COSMIC somatic SNVs and were independently replicated using 1KGP common and rare SNVs. ClinVar whole-genome files are provided for data provenance but were not included in whole-genome enrichment tests because of their strong coding-region ascertainment. ClinVar variants were evaluated only in the MANE-defined coding-sequence analyses deposited separately.

File schemas

The HGDP, ClinVar, and COSMIC files contain six tab-delimited columns:

1. chromosome;
2. zero-based start coordinate;
3. end coordinate;
4. VEP consequence;
5. reference allele; and
6. alternate allele.

The 1KGP files contain six tab-delimited columns:

1. chromosome;
2. zero-based start coordinate;
3. end coordinate;
4. source variant identifier in CHROM:POS:REF format;
5. global alternate-allele frequency; and
6. number of 1KGP superpopulations in which the alternate-allele frequency is at least 1%.

The 1KGP files were generated for population-frequency classification and exact-coordinate overlap testing and were not annotated with VEP. Consequently, their fourth through sixth columns differ from those of the HGDP, ClinVar, and COSMIC files.

File descriptions

• SNPs_WG.bed.gz: HGDP common SNVs. Autosomal biallelic SNVs with global allele frequency of at least 1% and allele frequency of at least 1% in two or more of the seven HGDP geographic regions, after linkage-disequilibrium pruning.
• rares_WG.bed.gz: HGDP rare SNVs. Autosomal biallelic SNVs with global allele frequency below 1%, after linkage-disequilibrium pruning.
• 1KGP_common_WG.bed.gz: 1KGP common SNVs. Autosomal biallelic SNVs with global allele frequency of at least 1% and allele frequency of at least 1% in two or more of the five official 1KGP superpopulations, after linkage-disequilibrium pruning.
• 1KGP_rare_WG.bed.gz: 1KGP rare SNVs. Autosomal biallelic SNVs with global allele frequency below 1%, after linkage-disequilibrium pruning.
• patho_WG.bed.gz: ClinVar SNVs classified as pathogenic or likely pathogenic and restricted to records with a review status of two to four stars. This file was not included in the whole-genome enrichment analyses.
• benign_WG.bed.gz: ClinVar SNVs classified as benign or likely benign. This file was not included in the whole-genome enrichment analyses.
• cosmic_WG.bed.gz: Somatic SNVs obtained from COSMIC and deduplicated by chromosome, genomic position, reference allele, and alternate allele.

These analysis-ready datasets support reproduction of the whole-genome exact-coordinate overlap analyses and independent replication across the HGDP and 1KGP population reference panels.