Abstract
BackgroundStructural variants (SVs) are less common than single nucleotide polymorphisms and indels in the population, but collectively account for a significant fraction of genetic polymorphism and diseases. Base pair differences arising from SVs are on a much higher order (>100 fold) than point mutations; however, none of the current detection methods are comprehensive, and currently available methodologies are incapable of providing sufficient resolution and unambiguous information across complex regions in the human genome. To address these challenges, we applied a high-throughput, cost-effective genome mapping technology to comprehensively discover genome-wide SVs and characterize complex regions of the YH genome using long single molecules (>150 kb) in a global fashion.ResultsUtilizing nanochannel-based genome mapping technology, we obtained 708 insertions/deletions and 17 inversions larger than 1 kb. Excluding the 59 SVs (54 insertions/deletions, 5 inversions) that overlap with N-base gaps in the reference assembly hg19, 666 non-gap SVs remained, and 396 of them (60%) were verified by paired-end data from whole-genome sequencing-based re-sequencing or de novo assembly sequence from fosmid data. Of the remaining 270 SVs, 260 are insertions and 213 overlap known SVs in the Database of Genomic Variants. Overall, 609 out of 666 (90%) variants were supported by experimental orthogonal methods or historical evidence in public databases. At the same time, genome mapping also provides valuable information for complex regions with haplotypes in a straightforward fashion. In addition, with long single-molecule labeling patterns, exogenous viral sequences were mapped on a whole-genome scale, and sample heterogeneity was analyzed at a new level.ConclusionOur study highlights genome mapping technology as a comprehensive and cost-effective method for detecting structural variation and studying complex regions in the human genome, as well as deciphering viral integration into the host genome.Electronic supplementary materialThe online version of this article (doi:10.1186/2047-217X-3-34) contains supplementary material, which is available to authorized users.
Highlights
Structural variants (SVs) are less common than single nucleotide polymorphisms and indels in the population, but collectively account for a significant fraction of genetic polymorphism and diseases
Rare, large de novo Copy number variant (CNV) were identified to be enriched in autism spectrum disorder (ASD) cases [16], and other structural variant (SV) were described as contributing factors for other complex traits including cancer, schizophrenia, epilepsy, Parkinson’s disease and immune diseases, such as psoriasis
We identified 725 SVs including insertions/deletions, inversions, as well as SVs involved in N-base gap regions that are difficult to assess by current methods
Summary
Structural variants (SVs) are less common than single nucleotide polymorphisms and indels in the population, but collectively account for a significant fraction of genetic polymorphism and diseases. Base pair differences arising from SVs are on a much higher order (>100 fold) than point mutations; none of the current detection methods are comprehensive, and currently available methodologies are incapable of providing sufficient resolution and unambiguous information across complex regions in the human genome. Recent studies have firmly established that SVs are associated with a number of human diseases ranging from sporadic syndromes and Mendelian diseases to common complex traits, neurodevelopmental disorders [11,12,13]. Chromosomal aneuploidies, such as trisomy 21 and monosomy X have long been known to be the cause of Down’s and Turner syndromes, respectively. With the increasing recognition of the important role of genomic aberrations in disease and the need for improved molecular diagnostics, comprehensive characterization of these genomic SVs is vital for, differentiating pathogenic events from benign ones, and for rapid and full-scale clinical diagnosis
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