Haplotype resolved genomes: Computational challenges and applications

David Porubský

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    Genomes of diploid organisms, like humans, are organized in pairs of chromosomes, one inherited from the father and one from the mother. Each homologous chromosome harbors a specific set of parental alleles, called haplotype. Unfortunately, to obtain haplotype information using current methods remains challenging. Here we introduce a single cell DNA template strand sequencing (Strand-seq) as a novel haplotyping approach able to separate parental alleles along the entire length of all chromosomes. We demonstrate this by building a complete haplotypes for HapMap individual (NA12878) at high accuracy (concordance 99.3%), without using generational information or statistical inference. Furthermore we mapped all meiotic recombination events in a family trio with high resolution (median range ~14 kb), and phased larger structural variants like deletions, indels as well as balanced rearrangements like inversions. The single cell resolution of Strand-seq allowed us to observe loss of heterozygosity regions in a small number of cells, a significant advantage for studies of heterogeneous cell populations, such as cancer cells. Lastly, we prove that integration of Strand-seq with other whole-genome sequencing methods brings significant increase in haplotype completeness while reducing sequencing costs. The implementation of Strand-seq and our analysis pipeline brings a powerful, high-throughput approach to assemble haplotypes that will open up new possibilities to study diploid architecture of human genomes in health and disease.
    Originele taal-2English
    KwalificatieDoctor of Philosophy
    Toekennende instantie
    • Rijksuniversiteit Groningen
    Begeleider(s)/adviseur
    • Lansdorp, Peter, Supervisor
    • Guryev, Victor, Co-supervisor
    • Bevova, Marianna, Co-supervisor
    • Cuppen, Edwin, Beoordelingscommissie, Externe Persoon
    • van Vugt, Marcel, Beoordelingscommissie
    • Korbel, Jan O., Beoordelingscommissie, Externe Persoon
    Datum van toekenning27-mrt-2017
    Plaats van publicatie[Groningen]
    Uitgever
    Gedrukte ISBN's978-90-367-9637-8
    Elektronische ISBN's978-90-367-9636-1
    StatusPublished - 2017

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