Inversion polymorphism in a complete human genome assembly

Porubský, David; Harvey, William T.; Rozanski, Allison N.; Ebler, Jana; Höps, Wolfram; Ashraf, Hufsah; Hasenfeld, Patrick; Paten, Benedict; Sanders, Ashley D.; Marschall, Tobias; Korbel, Jan O.; Eichler, Evan E.

doi:10.1101/2022.10.06.511148

Cited by 11 publications

(14 citation statements)

References 52 publications

(78 reference statements)

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“…In a recent analysis of human genomes sequenced as part of the Human Pangenome Reference Consortium (HPRC), no other human genome was completely sequenced across its centromeres 10 . The centromeres, in particular, were among the most gap-ridden regions 11 and were excluded from the construction of a pangenome 10 . Additional methods and approaches are still required to fully sequence and assemble these regions 12 .…”

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confidence: 99%

The variation and evolution of complete human centromeres

Logsdon,

Rozanski,

Ryabov

et al. 2024

Nature

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Human centromeres have been traditionally very difficult to sequence and assemble owing to their repetitive nature and large size1. As a result, patterns of human centromeric variation and models for their evolution and function remain incomplete, despite centromeres being among the most rapidly mutating regions2,3. Here, using long-read sequencing, we completely sequenced and assembled all centromeres from a second human genome and compared it to the finished reference genome4,5. We find that the two sets of centromeres show at least a 4.1-fold increase in single-nucleotide variation when compared with their unique flanks and vary up to 3-fold in size. Moreover, we find that 45.8% of centromeric sequence cannot be reliably aligned using standard methods owing to the emergence of new α-satellite higher-order repeats (HORs). DNA methylation and CENP-A chromatin immunoprecipitation experiments show that 26% of the centromeres differ in their kinetochore position by >500 kb. To understand evolutionary change, we selected six chromosomes and sequenced and assembled 31 orthologous centromeres from the common chimpanzee, orangutan and macaque genomes. Comparative analyses reveal a nearly complete turnover of α-satellite HORs, with characteristic idiosyncratic changes in α-satellite HORs for each species. Phylogenetic reconstruction of human haplotypes supports limited to no recombination between the short (p) and long (q) arms across centromeres and reveals that novel α-satellite HORs share a monophyletic origin, providing a strategy to estimate the rate of saltatory amplification and mutation of human centromeric DNA.

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confidence: 99%

The variation and evolution of complete human centromeres

Logsdon,

Rozanski,

Ryabov

et al. 2024

Nature

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“…We do not find inversions flanked by hundreds of kbp of SD sequence, in spite of their commonness in the genome, consistent with these SVs requiring long-read lengths in excess of the SD length for their detection 54 . Strand-seq 54,67 or hybrid genomic assemblies using a combination of high-accuracy and ultra-long reads 68,69 will be required to resolve this SV class at the population-scale in the future.…”

Section: Resultsmentioning

confidence: 99%

Long-read sequencing and structural variant characterization in 1,019 samples from the 1000 Genomes Project

Schloissnig,

Pani,

Rodriguez-Martin

et al. 2024

Preprint

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Structural variants (SVs) contribute significantly to human genetic diversity and disease. Previously, SVs have remained incompletely resolved by population genomics, with short-read sequencing facing limitations in capturing the whole spectrum of SVs at nucleotide resolution. Here we leveraged nanopore sequencing to construct an intermediate coverage resource of 1,019 long-read genomes sampled within 26 human populations from the 1000 Genomes Project. By integrating linear and graph-based approaches for SV analysis via pangenome graph-augmentation, we uncover 167,291 sequence-resolved SVs in these samples, considerably advancing SV characterization compared to population-wide short-read sequencing studies. Our analysis details diverse SV classes-deletions, duplications, insertions, and inversions-at population-scale. LINE-1 and SVA retrotransposition activities frequently mediate transductions of unique sequences, with both mobile element classes transducing sequences at either the 3′- or 5′-end, depending on the source element locus. Furthermore, analyses of SV breakpoint junctions suggest a continuum of homology-mediated rearrangement processes are integral to SV formation, and highlight evidence for SV recurrence involving repeat sequences. Our open-access dataset underscores the transformative impact of long-read sequencing in advancing the characterisation of polymorphic genomic architectures, and provides a resource for guiding variant prioritisation in future long-read sequencing-based disease studies.

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“…reference has provided a more complete view of the genome-wide inversion polymorphism (Porubsky et al 2022;Hanlon et al 2022;Porubsky et al 2023). Although not directly related to disease, LCRmediated inversion polymorphisms drive NAHR, thus can lead to genomic disorders (Shaw and Lupski 2004).…”

Section: Discussionmentioning

confidence: 99%

“…However, availability of a gapless telomere-to-telomere assembly of the human genome (T2T-CHM13) has enabled a more complete analysis of genomic variation (Nurk et al 2022). Using long read sequencing and Strand-seq data of 52 samples from the 1000 Genomes project and mapping these against the T2T-CHM13 reference has provided a more complete view of the genome-wide inversion polymorphism (Porubsky et al 2022; Hanlon et al 2022; Porubsky et al 2023). Although not directly related to disease, LCR-mediated inversion polymorphisms drive NAHR, thus can lead to genomic disorders (Shaw and Lupski 2004).…”

Section: Discussionmentioning

confidence: 99%

Multiple paralogues and recombination mechanisms drive the high incidence of 22q11.2 Deletion Syndrome

Vervoort,

Dierckxsens,

Santos

et al. 2024

Preprint

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The 22q11.2 deletion syndrome (22q11.2DS) is the most common microdeletion disorder. Why the incidence of 22q11.2DS is much greater than that of other genomic disorders remains unknown. Short read sequencing cannot resolve the complex segmental duplicon structure to provide direct confirmation of the hypothesis that the rearrangements are caused by non-allelic homologous recombination between the low copy repeats on chromosome 22 (LCR22s). To enable haplotype-specific assembly and rearrangement mapping in LCR22 regions, we combined fiber-FISH optical mapping with whole genome (ultra-)long read sequencing or rearrangement-specific long-range PCR on 24 duos (22q11.2DS patient and parent-of-origin) comprising several different LCR22-mediated rearrangements. Unexpectedly, we demonstrate that not only different paralogous segmental duplicon but also palindromic AT-rich repeats (PATRR) are driving 22q11.2 rearrangements. In addition, we show the existence of two different inversion polymorphisms preceding rearrangement, and somatic mosaicism. The existence of different recombination sites and mechanisms in paralogues and PATRRs which are copy number expanding in the human population are a likely explanation for the high 22q11.2DS incidence.

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Inversion polymorphism in a complete human genome assembly

Cited by 11 publications

References 52 publications

The variation and evolution of complete human centromeres

The variation and evolution of complete human centromeres

Long-read sequencing and structural variant characterization in 1,019 samples from the 1000 Genomes Project

Multiple paralogues and recombination mechanisms drive the high incidence of 22q11.2 Deletion Syndrome

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