Human Genome Research

The promise of genomics in relation to human disease is being held back by the inability to resolve large structural variations. Existing technologies, including next-generation sequencing (NGS), diagnose less than 50% of patients with genetic disorders.^1,2 Bionano genome mapping offers unmatched structural variation discovery, making Saphyr™ essential to human genome and translational research.

Large structural variants such as deletions, duplications, inversions and translocations are extensively present, and many are known to affect biological functions and cause disease, including cancers and developmental disorders.

Precision medicine initiatives require accurate analyses of human genomes. While improvements in sequencing technology have allowed for spectacular progress in the detection of single nucleotide changes, the analysis of larger structural variations has remained ineffective. Standard methodologies for detecting structural variations have significant limitations. Chromosomal microarray is insensitive to novel insertions, mobile element insertions, many low copy repeats, and all balanced translocations and inversions. In addition, short-read sequencing methods have low sensitivity to most large variants and often fail in repetitive regions or those with high GC-content. Long-read sequencing has better sensitivity for heterozygous structural variations but is unable to span larger repetitive regions.

Saphyr fills in what’s missing from sequencing-based and other approaches with unparalleled sensitivity for large structural variations from 500 bp to megabase pair lengths.

99% sensitivity for large homozygous insertions and deletions
87% sensitivity for large heterozygous insertions and deletions
98% sensitivity for translocations
98% sensitivity for inversions

Saphyr provides this performance with a false positive rate of less than 3%. Saphyr also calls repeats, copy number variants, and complex rearrangements.

Unlike NGS, which algorithmically infers structural variants from fragmented DNA data, Bionano optical genome mapping directly observes structural variations by linearizing and imaging DNA in its native state using massively parallel NanoChannels. This direct observation results in some of the longest read lengths in genomic research. As a result, Bionano next-generation mapping yields hundreds of times more contiguous assembly than sequencing technologies alone can provide.

In fact, every recent human reference-quality genome published uses Bionano genome mapping data.^3,4,5,6

See below for publications, white papers and other resources regarding Bionano genome mapping in human genome and translational research.

LEARN ABOUT SAPHYR

Use Cases

Undiagnosed Genetic Disorders – close the diagnosis gap by detecting large structural events missed by NGS
Gene discovery and therapy development – identify genes of interest, their locations and how structural variations impact them to inform effective therapy development
Cancer – detect and visualize large rearrangements occurring in cancer genomes
Cell line studies – monitor genomic integrity of cell lines and off-target effects of genetic engineering
Reference genome assembly – perform de novo assembly and correct assemblies generated by sequencing-based systems

Publications

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OMSV enables accurate and comprehensive identification of large structural variations from nanochannel-based single-molecule optical maps
Genome Biology 2017
Li L et al
Next-generation mapping: a novel approach for detection of pathogenic structural variants with a potential utility in clinical diagnosis
Genome Medicine 2017
Barseghyan H et al.
Multi-platform discovery of haplotype-resolved structural variation in human genomes
BioRxiv 2017
Chaisson MJP et al

Videos

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Dr. Pui Kwok

University of California San Francisco, USA

Dr. Kwok discusses Bionano structural variant discovery in human diseases

Dr. Vanessa Hayes

Garvan Institute for Medical Research, Australia

Dr. Hayes discusses how Bionano aids her work prostate cancer

Posters

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Building High Quality, Chromosome-Scale, De Novo Genome Assemblies by Scaffolding Next-Generation Sequencing Assemblies with Bionano Genome Maps
February, 2018
Advances in Genome Technology and Biology, Orlando, Fl
Broad Range Chromosomal Abnormality Detection through Bionano Genome Mapping
February, 2018
Advances in Genome Biology and Technology, Orlando, Fl
Labeling Human DNA with Bionano’s Direct Labeling Enzyme Avoids Nickase-Based Double-Stranded Breaks and Allows for Chromosome-Arm Length Assemblies
February, 2018
Advances in Genome Biology and Technology, Orlando, Fl

Literature

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Case Studies

Assembling High Quality Human Genomes: Going Beyond the ‘$1,000 genome’
This Case Study demonstrates the power of combining 2 single molecule technologies to produce Gold-quality genomes. Those allow the discovery of substantial amount of structural variation unique to individuals and populations otherwise not accessed by other short-read technologies.

White Papers

Bionano Genome Mapping Identifies Large Structural Variants in Cancer and Genetic Disorders
This White Paper explains how NGS leaves half of patients with genetic disorders without a molecular diagnosis, because it fails to adequately analyze repetitive parts of the genome and large structural variation. Bionano Genome Mapping is able to detect all SV types with high sensitivity and specificity, and examples of cancer and genetic disease are shown.

References

Miller DT, A. M. (2010). Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Am J Hum Genet, 86 (5), 749-64.
Hane Lee, J. L.-R.-A. (2014). Clinical Exome Sequencing for Genetic Identification of Rare Mendelian Disorders. JAMA, 312 (18), 1880-1887.
Pendleton, M., Sebra, R., et al. Assembly and diploid architecture of an individual human genome via single-molecule technologies. Nature Methods (2015); e3454.
Zimin et al. Hybrid assembly of the large and highly repetitive genome of Aegilops tauschii, a progenitor of bread wheat, with the mega-reads algorithm bioRxiv. (2016).
Shi et al. Long-read sequencing and de novo assembly of a Chinese genome. Nature Communications (2016).
Seo, JS, et al. De novo assembly and phasing of a Korean human genome. Nature (2016).