Browsing by Author "Paulin, Luis F."

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    FixItFelix: improving genomic analysis by fixing reference errors
    (Springer Nature, 2023) Behera, Sairam; LeFaive, Jonathon; Orchard, Peter; Mahmoud, Medhat; Paulin, Luis F.; Farek, Jesse; Soto, Daniela C.; Parker, Stephen C. J.; Smith, Albert V.; Dennis, Megan Y.; Zook, Justin M.; Sedlazeck, Fritz J.
    The current version of the human reference genome, GRCh38, contains a number of errors including 1.2 Mbp of falsely duplicated and 8.04 Mbp of collapsed regions. These errors impact the variant calling of 33 protein-coding genes, including 12 with medical relevance. Here, we present FixItFelix, an efficient remapping approach, together with a modified version of the GRCh38 reference genome that improves the subsequent analysis across these genes within minutes for an existing alignment file while maintaining the same coordinates. We showcase these improvements over multi-ethnic control samples, demonstrating improvements for population variant calling as well as eQTL studies.
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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.