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Gaps and complex structurally variant loci in phased genome assemblies

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Item Type:Article
Title:Gaps and complex structurally variant loci in phased genome assemblies
Creators Name:Porubsky, D. and Vollger, M.R. and Harvey, W.T. and Rozanski, A.N. and Ebert, P. and Hickey, G. and Hasenfeld, P. and Sanders, A.D. and Stober, C. and Korbel, J.O. and Paten, B. and Marschall, T. and Eichler, E.E.
Abstract:There has been tremendous progress in phased genome assembly production by combining long-read data with parental information or linked-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 182 haploid assemblies obtained from a diversity panel of 77 unique human samples. Although trio-based approaches using HiFi are the current gold standard, chromosome-wide phasing accuracy is comparable when using Strand-seq instead of parental data. Importantly, the majority of assembly gaps cluster near the largest and most identical repeats (including segmental duplications [35.4%], satellite DNA [22.3%], or regions enriched in GA/AT-rich DNA [27.4%]). Consequently, 1513 protein-coding genes overlap assembly gaps in at least one haplotype, and 231 are recurrently disrupted or missing from five or more haplotypes. Furthermore, we estimate that 6-7 Mbp of DNA are misorientated per haplotype irrespective of whether trio-free or trio-based approaches are used. Of these misorientations, 81% correspond to bona fide large inversion polymorphisms in the human species, most of which are flanked by large segmental duplications. We also identify large-scale alignment discontinuities consistent with 11.9 Mbp of deletions and 161.4 Mbp of insertions per haploid genome. Although 99% of this variation corresponds to satellite DNA, we identify 230 regions of euchromatic DNA with frequent expansions and contractions, nearly half of which overlap with 197 protein-coding genes. Such variable and incompletely assembled regions are important targets for future algorithmic development and pangenome representation.
Keywords:DNA Sequence Analysis, Genetic Polymorphism, Genomic Segmental Duplications, Haplotypes, Satellite DNA
Source:Genome Research
Publisher:Cold Spring Harbor Laboratory Press
Page Range:496-510
Date:April 2023
Official Publication:https://doi.org/10.1101/gr.277334.122
PubMed:View item in PubMed

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