LongTR: genome-wide profiling of genetic variation at tandem repeats from long reads

Tandem repeat (TR) catalogs are important components of repeat genotyping studies as they define the genomic coordinates and expected motifs of all TR loci being analyzed. In recent years, genome-wide studies have used catalogs ranging in size from fewer than 200,000 to over 7 million loci. Where these catalogs overlapped, they often disagreed on locus boundaries, hindering the comparison and reuse of results across studies. Now, with multiple groups developing public databases of TR variation in large population cohorts, there is a risk that, without sufficient consensus in the choice of locus definitions, the use of divergent repeat catalogs will lead to confusion, fragmentation, and incompatibility across future resources. In this paper, we compare existing TR catalogs and discuss desirable features of a comprehensive genome-wide catalog. We then present a new, richly annotated catalog designed for large-scale analyses and population databases. Our catalog stratifies TRs into two groups: 1) isolated TRs suitable for repeat copy number analysis using short read or long read data and 2) so-called variation clusters that contain TRs within wider polymorphic regions that are best studied through sequence-level analysis. To define variation clusters, we present a novel algorithm that leverages long-read HiFi sequencing data to group repeats with surrounding polymorphisms. We show that the human genome contains at least 25,000 complex variation clusters, most of which span over 120 bp and contain five or more TRs. Resolving the sequence of entire variation clusters instead of individually genotyping constituent TRs leads to a more accurate analysis of these regions and enables us to profile variation that would have been missed otherwise.

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Genotyping Short Tandem Repeats Across Copy Number Alterations, Aneuploidies, and Polyploid Organisms

Verbiest,

Grassi,

Bertotti

et al. 2024

Preprint

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Short tandem repeats (STRs) are a rich source of genetic variation, but are difficult to genotype. While specialized repeat variant callers exist, they typically assume a euploid human genome. This means recent findings regarding phenotypic effects of STR variants in human health and disease cannot be readily extended to polyploid organisms or cancer, which is characterised by copy number alterations (CNAs). Here we present ConSTRain, a novel STR variant caller that explicitly accounts for the copy number of loci in its genotyping approach. We benchmark ConSTRain using a euploid human 100X whole genome sequencing sample where it calls STR allele lengths for over 1.7×106loci in under 20 minutes with an accuracy of 98.28%. Subsequently, we show that ConSTRain resolves complex STR genotypes in an artificial trisomy 21 sample and a polyploid Dwarf Cavendish banana harbouring a large duplication. Finally, we analyse a microsatellite instable colorectal cancer tumoroid, where ConSTRain tackles CNAs and whole-genome duplications. ConSTRain is the first STR variant caller that allows for the investigation of repeats affected by CNAs, aneuploidies, and polyploid genomes. This unlocks the investigation of STRs across a wide range of contexts and organisms where they previously could not be easily studied.

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LongTR: genome-wide profiling of genetic variation at tandem repeats from long reads

Cited by 5 publications

References 30 publications

The GENESIS database and tools: A decade of discovery in Mendelian genomics

The GENESIS database and tools: A decade of discovery in Mendelian genomics

Defining a tandem repeat catalog and variation clusters for genome-wide analyses and population databases

Genotyping Short Tandem Repeats Across Copy Number Alterations, Aneuploidies, and Polyploid Organisms

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