Tandem-genotypes: robust detection of tandem repeat expansions from long DNA reads

AbstractTandemly repeated sequences are highly mutable and variable features of genomes. Tandem repeat expansions are responsible for a growing list of human diseases, even though it is hard to determine tandem repeat sequences with current DNA sequencing technology. Recent long-read technologies are promising, because the DNA reads are often longer than the repetitive regions, but are hampered by high error rates. Here, we report robust detection of human repeat expansions from careful alignments of long (PacBio and nanopore) reads to a reference genome. Our method (tandem-genotypes) is robust to systematic sequencing errors, inexact repeats with fuzzy boundaries, and low sequencing coverage. By comparing to healthy controls, we can prioritize pathological expansions within the top 10 out of 700000 tandem repeats in the genome. This may help to elucidate the many genetic diseases whose causes remain unknown.

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Correction to: Genome-wide sequencing as a first-tier screening test for short tandem repeat expansions

Genome Medicine ◽

10.1186/s13073-021-00961-4 ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Indhu-Shree Rajan-Babu ◽

Junran J. Peng ◽

Readman Chiu ◽

Patricia Birch ◽

Madeline Couse ◽

...

Keyword(s):

Tandem Repeat ◽

Short Tandem Repeat ◽

Screening Test ◽

Genome Wide ◽

Repeat Expansions ◽

Short Tandem

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Human-specific tandem repeat expansion and differential gene expression during primate evolution

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1912175116 ◽

2019 ◽

Vol 116 (46) ◽

pp. 23243-23253 ◽

Cited By ~ 13

Author(s):

Arvis Sulovari ◽

Ruiyang Li ◽

Peter A. Audano ◽

David Porubsky ◽

Mitchell R. Vollger ◽

...

Keyword(s):

Tandem Repeat ◽

Tandem Repeats ◽

Sequence Data ◽

Variable Number ◽

Specific Expression ◽

Sequence Composition ◽

Transcription Profiles ◽

Long Read ◽

Repeat Expansions ◽

Human Specific

Short tandem repeats (STRs) and variable number tandem repeats (VNTRs) are important sources of natural and disease-causing variation, yet they have been problematic to resolve in reference genomes and genotype with short-read technology. We created a framework to model the evolution and instability of STRs and VNTRs in apes. We phased and assembled 3 ape genomes (chimpanzee, gorilla, and orangutan) using long-read and 10x Genomics linked-read sequence data for 21,442 human tandem repeats discovered in 6 haplotype-resolved assemblies of Yoruban, Chinese, and Puerto Rican origin. We define a set of 1,584 STRs/VNTRs expanded specifically in humans, including large tandem repeats affecting coding and noncoding portions of genes (e.g., MUC3A, CACNA1C). We show that short interspersed nuclear element–VNTR–Alu (SVA) retrotransposition is the main mechanism for distributing GC-rich human-specific tandem repeat expansions throughout the genome but with a bias against genes. In contrast, we observe that VNTRs not originating from retrotransposons have a propensity to cluster near genes, especially in the subtelomere. Using tissue-specific expression from human and chimpanzee brains, we identify genes where transcript isoform usage differs significantly, likely caused by cryptic splicing variation within VNTRs. Using single-cell expression from cerebral organoids, we observe a strong effect for genes associated with transcription profiles analogous to intermediate progenitor cells. Finally, we compare the sequence composition of some of the largest human-specific repeat expansions and identify 52 STRs/VNTRs with at least 40 uninterrupted pure tracts as candidates for genetically unstable regions associated with disease.

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Finding Long Tandem Repeats In Long Noisy Reads

Bioinformatics ◽

10.1093/bioinformatics/btaa865 ◽

2020 ◽

Author(s):

Shinichi Morishita ◽

Kazuki Ichikawa ◽

Gene Myers

Keyword(s):

Tandem Repeat ◽

Error Rate ◽

Tandem Repeats ◽

Repeat Unit ◽

Error Rates ◽

De Bruijn Graph ◽

Frequency Distributions ◽

Sequencing Technologies ◽

Long Reads ◽

Repeat Expansions

Abstract Motivation Long tandem repeat expansions of more than 1000 nt have been suggested to be associated with diseases, but remain largely unexplored in individual human genomes because read lengths have been too short. However, new long-read sequencing technologies can produce single reads of 10,000 nt or more that can span such repeat expansions, although these long reads have high error rates, of 10%-20%, which complicates the detection of repetitive elements. Moreover, most traditional algorithms for finding tandem repeats are designed to find short tandem repeats (< 1000 nt) and cannot effectively handle the high error rate of long reads in a reasonable amount of time. Results Here, we report an efficient algorithm for solving this problem that takes advantage of the length of the repeat. Namely, a long tandem repeat has hundreds or thousands of approximate copies of the repeated unit, so despite the error rate, many short k-mers will be error-free in many copies of the unit. We exploited this characteristic to develop a method for first estimating regions that could contain a tandem repeat, by analyzing the k-mer frequency distributions of fixed-size windows across the target read, followed by an algorithm that assembles the k-mers of a putative region into the consensus repeat unit by greedily traversing a de Bruijn graph. Experimental results indicated that the proposed algorithm largely outperformed Tandem Repeats Finder (TRF), a widely used program for finding tandem repeats, in terms of sensitivity. Software availability https://github.com/morisUtokyo/mTR

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Analysis of short tandem repeat expansions and their methylation state with nanopore sequencing

Nature Biotechnology ◽

10.1038/s41587-019-0293-x ◽

2019 ◽

Vol 37 (12) ◽

pp. 1478-1481 ◽

Cited By ~ 18

Author(s):

Pay Giesselmann ◽

Björn Brändl ◽

Etienne Raimondeau ◽

Rebecca Bowen ◽

Christian Rohrandt ◽

...

Keyword(s):

Tandem Repeat ◽

Short Tandem Repeat ◽

Nanopore Sequencing ◽

Methylation State ◽

Repeat Expansions ◽

Short Tandem

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Genome-wide tandem repeat expansions contribute to schizophrenia risk

10.1101/2021.12.17.21267642 ◽

2021 ◽

Author(s):

Bahareh A Mojarad ◽

Worrawat Engchuan ◽

Brett Trost ◽

Ian Backstrom ◽

Yue Yin ◽

...

Keyword(s):

General Population ◽

Tandem Repeat ◽

Genetic Variants ◽

Neurological Diseases ◽

Association Studies ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Genome Sequences ◽

Genome Wide ◽

Repeat Expansions

Tandem repeat expansions (TREs) can cause neurological diseases but their impact in schizophrenia is unclear. Here we analyzed genome sequences of adults with schizophrenia and found that they have a higher burden of TREs that are near exons and rare in the general population, compared with non-psychiatric controls. These TREs are disproportionately found at loci known to be associated with schizophrenia from genome-wide association studies, in individuals with clinically-relevant genetic variants at other schizophrenia loci, and in families where multiple individuals have schizophrenia. Our findings support the involvement of genome-wide rare TREs in the polygenic nature of schizophrenia.

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Straglr: discovering and genotyping tandem repeat expansions using whole genome long-read sequences

Genome Biology ◽

10.1186/s13059-021-02447-3 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Readman Chiu ◽

Indhu-Shree Rajan-Babu ◽

Jan M. Friedman ◽

Inanc Birol

Keyword(s):

Whole Genome Sequencing ◽

Genome Sequencing ◽

Tandem Repeat ◽

Neurological Disorders ◽

Software Tool ◽

Whole Genome Sequencing Data ◽

Whole Genome ◽

Sequencing Data ◽

Long Read ◽

Repeat Expansions

AbstractTandem repeat (TR) expansion is the underlying cause of over 40 neurological disorders. Long-read sequencing offers an exciting avenue over conventional technologies for detecting TR expansions. Here, we present Straglr, a robust software tool for both targeted genotyping and novel expansion detection from long-read alignments. We benchmark Straglr using various simulations, targeted genotyping data of cell lines carrying expansions of known diseases, and whole genome sequencing data with chromosome-scale assembly. Our results suggest that Straglr may be useful for investigating disease-associated TR expansions using long-read sequencing.

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STRetch: detecting and discovering pathogenic short tandem repeat expansions

Genome Biology ◽

10.1186/s13059-018-1505-2 ◽

2018 ◽

Vol 19 (1) ◽

Cited By ~ 46

Author(s):

Harriet Dashnow ◽

Monkol Lek ◽

Belinda Phipson ◽

Andreas Halman ◽

Simon Sadedin ◽

...

Keyword(s):

Tandem Repeat ◽

Short Tandem Repeat ◽

Repeat Expansions ◽

Short Tandem

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An update on the neurological short tandem repeat expansion disorders and the emergence of long-read sequencing diagnostics

Acta Neuropathologica Communications ◽

10.1186/s40478-021-01201-x ◽

2021 ◽

Vol 9 (1) ◽

Author(s):

Sanjog R. Chintalaphani ◽

Sandy S. Pineda ◽

Ira W. Deveson ◽

Kishore R. Kumar

Keyword(s):

Tandem Repeat ◽

Short Tandem Repeat ◽

Fragile X ◽

Cost Effective ◽

Repeat Expansion ◽

Main Body ◽

Cgg Repeat ◽

Long Read ◽

Repeat Expansions ◽

Short Tandem

Abstract Background Short tandem repeat (STR) expansion disorders are an important cause of human neurological disease. They have an established role in more than 40 different phenotypes including the myotonic dystrophies, Fragile X syndrome, Huntington’s disease, the hereditary cerebellar ataxias, amyotrophic lateral sclerosis and frontotemporal dementia. Main body STR expansions are difficult to detect and may explain unsolved diseases, as highlighted by recent findings including: the discovery of a biallelic intronic ‘AAGGG’ repeat in RFC1 as the cause of cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS); and the finding of ‘CGG’ repeat expansions in NOTCH2NLC as the cause of neuronal intranuclear inclusion disease and a range of clinical phenotypes. However, established laboratory techniques for diagnosis of repeat expansions (repeat-primed PCR and Southern blot) are cumbersome, low-throughput and poorly suited to parallel analysis of multiple gene regions. While next generation sequencing (NGS) has been increasingly used, established short-read NGS platforms (e.g., Illumina) are unable to genotype large and/or complex repeat expansions. Long-read sequencing platforms recently developed by Oxford Nanopore Technology and Pacific Biosciences promise to overcome these limitations to deliver enhanced diagnosis of repeat expansion disorders in a rapid and cost-effective fashion. Conclusion We anticipate that long-read sequencing will rapidly transform the detection of short tandem repeat expansion disorders for both clinical diagnosis and gene discovery.

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Profiling the genome-wide landscape of tandem repeat expansions

10.1101/361162 ◽

2018 ◽

Cited By ~ 6

Author(s):

Nima Mousavi ◽

Sharona Shleizer-Burko ◽

Richard Yanicky ◽

Melissa Gymrek

Keyword(s):

Tandem Repeat ◽

Complex Traits ◽

Fragile X ◽

Genetic Diseases ◽

Simulated Data ◽

Alternative Methods ◽

Read Length ◽

Genome Wide ◽

Healthy Family ◽

Repeat Expansions

AbstractTandem Repeat (TR) expansions have been implicated in dozens of genetic diseases, including Huntington’s Disease, Fragile X Syndrome, and hereditary ataxias. Furthermore, TRs have recently been implicated in a range of complex traits, including gene expression and cancer risk. While the human genome harbors hundreds of thousands of TRs, analysis of TR expansions has been mainly limited to known pathogenic loci. A major challenge is that expanded repeats are beyond the read length of most next-generation sequencing (NGS) datasets and are not profiled by existing genome-wide tools. We present GangSTR, a novel algorithm for genome-wide genotyping of both short and expanded TRs. GangSTR extracts information from paired-end reads into a unified model to estimate maximum likelihood TR lengths. We validate GangSTR on real and simulated data and show that GangSTR outperforms alternative methods in both accuracy and speed. We apply GangSTR to a deeply sequenced trio to profile the landscape of TR expansions in a healthy family and validate novel expansions using orthogonal technologies. Our analysis reveals that healthy individuals harbor dozens of long TR alleles not captured by current genome-wide methods. GangSTR will likely enable discovery of novel disease-associated variants not currently accessible from NGS.

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