Genome-wide Survey of Tandem Repeats by Nanopore Sequencing Shows that Disease-associated Repeats are More Polymorphic in the General Population

Abstract Background: Tandem repeats are highly mutable and contribute to the development of human disease by a variety of mechanisms. It is difficult to predict which tandem repeats may cause a disease. One hypothesis is that changeable tandem repeats are the source of genetic diseases, because disease-causing repeats are polymorphic in healthy individuals. However, it is not clear whether disease-causing repeats are more polymorphic than other repeats. Methods: We performed a genome-wide survey of the millions of human tandem repeats using publicly available long read genome sequencing data from 21 humans. We measured tandem repeat copy number changes using tandem-genotypes. Length variation of known disease-associated repeats was compared to other repeat loci. Results: We found that known Mendelian disease-causing or disease-associated repeats, especially CAG and 5'UTR GGC repeats, are relatively long and polymorphic in the general population. We also show that repeat lengths of two disease-causing tandem repeats, in ATXN3 and GLS, are correlated with near-by GWAS SNP genotypes. Conclusions: We provide a catalog of polymorphic tandem repeats across a variety of repeat unit lengths and sequences, from long read sequencing data. This method especially if used in genome wide association study (GWAS), may indicate possible new candidates of pathogenic or biologically important tandem repeats in human genomes.

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Genome-wide survey of tandem repeats by nanopore sequencing shows that disease-associated repeats are more polymorphic in the general population

BMC Medical Genomics ◽

10.1186/s12920-020-00853-3 ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Satomi Mitsuhashi ◽

Martin C. Frith ◽

Naomichi Matsumoto

Keyword(s):

General Population ◽

Tandem Repeats ◽

Repeat Unit ◽

Mendelian Disease ◽

Length Variation ◽

Sequencing Data ◽

Genome Wide ◽

A Genome ◽

Long Read ◽

Genome Wide Survey

Abstract Background Tandem repeats are highly mutable and contribute to the development of human disease by a variety of mechanisms. It is difficult to predict which tandem repeats may cause a disease. One hypothesis is that changeable tandem repeats are the source of genetic diseases, because disease-causing repeats are polymorphic in healthy individuals. However, it is not clear whether disease-causing repeats are more polymorphic than other repeats. Methods We performed a genome-wide survey of the millions of human tandem repeats using publicly available long read genome sequencing data from 21 humans. We measured tandem repeat copy number changes using . Length variation of known disease-associated repeats was compared to other repeat loci. Results We found that known Mendelian disease-causing or disease-associated repeats, especially CAG and 5′UTR GGC repeats, are relatively long and polymorphic in the general population. We also show that repeat lengths of two disease-causing tandem repeats, in ATXN3 and GLS, are correlated with near-by GWAS SNP genotypes. Conclusions We provide a catalog of polymorphic tandem repeats across a variety of repeat unit lengths and sequences, from long read sequencing data. This method especially if used in genome wide association study, may indicate possible new candidates of pathogenic or biologically important tandem repeats in human genomes.

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Genome-wide survey of tandem repeats by nanopore sequencing shows that disease-associated repeats are more polymorphic in the general population

10.1101/2019.12.19.883389 ◽

2019 ◽

Author(s):

Satomi Mitsuhashi ◽

Martin C Frith ◽

Naomichi Matsumoto

Keyword(s):

General Population ◽

Tandem Repeats ◽

Mendelian Disease ◽

Nanopore Sequencing ◽

Sequencing Data ◽

Human Genomes ◽

Genome Wide ◽

A Genome ◽

Long Read ◽

Genome Wide Survey

AbstractTandem repeats are highly mutable and contribute to the development of human disease by a variety of mechanisms. However, it is difficult to predict which tandem repeats may cause a disease. We performed a genome-wide survey of the millions of human tandem repeats using long read genome sequencing data from 16 humans. We found that known Mendelian disease-causing or disease-associated repeats, especially coding CAG and 5’UTR GGC repeats, are relatively long and polymorphic in the general population. This method, especially if used in GWAS, may indicate possible new candidates of pathogenic or biologically important tandem repeats in human genomes.

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Genome-wide profiling of heritable and de novo STR variations

10.1101/077727 ◽

2016 ◽

Cited By ~ 7

Author(s):

Thomas Willems ◽

Dina Zielinski ◽

Assaf Gordon ◽

Melissa Gymrek ◽

Yaniv Erlich

Keyword(s):

Tandem Repeats ◽

High Throughput Sequencing ◽

De Novo ◽

Genetic Diseases ◽

Whole Genome Sequencing Data ◽

Sequencing Data ◽

High Throughput Sequencing Data ◽

Genome Wide ◽

A Genome ◽

Short Tandem

AbstractShort tandem repeats (STRs) are highly variable elements that play a pivotal role in multiple genetic diseases, population genetics applications, and forensic casework. However, STRs have proven problematic to genotype from high-throughput sequencing data. Here, we describe HipSTR, a novel haplotype-based method for robustly genotyping, haplotyping, and phasing STRs from whole genome sequencing data and report a genome-wide analysis and validation of de novo STR mutations.

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Dense and accurate whole-chromosome haplotyping of individual genomes

10.1101/126136 ◽

2017 ◽

Cited By ~ 1

Author(s):

David Porubsky ◽

Shilpa Garg ◽

Ashley D. Sanders ◽

Jan O. Korbel ◽

Victor Guryev ◽

...

Keyword(s):

Target Genes ◽

Chromosome Length ◽

Single Individual ◽

Sequencing Data ◽

Individual Genome ◽

Sequencing Technologies ◽

Biological Phenomena ◽

Genome Wide ◽

A Genome ◽

Long Read

ABSTRACTThe diploid nature of the genome is neglected in many analyses done today, where a genome is perceived as a set of unphased variants with respect to a reference genome. Many important biological phenomena such as compound heterozygosity and epistatic effects between enhancers and target genes, however, can only be studied when haplotype-resolved genomes are available. This lack of haplotype-level analyses can be explained by a dearth of methods to produce dense and accurate chromosome-length haplotypes at reasonable costs. Here we introduce an integrative phasing strategy that combines global, but sparse haplotypes obtained from strand-specific single cell sequencing (Strand-seq) with dense, yet local, haplotype information available through long-read or linked-read sequencing. Our experiments provide comprehensive guidance on favorable combinations of Strand-seq libraries and sequencing coverages to obtain complete and genome-wide haplotypes of a single individual genome (NA12878) at manageable costs. We were able to reliably assign > 95% of alleles to their parental haplotypes using as few as 10 Strand-seq libraries in combination with 10-fold coverage PacBio data or, alternatively, 10X Genomics linked-read sequencing data. We conclude that the combination of Strand-seq with different sequencing technologies represents an attractive solution to chart the unique genetic variation of diploid genomes.

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DNAModAnnot: a R toolbox for DNA modification filtering and annotation

Bioinformatics ◽

10.1093/bioinformatics/btab032 ◽

2021 ◽

Author(s):

Alexis Hardy ◽

Mélody Matelot ◽

Amandine Touzeau ◽

Christophe Klopp ◽

Céline Lopez-Roques ◽

...

Keyword(s):

Global Analysis ◽

R Package ◽

Supplementary Information ◽

Dna Modification ◽

Paramecium Tetraurelia ◽

Sequencing Data ◽

Genome Wide ◽

A Genome ◽

Dna Modifications ◽

Long Read

Abstract Motivation Long-read sequencing technologies can be employed to detect and map DNA modifications at the nucleotide resolution on a genome-wide scale. However, published software packages neglect the integration of genomic annotation and comprehensive filtering when analyzing patterns of modified bases detected using Pacific Biosciences (PacBio) or Oxford Nanopore Technologies (ONT) data. Here, we present DNAModAnnot, a R package designed for the global analysis of DNA modification patterns using adapted filtering and visualization tools. Results We tested our package using PacBio sequencing data to analyze patterns of the 6-methyladenine (6 mA) in the ciliate Paramecium tetraurelia, in which high 6 mA amounts were previously reported. We found Paramecium tetraurelia 6 mA genome-wide distribution to be similar to other ciliates. We also performed 5-methylcytosine (5mC) analysis in human lymphoblastoid cells using ONT data and confirmed previously known patterns of 5mC. DNAModAnnot provides a toolbox for the genome-wide analysis of different DNA modifications using PacBio and ONT long-read sequencing data. Availability DNAModAnnot is distributed as a R package available via GitHub (https://github.com/AlexisHardy/DNAModAnnot) Supplementary information Supplementary data are available at Bioinformatics online.

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Quinoa genome assembly employing genomic variation for guided scaffolding

Theoretical and Applied Genetics ◽

10.1007/s00122-021-03915-x ◽

2021 ◽

Author(s):

Alexandrina Bodrug-Schepers ◽

Nancy Stralis-Pavese ◽

Hermann Buerstmayr ◽

Juliane C. Dohm ◽

Heinz Himmelbauer

Keyword(s):

Genome Assembly ◽

Chenopodium Quinoa ◽

Genomic Variation ◽

Valuable Resource ◽

Sequencing Data ◽

Genome Wide ◽

A Genome ◽

Long Read ◽

Genome Assemblies ◽

Haplotype Information

Abstract Key message We propose to use the natural variation between individuals of a population for genome assembly scaffolding. In today’s genome projects, multiple accessions get sequenced, leading to variant catalogs. Using such information to improve genome assemblies is attractive both cost-wise as well as scientifically, because the value of an assembly increases with its contiguity. We conclude that haplotype information is a valuable resource to group and order contigs toward the generation of pseudomolecules. Abstract Quinoa (Chenopodium quinoa) has been under cultivation in Latin America for more than 7500 years. Recently, quinoa has gained increasing attention due to its stress resistance and its nutritional value. We generated a novel quinoa genome assembly for the Bolivian accession CHEN125 using PacBio long-read sequencing data (assembly size 1.32 Gbp, initial N50 size 608 kbp). Next, we re-sequenced 50 quinoa accessions from Peru and Bolivia. This set of accessions differed at 4.4 million single-nucleotide variant (SNV) positions compared to CHEN125 (1.4 million SNV positions on average per accession). We show how to exploit variation in accessions that are distantly related to establish a genome-wide ordered set of contigs for guided scaffolding of a reference assembly. The method is based on detecting shared haplotypes and their expected continuity throughout the genome (i.e., the effect of linkage disequilibrium), as an extension of what is expected in mapping populations where only a few haplotypes are present. We test the approach using Arabidopsis thaliana data from different populations. After applying the method on our CHEN125 quinoa assembly we validated the results with mate-pairs, genetic markers, and another quinoa assembly originating from a Chilean cultivar. We show consistency between these information sources and the haplotype-based relations as determined by us and obtain an improved assembly with an N50 size of 1079 kbp and ordered contig groups of up to 39.7 Mbp. We conclude that haplotype information in distantly related individuals of the same species is a valuable resource to group and order contigs according to their adjacency in the genome toward the generation of pseudomolecules.

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