Genome-wide profiling of genetic variation at tandem repeat from long reads.

Tandem repeats are frequent across the human genome, and variation in repeat length has been linked to a variety of traits. Recent improvements in long read sequencing technologies have the potential to greatly improve TR analysis, especially for long or complex repeats. Here we introduce LongTR, which accurately genotypes tandem repeats from high fidelity long reads available from both PacBio and Oxford Nanopore Technologies. LongTR is freely available at https://github.com/gymrek-lab/longtr.

Benchmarking of small and large variants across tandem repeats.

Tandem repeats (TRs) are highly polymorphic in the human genome, have thousands of associated molecular traits, and are linked to over 60 disease phenotypes. However, their complexity often excludes them from at-scale studies due to challenges with variant calling, representation, and lack of a genome-wide standard. To promote TR methods development, we create a comprehensive catalog of TR regions and explore its properties across 86 samples. We then curate variants from the GIAB HG002 individual to create a tandem repeat benchmark. We also present a variant comparison method that handles small and large alleles and varying allelic representation. The 8.1% of the genome covered by the TR catalog holds ∼24.9% of variants per individual, including 124,728 small and 17,988 large variants for the GIAB HG002 TR benchmark. We work with the GIAB community to demonstrate the utility of this benchmark across short and long read technologies.

WebSTR: A Population-wide Database of Short Tandem Repeat Variation in Humans.

Short tandem repeats (STRs) are consecutive repetitions of one to six nucleotide motifs. They are hypervariable due to the high prevalence of repeat unit insertions or deletions primarily caused by polymerase slippage during replication. Genetic variation at STRs has been shown to influence a range of traits in humans, including gene expression, cancer risk, and autism. Until recently STRs have been poorly studied since they pose significant challenges to bioinformatics analyses. Moreover, genome-wide analysis of STR variation in population-scale cohorts requires large amounts of data and computational resources. However, the recent advent of genome-wide analysis tools has resulted in multiple large genome-wide datasets of STR variation spanning nearly two million genomic loci in thousands of individuals from diverse populations. Here we present WebSTR, a database of genetic variation and other characteristics of genome-wide STRs across human populations. WebSTR is based on reference panels of more than 1.7 million human STRs created with state of the art repeat annotation methods and can easily be extended to include additional cohorts or species. It currently contains data based on STR genotypes for individuals from the 1000 Genomes Project, H3Africa, the Genotype-Tissue Expression (GTEx) Project and colorectal cancer patients from the TCGA dataset. WebSTR is implemented as a relational database with programmatic access available through an API and a web portal for browsing data. The web portal is publicly available at https://webstr.ucsd.edu.

A deep population reference panel of tandem repeat variation.

Tandem repeats (TRs) represent one of the largest sources of genetic variation in humans and are implicated in a range of phenotypes. Here we present a deep characterization of TR variation based on high coverage whole genome sequencing from 3,550 diverse individuals from the 1000 Genomes Project and H3Africa cohorts. We develop a method, EnsembleTR, to integrate genotypes from four separate methods resulting in high-quality genotypes at more than 1.7 million TR loci. Our catalog reveals novel sequence features influencing TR heterozygosity, identifies population-specific trinucleotide expansions, and finds hundreds of novel eQTL signals. Finally, we generate a phased haplotype panel which can be used to impute most TRs from nearby single nucleotide polymorphisms (SNPs) with high accuracy. Overall, the TR genotypes and reference haplotype panel generated here will serve as valuable resources for future genome-wide and population-wide studies of TRs and their role in human phenotypes.