Browsing by Author "Juul, Sissel"

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    Inverted triplications formed by iterative template switches generate structural variant diversity at genomic disorder loci
    (Elsevier, 2024) Grochowski, Christopher M.; Bengtsson, Jesse D.; Du, Haowei; Gandhi, Mira; Lun, Ming Yin; Mehaffey, Michele G.; Park, KyungHee; Höps, Wolfram; Benito, Eva; Hasenfeld, Patrick; Korbel, Jan O.; Mahmoud, Medhat; Paulin, Luis F.; Jhangiani, Shalini N.; Hwang, James Paul; Bhamidipati, Sravya V.; Muzny, Donna M.; Fatih, Jawid M.; Gibbs, Richard A.; Pendleton, Matthew; Harrington, Eoghan; Juul, Sissel; Lindstrand, Anna; Sedlazeck, Fritz J.; Pehlivan, Davut; Lupski, James R.; Carvalho, Claudia M. B.
    The duplication-triplication/inverted-duplication (DUP-TRP/INV-DUP) structure is a complex genomic rearrangement (CGR). Although it has been identified as an important pathogenic DNA mutation signature in genomic disorders and cancer genomes, its architecture remains unresolved. Here, we studied the genomic architecture of DUP-TRP/INV-DUP by investigating the DNA of 24 patients identified by array comparative genomic hybridization (aCGH) on whom we found evidence for the existence of 4 out of 4 predicted structural variant (SV) haplotypes. Using a combination of short-read genome sequencing (GS), long-read GS, optical genome mapping, and single-cell DNA template strand sequencing (strand-seq), the haplotype structure was resolved in 18 samples. The point of template switching in 4 samples was shown to be a segment of ∼2.2–5.5 kb of 100% nucleotide similarity within inverted repeat pairs. These data provide experimental evidence that inverted low-copy repeats act as recombinant substrates. This type of CGR can result in multiple conformers generating diverse SV haplotypes in susceptible dosage-sensitive loci.
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    MethPhaser: methylation-based long-read haplotype phasing of human genomes
    (Springer Nature, 2024) Fu, Yilei; Aganezov, Sergey; Mahmoud, Medhat; Beaulaurier, John; Juul, Sissel; Treangen, Todd J.; Sedlazeck, Fritz J.; Bioengineering; Computer Science
    The assignment of variants across haplotypes, phasing, is crucial for predicting the consequences, interaction, and inheritance of mutations and is a key step in improving our understanding of phenotype and disease. However, phasing is limited by read length and stretches of homozygosity along the genome. To overcome this limitation, we designed MethPhaser, a method that utilizes methylation signals from Oxford Nanopore Technologies to extend Single Nucleotide Variation (SNV)-based phasing. We demonstrate that haplotype-specific methylations extensively exist in Human genomes and the advent of long-read technologies enabled direct report of methylation signals. For ONT R9 and R10 cell line data, we increase the phase length N50 by 78%-151% at a phasing accuracy of 83.4-98.7% To assess the impact of tissue purity and random methylation signals due to inactivation, we also applied MethPhaser on blood samples from 4 patients, still showing improvements over SNV-only phasing. MethPhaser further improves phasing across HLA and multiple other medically relevant genes, improving our understanding of how mutations interact across multiple phenotypes. The concept of MethPhaser can also be extended to non-human diploid genomes. MethPhaser is available at https://github.com/treangenlab/methphaser.