OMSV enables accurate and comprehensive identification of large structural variations from nanochannel-based single-molecule optical maps

Large structural variants (SVs) in the human genome are difficult to detect and study by conventional sequencing technologies. With long-range genome analysis platforms, such as optical mapping, one can identify large SVs (>2 kb) across the genome in one experiment. Analyzing optical genome maps of 154 individuals from the 26 populations sequenced in the 1000 Genomes Project, we find that phylogenetic population patterns of large SVs are similar to those of single nucleotide variations in 86% of the human genome, while ~2% of the genome has high structural complexity. We are able to characterize SVs in many intractable regions of the genome, including segmental duplications and subtelomeric, pericentromeric, and acrocentric areas. In addition, we discover ~60 Mb of non-redundant genome content missing in the reference genome sequence assembly. Our results highlight the need for a comprehensive set of alternate haplotypes from different populations to represent SV patterns in the genome.

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“…We used a modified version of OMSV 19 to identify large (>2 kb) SVs from each of the 154 samples (Supplementary Data 4–8; Supplementary Fig. 4).…”

Section: Resultsmentioning

confidence: 99%

Genome maps across 26 human populations reveal population-specific patterns of structural variation

et al. 2019

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“…Due to the inherent constraints of optical mapping, this strategy only allowed us to detect large insertions (>2 kb in size). We applied two SV calling pipelines: one from BioNano Genomics and one from a modified version of OMSV 16 . Detailed methods used to validate the NUI call set are described in Methods.…”

Section: Resultsmentioning

confidence: 99%

“…We used BioNano optical maps insertion calls to validate our NUI call set. Our SV calling strategies involved two pipelines: BioNano pipeline 4618/4555 and a modified version of OMSV 16 . Insertions called by either algorithm are merged together for downstream analysis.…”

Section: Methodsmentioning

confidence: 99%

De novo human genome assemblies reveal spectrum of alternative haplotypes in diverse populations

2018

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The human reference genome is used extensively in modern biological research. However, a single consensus representation is inadequate to provide a universal reference structure because it is a haplotype among many in the human population. Using 10× Genomics (10×G) “Linked-Read” technology, we perform whole genome sequencing (WGS) and de novo assembly on 17 individuals across five populations. We identify 1842 breakpoint-resolved non-reference unique insertions (NUIs) that, in aggregate, add up to 2.1 Mb of so far undescribed genomic content. Among these, 64% are considered ancestral to humans since they are found in non-human primate genomes. Furthermore, 37% of the NUIs can be found in the human transcriptome and 14% likely arose from Alu-recombination-mediated deletion. Our results underline the need of a set of human reference genomes that includes a comprehensive list of alternative haplotypes to depict the complete spectrum of genetic diversity across populations.

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“…Further, each optical map may span multiple adjacent breakpoints, providing additional information on how the breakpoints relate to each other. Bionano optical maps show great promise for SV detection and phasing [12], although optical maps are currently limited by lower resolution compared to sequencing technologies and the availability of the technology itself. Linked-read sequencing is a method provided by 10X Genomics, where linked reads are used to detect structural variation and allows for detection of SVs located within repetitive regions using barcoding of long DNA molecules [13, 14] but it is also limited by availability of a comprehensive software and high false-positive rate.…”

Section: Introductionmentioning

confidence: 99%

Comprehensive structural variation genome map of individuals carrying complex chromosomal rearrangements

et al. 2019

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Complex chromosomal rearrangements (CCRs) are rearrangements involving more than two chromosomes or more than two breakpoints. Whole genome sequencing (WGS) allows for outstanding high resolution characterization on the nucleotide level in unique sequences of such rearrangements, but problems remain for mapping breakpoints in repetitive regions of the genome, which are known to be prone to rearrangements. Hence, multiple complementary WGS experiments are sometimes needed to solve the structures of CCRs. We have studied three individuals with CCRs: Case 1 and Case 2 presented with de novo karyotypically balanced, complex interchromosomal rearrangements (46,XX,t(2;8;15)(q35;q24.1;q22) and 46,XY,t(1;10;5)(q32;p12;q31)), and Case 3 presented with a de novo, extremely complex intrachromosomal rearrangement on chromosome 1. Molecular cytogenetic investigation revealed cryptic deletions in the breakpoints of chromosome 2 and 8 in Case 1, and on chromosome 10 in Case 2, explaining their clinical symptoms. In Case 3, 26 breakpoints were identified using WGS, disrupting five known disease genes. All rearrangements were subsequently analyzed using optical maps, linked-read WGS, and short-read WGS. In conclusion, we present a case series of three unique de novo CCRs where we by combining the results from the different technologies fully solved the structure of each rearrangement. The power in combining short-read WGS with long-molecule sequencing or optical mapping in these unique de novo CCRs in a clinical setting is demonstrated.

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OMSV enables accurate and comprehensive identification of large structural variations from nanochannel-based single-molecule optical maps

Cited by 27 publications

References 51 publications

Genome maps across 26 human populations reveal population-specific patterns of structural variation

Genome maps across 26 human populations reveal population-specific patterns of structural variation

De novo human genome assemblies reveal spectrum of alternative haplotypes in diverse populations

Comprehensive structural variation genome map of individuals carrying complex chromosomal rearrangements

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