EnsembleTR

EnsembleTR is a tool for ensemble Tandem Repeat (TR) calling. It takes one or more VCF files with TR genotypes for a panel of samples and outputs a consensus set of genotypes.

Installation

pip install --upgrade pip
pip install ensembletr

Type ensembletr --help. You should see the help message appear.

Usage

To run EnsembleTR, use the following command

ensembletr --out output.vcf
           --ref ref.fa
           --vcfs vcf1.vcf,vcf2.vcf,...

Required parameters:

• --vcfs <file.vcf,[file2.vcf]> Comma separated list of input VCF files
• --ref Refererence genome (.fa)
• --out Path to output VCF file

File formats

VCF (--vcfs)

Both zipped and unzipped VCF files are accepted as input. EnsembleTR can currently process VCF files generated by hipSTR, GangSTR, adVNTR, and ExpansionHunter.

FASTA Reference genome (--ref)

You must input a reference genome in FASTA format. This must be the same reference build used for TR calling in input files.

VCF (--out)

For more information on VCF file format, see the VCF spec. The output VCF is not necessarily sorted, please use vcf-sort or other VCF sorting tools to sort the output before downstream analysis. EnsembleTR output VCF file contains several fields described below.

INFO fields

INFO fields contain aggregated statistics about each TR. The following custom fields are added:

FIELD	DESCRIPTION
START	Start position of the TR
END	End position of the TR
PERIOD	Length of the repeat unit
RU	Repeat motif
METHODS	Methods that attempted to genotype this locus (AdVNTR, EH, HipSTR, GangSTR)

Note that the RU shows the canonical sequence of the repeat unit, which is the first alphabetically out of all possible rotations on + and - strands of the sequence. e.g. “TG” canonical sequence is “AC”.

FORMAT fields

FORMAT fields contain information specific to each genotype call. The following custom fields are added:

FIELD	DESCRIPTION
GT	Genotype
GB	Base pair difference from ref allele
NCOPY	Genotype given in number of copies of the repeat motif
EXP	Boolean showing if the genotype alleles were expanded
SCORE	Score of the consensus call
GTS	Method(s) that support the consensus call
ALS	Number of times each bp difference was seen across all calls
INPUTS	Raw calls

Score is calculated by aggregating quality information from calls that are getting merged at each locus.

Using statSTR on EnsembleTR files

You can use statSTR from TRTools to compute various per-locus statistics for EnsembleTR .VCF files.

For example, to compute per-locus allele frequency use the following command:

statSTR --vcf EnsembleTR_file.vcf.gz
        --vcftype hipstr
        --afreq
        --out EnsembleTR_per_locus_allele_frequency

EnsembleTR data releases

Archived datasets, including the Version II calls and other versions of haplotype panel files can be found here.

Version II of EnsembleTR calls on samples from 1000 Genomes Project and H3Africa

Chromosome 1 VCF file and tbi file

Chromosome 2 VCF file and tbi file

Chromosome 3 VCF file and tbi file

Chromosome 4 VCF file and tbi file

Chromosome 5 VCF file and tbi file

Chromosome 6 VCF file and tbi file

Chromosome 7 VCF file and tbi file

Chromosome 8 VCF file and tbi file

Chromosome 9 VCF file and tbi file

Chromosome 10 VCF file and tbi file

Chromosome 11 VCF file and tbi file

Chromosome 12 VCF file and tbi file

Chromosome 13 VCF file and tbi file

Chromosome 14 VCF file and tbi file

Chromosome 15 VCF file and tbi file

Chromosome 16 VCF file and tbi file

Chromosome 17 VCF file and tbi file

Chromosome 18 VCF file and tbi file

Chromosome 19 VCF file and tbi file

Chromosome 20 VCF file and tbi file

Chromosome 21 VCF file and tbi file

Chromosome 22 VCF file and tbi file

Version IV of reference SNP+TR haplotype panel for imputation of TR variants

These files contain:

• Phased SNP and indel variants of 3,202 samples from the 1000 Genomes Project (1kGP).
• TRs phased/imputed from 3,202 1kGP samples based on EnsembleTR calls.

There are in total 1,070,762 TRs and 70,692,015 SNPs/indels.

All the coordinates are based on hg38 human reference genome.

These files contain the same data as Version II, with the following updates to facilitate use in downstream imputation pipelines:

1. Remove TRs for which the REF allele does not match the expected sequence based on CHR:POS
2. For each TR, remove alelles with 0 count.
   • If reference allele have 0 count, keep the reference alleles.
3. Remove TRs which have more than 100 alleles.
4. Remove TRs which have less than 2 alleles.
5. Remove the DS/GP fields which are large and not used by downstream steps.
6. Add unique IDs for each TR of the format EnsTR:CHROM:POS. For TRs with the same CHR:POS, add the duplicate number of the TR following format: EnsTR:CHROM:POS:Duplicate_num. Duplicated loci with identical alleles are removed.
7. Add VT field, set to VT=TR for TRs and VT=OTHER for other variant types
8. Add the bref format files which have the same information as the VCFs but can improve Beagle imputation performance.

All file description and download links can be found here. Data and links for each chromosome for the Verson IV panel are also provided below.

Chromosome 1 [VCF] [tbi] [bref] SNPs/indels=5,759,060 TRs=92,378

Chromosome 2 [VCF] [tbi] [bref] SNPs/indels=6,088,598 TRs=91,137

Chromosome 3 [VCF] [tbi] [bref] SNPs/indels=4,983,185 TRs=75,243

Chromosome 4 [VCF] [tbi] [bref] SNPs/indels=4,875,465 TRs=69,327

Chromosome 5 [VCF] [tbi] [bref] SNPs/indels=4,536,819 TRs=66,492

Chromosome 6 [VCF] [tbi] [bref] SNPs/indels=4,315,217 TRs=65,940

Chromosome 7 [VCF] [tbi] [bref] SNPs/indels=4,137,254 TRs=59,422

Chromosome 8 [VCF] [tbi] [bref] SNPs/indels=3,886,222 TRs=55,144

Chromosome 9 [VCF] [tbi] [bref] SNPs/indels=3,165,513 TRs=44,189

Chromosome 10 [VCF] [tbi] [bref] SNPs/indels=3,495,473 TRs=51,640

Chromosome 11 [VCF] [tbi] [bref] SNPs/indels=3,423,341 TRs=49,603

Chromosome 12 [VCF] [tbi] [bref] SNPs/indels=3,332,788 TRs=55,887

Chromosome 13 [VCF] [tbi] [bref] SNPs/indels=2,509,179 TRs=35,720

Chromosome 14 [VCF] [tbi] [bref] SNPs/indels=2,290,400 TRs=36,203

Chromosome 15 [VCF] [tbi] [bref] SNPs/indels=2,109,285 TRs=32,338

Chromosome 16 [VCF] [tbi] [bref] SNPs/indels=2,362,361 TRs=35,452

Chromosome 17 [VCF] [tbi] [bref] SNPs/indels=2,073,624 TRs=38,382

Chromosome 18 [VCF] [tbi] [bref] SNPs/indels=1,963,845 TRs=28,446

Chromosome 19 [VCF] [tbi] [bref] SNPs/indels=1,670,692 TRs=33,536

Chromosome 20 [VCF] [tbi] [bref] SNPs/indels=1,644,384 TRs=25,745

Chromosome 21 [VCF] [tbi] [bref] SNPs/indels=1,002,753 TRs=12,894

Chromosome 22 [VCF] [tbi] [bref] SNPs/indels=1,066,557 TRs=15,644

Usage

Use Beagle to impute TRs into SNP data:

java -Xmx4g -jar beagle.version.jar \
            gt=SNPs_chr${chrom}.vcf.gz \
            ref=ensembletr_refpanel_v4_chr${chrom}.bref3 \
            out=imputed_TR_SNPs_chr${chrom}

We have tested this with Beagle jar file beagle.27May24.118.jar. Earlier releases of Beagle 5.4 had problems imputing from this panel due to a file decompression issue.

Additional resources

Per locus summary statistics can be downloaded from here. Each table has information on coordinates, repeat unit sequence, and potential overlap with genes listed in GENCODE v22 for repeats in EnsembleTR catalog.

Population-specific per locus statistics on allele frequency, heterozygosity, and the number of called samples can be found here. Statistics are computed using statSTR from the TRTools package.