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

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.

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

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.

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

2020 ◽  
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 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.

scholarly journals Evaluating nanopore sequencing data processing pipelines for structural variation identification

2019 ◽  
Vol 20 (1) ◽  
Author(s):  
Anbo Zhou ◽  
Timothy Lin ◽  
Jinchuan Xing
Keyword(s):  
Detection Accuracy ◽  
Nanopore Sequencing ◽  
Sequencing Data ◽  
Sequencing Technology ◽  
Structural Variations ◽  
Human Genomes ◽  
Data Assessment ◽  
Machine Learning Approach ◽  
Long Read ◽  
The Impact

Abstract Background Structural variations (SVs) account for about 1% of the differences among human genomes and play a significant role in phenotypic variation and disease susceptibility. The emerging nanopore sequencing technology can generate long sequence reads and can potentially provide accurate SV identification. However, the tools for aligning long-read data and detecting SVs have not been thoroughly evaluated. Results Using four nanopore datasets, including both empirical and simulated reads, we evaluate four alignment tools and three SV detection tools. We also evaluate the impact of sequencing depth on SV detection. Finally, we develop a machine learning approach to integrate call sets from multiple pipelines. Overall SV callers’ performance varies depending on the SV types. For an initial data assessment, we recommend using aligner minimap2 in combination with SV caller Sniffles because of their speed and relatively balanced performance. For detailed analysis, we recommend incorporating information from multiple call sets to improve the SV call performance. Conclusions We present a workflow for evaluating aligners and SV callers for nanopore sequencing data and approaches for integrating multiple call sets. Our results indicate that additional optimizations are needed to improve SV detection accuracy and sensitivity, and an integrated call set can provide enhanced performance. The nanopore technology is improving, and the sequencing community is likely to grow accordingly. In turn, better benchmark call sets will be available to more accurately assess the performance of available tools and facilitate further tool development.

scholarly journals NovoGraph: Human genome graph construction from multiple long-read de novo assemblies

F1000Research ◽  
2018 ◽  
Vol 7 ◽  
pp. 1391
Author(s):  
Evan Biederstedt ◽  
Jeffrey C. Oliver ◽  
Nancy F. Hansen ◽  
Aarti Jajoo ◽  
Nathan Dunn ◽  
...  
Keyword(s):  
Human Genome ◽  
De Novo ◽  
Wide Spectrum ◽  
Third Party ◽  
Sequencing Data ◽  
Multiple Sequence ◽  
Human Genomes ◽  
A Genome ◽  
Long Read ◽  
Genome Graph

Genome graphs are emerging as an important novel approach to the analysis of high-throughput human sequencing data. By explicitly representing genetic variants and alternative haplotypes in a mappable data structure, they can enable the improved analysis of structurally variable and hyperpolymorphic regions of the genome. In most existing approaches, graphs are constructed from variant call sets derived from short-read sequencing. As long-read sequencing becomes more cost-effective and enables de novo assembly for increasing numbers of whole genomes, a method for the direct construction of a genome graph from sets of assembled human genomes would be desirable. Such assembly-based genome graphs would encompass the wide spectrum of genetic variation accessible to long-read-based de novo assembly, including large structural variants and divergent haplotypes. Here we present NovoGraph, a method for the construction of a human genome graph directly from a set of de novo assemblies. NovoGraph constructs a genome-wide multiple sequence alignment of all input contigs and creates a graph by merging the input sequences at positions that are both homologous and sequence-identical. NovoGraph outputs resulting graphs in VCF format that can be loaded into third-party genome graph toolkits. To demonstrate NovoGraph, we construct a genome graph with 23,478,835 variant sites and 30,582,795 variant alleles from de novo assemblies of seven ethnically diverse human genomes (AK1, CHM1, CHM13, HG003, HG004, HX1, NA19240). Initial evaluations show that mapping against the constructed graph reduces the average mismatch rate of reads from sample NA12878 by approximately 0.2%, albeit at a slightly increased rate of reads that remain unmapped.

scholarly journals Genome-wide profiling of heritable and de novo STR variations

2016 ◽  
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.

scholarly journals Dense and accurate whole-chromosome haplotyping of individual genomes

2017 ◽  
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.

scholarly journals DNAModAnnot: a R toolbox for DNA modification filtering and annotation

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.

scholarly journals Quinoa genome assembly employing genomic variation for guided scaffolding

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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