Haplotype-resolved diverse human genomes and integrated analysis of structural variation

Ebert, Peter; Audano, Peter A.; Zhu, Qihui; Rodríguez-Martín, Bernardo; Porubský, David; Bonder, Marc Jan; Sulovari, Arvis; Ebler, Jana; Zhou, Weichen; Mari, Rebecca Serra; Yilmaz, Feyza; Zhao, Xuefang; Hsieh, Ping Hsun; Lee, Joyce; Kumar, Sushant; Lin, Jiadong; Rausch, Tobias; Chen, Yu; Ren, Jimin; Santamarina, Martin; Höps, Wolfram; Ashraf, Hufsah; Chuang, Nelson T.; Yang, Xiaofei; Munson, Katherine M.; Lewis, Alexandra P.; Fairley, Susan; Tallon, Luke J.; Clarke, Wayne E.; Basile, Anna O.; Byrska-Bishop, Marta; Corvelo, André; Evani, Uday S.; Lu, Tsung Yu; Chaisson, Mark; Chen, Junjie; Li, Chong; Brand, Harrison; Wenger, Aaron M.; Ghareghani, Maryam; Harvey, William T.; Raeder, Benjamin; Hasenfeld, Patrick; Regier, Allison; Abel, Haley J.; Hall, Ira M.; Flicek, Paul; Stegle, Oliver; Gerstein, Mark; Tubío, José M. C.; Mu, Zepeng; Li, Yang; Shi, Xinghua; Hastie, Alex; Ye, Kai; Chong, Zechen; Sanders, Ashley D.; Zody, Michael C.; Talkowski, Michael E.; Mills, Ryan E.; Devine, Scott E.; Lee, Charles; Korbel, Jan O.; Marschall, Tobias; Eichler, Evan E.

doi:10.1126/science.abf7117

Cited by 519 publications

(949 citation statements)

References 197 publications

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“…( I ) Composition plot for the VNTR in SLC22A1 , with examples of duplication and deletion boxed in black and grey, respectively. The genomes used for this plot were previously sequenced and published (Ebert et al 2021).…”

Section: Resultsmentioning

confidence: 99%

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Characterizing nucleotide variation and expansion dynamics in human-specific variable number tandem repeats

Course

Sulovari

Gudsnuk

et al. 2021

Preprint

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There are over 55,000 variable number tandem repeats (VNTRs) in the human genome, notable for both their striking polymorphism and mutability. Despite their role in human evolution and genomic variation, they have yet to be studied collectively and in detail, partially due to their large size, variability, and predominant location in non-coding regions. Here, we examine 467 VNTRs that are human-specific expansions, unique to one location in the genome, and not associated with retrotransposons. We leverage publicly available long-read genomes – including from the Human Genome Structural Variant Consortium – to ascertain the exact nucleotide composition of these VNTRs, and compare their composition of alleles. We then confirm repeat unit composition in over 3000 short-read samples from the 1000 Genomes Project. Our analysis reveals that these VNTRs contain remarkably structured repeat motif organization, modified by frequent deletion and duplication events. While overall VNTR compositions tend to remain similar between 1000 Genomes Project super-populations, we describe a notable exception with substantial differences in repeat composition (in PCBP3), as well as several VNTRs that are significantly different in length between super-populations (in ART1, PROP1, WDR60, and LOC102723906). We also observe that most of these VNTRs are expanded in archaic human genomes, yet remain stable in length between single generations. Collectively, our findings indicate that repeat motif variability, repeat composition, and repeat length are all informative modalities to consider when characterizing VNTRs and their contribution to genomic variation.

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Section: Resultsmentioning

confidence: 99%

“…3H). Overall, we observed that most length and allelic differences were derived from duplications and deletions, as highlighted in an 82-bp repeat in SLC22A1 (long-read genomes used to analyze SLC22A1 were obtained from (Ebert et al 2021))(Fig. 3I), rather than unit-by-unit changes.…”

Section: Internal Sequence Variation Of Human-specific Vntr Expansionmentioning

confidence: 90%

Characterizing nucleotide variation and expansion dynamics in human-specific variable number tandem repeats

Course

Sulovari

Gudsnuk

et al. 2021

Preprint

Self Cite

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“…Current research employs optical mapping to outline the diversity found in the human genome and thus to assemble a more comprehensive map of the genome. In several recent studies, optical mapping greatly contributed to the resolution of haplotypes, SVs and complex regions such as telomeres and sub-telomeric regions, previously inaccessible by NGS alone [11,38,[74][75][76][77][78][79].…”

Section: The Biological Impact Of Optical Genome Mappingmentioning

confidence: 99%

“…Optical mapping is a vibrant field [1,2,8], and is currently the go-to method for detecting and validating large-scale genomic rearrangements, such as structural and copy number variations (SVs, CNVs respectively) [9][10][11][12][13] ( Figure 1D). With Mbp read lengths, optical mapping reveals such large-scale variations from the reference genome, while conventional short-read next-generation sequencing (NGS) is blind to them.…”

Section: Introductionmentioning

confidence: 99%

Single-molecule optical genome mapping in nanochannels: multidisciplinarity at the nanoscale

Jeffet

Margalit

Michaeli

et al. 2021

Essays in Biochemistry

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The human genome contains multiple layers of information that extend beyond the genetic sequence. In fact, identical genetics do not necessarily yield identical phenotypes as evident for the case of two different cell types in the human body. The great variation in structure and function displayed by cells with identical genetic background is attributed to additional genomic information content. This includes large-scale genetic aberrations, as well as diverse epigenetic patterns that are crucial for regulating specific cell functions. These genetic and epigenetic patterns operate in concert in order to maintain specific cellular functions in health and disease. Single-molecule optical genome mapping is a high-throughput genome analysis method that is based on imaging long chromosomal fragments stretched in nanochannel arrays. The access to long DNA molecules coupled with fluorescent tagging of various genomic information presents a unique opportunity to study genetic and epigenetic patterns in the genome at a single-molecule level over large genomic distances. Optical mapping entwines synergistically chemical, physical, and computational advancements, to uncover invaluable biological insights, inaccessible by sequencing technologies. Here we describe the method’s basic principles of operation, and review the various available mechanisms to fluorescently tag genomic information. We present some of the recent biological and clinical impact enabled by optical mapping and present recent approaches for increasing the method’s resolution and accuracy. Finally, we discuss how multiple layers of genomic information may be mapped simultaneously on the same DNA molecule, thus paving the way for characterizing multiple genomic observables on individual DNA molecules.

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“…This has produced various novel insights based on sequence complexity and previously underestimated genomic variability between individuals within the same species (Sudmant et al 2015). Since then, reports have described an ever-increasing number of novel genomic variations and their associated allele frequency estimates (Sedlazeck et al 2020;Collins et al 2020;Sudmant et al 2015;Ebert et al 2021;Audano et al 2019;Warren et al 2020). These findings are important for many fields in research and clinical applications, ultimately providing a better understanding of phenotype to genotype relationships (Lappalainen et al 2019;Mahmoud et al 2019;Ho et al 2020).…”

Section: Introductionmentioning

confidence: 99%

SVhound: Detection of future Structural Variation hotspots

Raveendran

et al. 2021

Preprint

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Recent population studies are ever growing in size of samples to investigate the diversity of a given population or species. These studies reveal ever new polymorphism that lead to important insights into the mechanisms of evolution, but are also important for the interpretation of these variations. Nevertheless, while the full catalog of variations across entire species remains unknown, we can predict which regions harbor additional variations that remain hidden and investigate their properties, thereby enhancing the analysis for potentially missed variants. To achieve this we implemented SVhound (https://github.com/lfpaulin/SVhound), which based on a population level SVs dataset can predict regions that harbor novel SV alleles. We tested SVhound using subsets of the 1000 genomes project data and showed that its correlation (average correlation of 2,800 tests r=0.7136) is high to the full data set. Next, we utilized SVhound to investigate potentially missed or understudied regions across 1KGP and CCDG that included multiple genes. Lastly we show the applicability for SVhound also on a small and novel SV call set for rhesus macaque (Macaca mulatta) and discuss the impact and choice of parameters for SVhound. Overall SVhound is a unique method to identify potential regions that harbor hidden diversity in model and non model organisms and can also be potentially used to ensure high quality of SV call sets.

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Haplotype-resolved diverse human genomes and integrated analysis of structural variation

Cited by 519 publications

References 197 publications

Characterizing nucleotide variation and expansion dynamics in human-specific variable number tandem repeats

Characterizing nucleotide variation and expansion dynamics in human-specific variable number tandem repeats

Single-molecule optical genome mapping in nanochannels: multidisciplinarity at the nanoscale

SVhound: Detection of future Structural Variation hotspots

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