Optimized & Highly Heterozygous SNP Reference VCF for FACETS (hg38/GRCh38)

1. Summary

This deposit contains an optimized reference VCF file for the human genome (hg38/GRCh38). It lists common Single Nucleotide Polymorphisms (SNPs) specifically filtered for high population heterozygosity.

This file is designed for use with allele-specific copy number analysis tools, particularly FACETS. It replaces previous methods relying on fixed-distance thinning with a biologically relevant filtering approach based on 1000Genomes population frequencies.

2. Rationale

Standard dbSNP files present significant challenges for somatic CNV/LOH analysis:

• Excessive Noise: They contain millions of rare variants or homozygous sites that provide no information for allelic imbalance detection.
• Computational Overhead: Processing uninformative sites significantly slows down snp-pileup.
• Biological Irrelevance: Chromosomes Y and M do not follow the diploid segregation models used by standard CNV algorithms.

This optimized reference solves these issues by retaining only common, strictly biallelic SNPs with a Reference Allele Frequency (RAF) between 0.25 and 0.75. This ensures that the chosen markers have the highest probability of being heterozygous in a patient, maximizing the resolution of FACETS while drastically reducing file size.

3. Contents of the Deposit

• facets_reference_snps_hg38_optimized.chr_style.vcf.gz
  • The primary SNP reference file (UCSC style chr1, chr2, etc.).
• facets_reference_snps_hg38_optimized.chr_style.vcf.gz.tbi
  • The Tabix index for the above file.
• facets_reference_snps_hg38_optimized.no_chr_style.vcf.gz
  • The primary SNP reference file (style 1, 2, etc.).
• facets_reference_snps_hg38_optimized.no_chr_style.vcf.gz.tbi
  • The Tabix index for the above file.
• Galaxy-Workflow-Optimed_VCF_for_facets.ga
  • The .ga file allows users to import and reproduce the exact generation pipeline in a Galaxy instance.
• Zenodo_fig1.png
  • Figure 1: Distribution of inter-SNP distances per chromosome. It demonstrates that despite filtering for heterozygosity, the average distance remains close to ~1kb (Avg: ~900-1100 bp), maintaining excellent coverage resolution.
• Zenodo_fig2.png
  • Figure 2: Distribution of Reference SNP frequencies. This validates the filtering step, showing a clean cut-off at 0.25 and 0.75 RAF.

4. Generation Workflow (Transparency)

The generation process has been fully automated using a Galaxy Workflow to ensure reproducibility. The legacy Python script has been re