Recurrent inversion polymorphisms in humans associate with genetic instability and genomic disorders

Porubský, David; Höps, Wolfram; Ashraf, Hufsah; Hsieh, PingHsun; Rodríguez-Martín, Bernardo; Yilmaz, Feyza; Ebler, Jana; Hallast, Pille; Maggiolini, Flavia Angela Maria; Harvey, William T.; Henning, Barbara; Audano, Peter A.; Gordon, David; Ebert, Peter; Hasenfeld, Patrick; Benito, Eva; Zhu, Qihui; Lee, Charles; Antonacci, Francesca; Steinrücken, Matthias; Beck, Christine R.; Sanders, Ashley D.; Marschall, Tobias; Eichler, Evan E.; Korbel, Jan O.

doi:10.1016/j.cell.2022.04.017

Cited by 90 publications

(209 citation statements)

References 142 publications

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“…Evaluation of inversion resolution for selected PGAS assemblies. In order to evaluate performance of trio-based and trio-free assemblies to resolve inversion, we selected a set of large inversions (≥100 kbp) from the previous study (Porubsky et al 2022). We mapped inversion coordinates from GRCh38 space to T2T-CHM13 (v1.1) coordinates using minimap2 (version 2.20) using following parameters: --secondary=no --eqx -ax asm20 -r 100,1k -z 10000,50.…”

Section: Evaluation Of Assembly Quality Using Strand-seqmentioning

confidence: 99%

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Gaps and complex structurally variant loci in phased genome assemblies

Porubský

Harvey

Rozanski

et al. 2022

Preprint

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There has been tremendous progress in the production of phased genome assemblies by combining long-read data with parental information or linking read data. Nevertheless, a typical phased genome assembly generated by trio-hifiasm still generates more than ~140 gaps. We perform a detailed analysis of gaps, assembly breaks, and misorientations from 77 phased and assembled human genomes (154 unique haplotypes). We find that trio-based approaches using HiFi are the current gold standard although chromosome-wide phasing accuracy is comparable when using Strand-seq instead of parental data. We find two-thirds of defined contig ends cluster near the largest and most identical repeats [including segmental duplications (35.4%) or satellite DNA (22.3%) or to regions enriched in GA/AT rich DNA (27.4%)]. As a result, 1513 protein-coding genes overlap assembly gaps in at least one haplotype and 231 are recurrently disrupted or missing from five or more haplotypes. In addition, we estimate that 6-7 Mbp of DNA are incorrectly orientated per haplotype irrespective of whether trio-free or trio-based approaches are employed. 81% of such misorientations correspond to bona fide large inversion polymorphisms in the human species, most of which are flanked by large identical segmental duplications. In addition, we also identify large-scale alignment discontinuities consistent with an 11.9 Mbp deletion and 161.4 Mbp of insertion per human haploid genome. While 99% of this variation corresponds to satellite DNA, we identify 230 regions of the euchromatic DNA with frequent expansions and contractions, nearly half of which overlap with 197 protein-coding genes. Although not completely resolved, these regions include copy number polymorphic and biomedically relevant genic regions where complete resolution and a pangenome representation will be most useful, yet most challenging, to realize.

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Section: Evaluation Of Assembly Quality Using Strand-seqmentioning

confidence: 99%

“…Each dotplot was evaluated manually. Inversion was deemed to be resolved if an inversion can be traced in a single contig in both haplotype and if the inversion status in both haplotypes matches reported inversion genotype presented in (Porubsky et al 2022).…”

Section: Evaluation Of Assembly Quality Using Strand-seqmentioning

confidence: 99%

Gaps and complex structurally variant loci in phased genome assemblies

Porubský

Harvey

Rozanski

et al. 2022

Preprint

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“…We evaluated the full-coverage Verkko trio assembly using orthogonal Strand-seq 29,48 data from the same sample, which allows for the detection of inversions and translocations in the assembly. We found that the Verkko trio assembly had a higher fraction of contigs and bases correctly assigned to chromosomes than the benchmark assembly 11 (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

Verkko: telomere-to-telomere assembly of diploid chromosomes

Rautiainen

Nurk

Walenz

et al. 2022

Preprint

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The Telomere-to-Telomere consortium recently assembled the first truly complete sequence of a human genome. To resolve the most complex repeats, this project relied on manual integration of ultra-long Oxford Nanopore sequencing reads with a high-resolution assembly graph built from long, accurate PacBio HiFi reads. We have improved and automated this strategy in Verkko, an iterative, graph-based pipeline for assembling complete, diploid genomes. Verkko begins with a multiplex de Bruijn graph built from long, accurate reads and progressively simplifies this graph via the integration of ultra-long reads and haplotype-specific markers. The result is a phased, diploid assembly of both haplotypes, with many chromosomes automatically assembled from telomere to telomere. Running Verkko on the HG002 human genome resulted in 20 of 46 diploid chromosomes assembled without gaps at 99.9997% accuracy. The complete assembly of diploid genomes is a critical step towards the construction of comprehensive pangenome databases and chromosome-scale comparative genomics.

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“…Other interesting peaks include the large inversion found on chromosome 8 (Porubsky et al 2022;Bansal et al 2007) and the HLA region on chromosome 6.…”

Section: Runtime and Memory Usagementioning

confidence: 99%

Fast and accurate out-of-core PCA framework for large scale biobank data

Meisner

Albrechtsen

2022

Preprint

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Principal component analysis (PCA) is a widely used dimensionality reduction technique in statistics, machine learning and genomics. Fast PCA methods, such as the accurate Implicitly Restarted Arnoldi Method (IRAM) and the fast Randomized Singular Value Decomposition (RSVD), are gaining popularity for capturing the top principal components efficiently. However, a fast and accurate PCA method with low memory usage is needed due to ever growing sample sizes. Here we present PCAone, a PCA framework with three PCA algorithms and an unified interface for different input data. We propose a new RSVD algorithm that can achieve high accuracy without passing through the data many times. Standard RSVD algorithms use the whole data matrix in each optimization step which makes out-of-core implementations slow. In contrast, PCAone uses a window based optimization scheme based on blocks of data which allows the algorithm to converge within a few passes through the whole data. Using largescale genetic data from the UK Biobank, we show that PCAone is much faster than existing state-of-the-art tools while using a negligible amount of memory and maintaining an accuracy comparable to the much slower IRAM algorithm. Applying PCAone to the imputed genotypes of the UK Biobank (around 0.5 million individuals and 6.1 millions common SNPs) took 9 hours using 13.5 GBs memory and 20 CPU threads to calculate the top 40 PCs which captured population structure, signals of selection (SLC45A2), structural variants and low recombination regions. PCAone applied to single-cell RNA sequencing data with 1.3 million mice brain cells took only 35 minutes to capture the top 20 PCs accurately. The software is open source and available at https://github.com/Zilong-Li/PCAone.

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Recurrent inversion polymorphisms in humans associate with genetic instability and genomic disorders

Cited by 90 publications

References 142 publications

Gaps and complex structurally variant loci in phased genome assemblies

Gaps and complex structurally variant loci in phased genome assemblies

Verkko: telomere-to-telomere assembly of diploid chromosomes

Fast and accurate out-of-core PCA framework for large scale biobank data

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