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A haplotype-aware de novo assembly of related individuals using pedigree graph

Shilpa Garg, John Aach, Heng Li, Richard Durbin, George Church
doi: https://doi.org/10.1101/580159
Shilpa Garg
1Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA
5Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, Massachusetts, USA
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John Aach
1Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA
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Heng Li
3Department of Biomedical Informatics, Harvard Medical School, Boston, Massachusetts, USA
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Richard Durbin
4Department of Genetics, University of Cambridge, Cambridge, United Kingdom
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George Church
1Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA
5Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, Massachusetts, USA
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Abstract

Motivation Reconstructing high-quality haplotype-resolved assemblies for related individuals of various species has important applications in understanding Mendelian diseases along with evolutionary and comparative genomics. Through major genomics sequencing efforts such as the Personal Genome Project, the Vertebrate Genome Project (VGP), the Earth Biogenome Project (EBP) and the Genome in a Bottle project (GIAB), a variety of sequencing datasets from mother-father-child trios of various diploid species are becoming available.

Current trio assembly approaches are not designed to incorporate long-read sequencing data from parents in a trio, and therefore require relatively high coverages of costly long-read data to produce high-quality assemblies. Thus, building a trio-aware assembler capable of producing accurate and chromosomal-scale diploid genomes in a pedigree, while being cost-effective in terms of sequencing costs, is a pressing need of the genomics community.

Results We present a novel pedigree-graph-based approach to diploid assembly using accurate Illumina data and long-read Pacific Biosciences (PacBio) data from all related individuals, thereby generalizing our previous work on single individuals. We demonstrate the effectiveness of our pedigree approach on a simulated trio of pseudo-diploid yeast genomes with different heterozygosity rates, and real data from Arabidopsis Thaliana. We show that we require as little as 30× coverage Illumina data and 15× PacBio data from each individual in a trio to generate chromosomal-scale phased assemblies. Additionally, we show that we can detect and phase variants from generated phased assemblies.

Availability https://github.com/shilpagarg/WHdenovo

Contact shilpa_garg{at}hms.harvard.edu, gchurch{at}genetics.med.harvard.edu

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted March 17, 2019.
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A haplotype-aware de novo assembly of related individuals using pedigree graph
Shilpa Garg, John Aach, Heng Li, Richard Durbin, George Church
bioRxiv 580159; doi: https://doi.org/10.1101/580159
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A haplotype-aware de novo assembly of related individuals using pedigree graph
Shilpa Garg, John Aach, Heng Li, Richard Durbin, George Church
bioRxiv 580159; doi: https://doi.org/10.1101/580159

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