title: Characterizing polymorphic inversions in human genomes by single-cell sequencing.
abstract: Identifying genomic features that differ between individuals and cells can help uncover the functional variants that drive phenotypes and disease susceptibilities. For this, single-cell studies are paramount, as it becomes increasingly clear that the contribution of rare but functional cellular subpopulations is important for disease prognosis, management, and progression. Until now, studying these associations has been challenged by our inability to map structural rearrangements accurately and comprehensively. To overcome this, we coupled single-cell sequencing of DNA template strands (Strand-seq) with custom analysis software to rapidly discover, map, and genotype genomic rearrangements at high resolution. This allowed us to explore the distribution and frequency of inversions in a heterogeneous cell population, identify several polymorphic domains in complex regions of the genome, and locate rare alleles in the reference assembly. We then mapped the entire genomic complement of inversions within two unrelated individuals to characterize their distinct inversion profiles and built a nonredundant global reference of structural rearrangements in the human genome. The work described here provides a powerful new framework to study structural variation and genomic heterogeneity in single-cell samples, whether from individuals for population studies or tissue types for biomarker discovery.
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia, V5Z 1L3, Canada.
authors.forename: Ashley D
authors.initials: AD
authors.lastname: Sanders
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia, V5Z 1L3, Canada.
authors.forename: Mark
authors.initials: M
authors.lastname: Hills
authors.affiliation: European Research Institute for the Biology of Ageing, University of Groningen, University Medical Centre Groningen, NL-9713 AV Groningen, The Netherlands.
authors.forename: David
authors.initials: D
authors.lastname: Porubský
authors.affiliation: European Research Institute for the Biology of Ageing, University of Groningen, University Medical Centre Groningen, NL-9713 AV Groningen, The Netherlands.
authors.forename: Victor
authors.initials: V
authors.lastname: Guryev
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia, V5Z 1L3, Canada.
authors.forename: Ester
authors.initials: E
authors.lastname: Falconer
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia, V5Z 1L3, Canada.|European Research Institute for the Biology of Ageing, University of Groningen, University Medical Centre Groningen, NL-9713 AV Groningen, The Netherlands.|Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, V6T 1Z4, Canada.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Lansdorp
mesh_terms: D000328:Adult; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D002478:Cells, Cultured; D007446:Chromosome Inversion; D005312:Fetal Blood / Q000166:cytology; D015894:Genome, Human; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D011110:Polymorphism, Genetic; D017422:Sequence Analysis, DNA / Q000379:methods*; D059010:Single-Cell Analysis / Q000379:methods*