Extended haplotype phasing of de novo genome assemblies with FALCON-Phase

Authors: KRONENBERG, ZEV - Phase Genomics, Inc; RHIE, ARANG - National Human Genome Research Institute; KOREN, SERGEY - National Human Genome Research Institute; CONCEPCION, GREGORY - Pacific Biosciences Inc; PELUSO, PAUL - Pacific Biosciences Inc; MUNSON, KATHERINE - University Of Washington Medical School; HIENDLEDER, STEFAN - University Of Adelaide; FEDRIGO, OLIVIER - Rockefeller University; JARVIS, ERICH - Howard Hughes Medical Institute; PHILLIPPY, ADAM - National Human Genome Research Institute; EICHLER, EVAN - University Of Washington; WILLIAMS, JOHN - University Of Adelaide; Smith, Timothy - Tim; HALL, RICHARD - National Human Genome Research Institute; SULLIVAN, SHAWN - Phase Genomics, Inc; KINGAN, SARAH - Pacific Biosciences Inc

Submitted to: bioRxiv
Publication Type: Pre-print Publication
Publication Acceptance Date: 5/20/2018
Publication Date: 4/19/2019
Citation: Kronenberg, Z.N., Rhie, A., Koren, S., Concepcion, G.T., Peluso, P., Munson, K.M., Hiendleder, S., Fedrigo, O., Jarvis, E.D., Phillippy, A.M., Eichler, E.E., Williams, J.L., Smith, T.P.L, Hall, R.J., Sullivan, S.T., Kingan, S.B. 2019. Extended haplotype phasing of de novo genome assemblies with FALCON-Phase. bioRxiv. 327064. https://doi.org/10.1101/327064.
DOI: https://doi.org/10.1101/327064

Interpretive Summary: We recently developed a new approach to creating reference genome assemblies called Triocanu, that relies on DNA sequence using long-read technology. Using Triocanu, we generated Angus and Brahman breed cattle genome assemblies that were the first to create chromosome sequences that fully resolved the contributions of the father (an Angus bull) and the mother (a Brahman cow). This allowed us to assemble genomes from two beef cattle breeds by sequencing a single crossbred Angus x Brahman individual. Each of the two breed assemblies is superior to what could be created with previously existing technology. The limitation of the method is that it requires short read sequence data from the parents, to assist in defining the parental contributions. In the present study, we report an alternative approach to assembling maternal and paternal genomes where parental data is not available, by making use of long-range interaction data available from a technique called Hi-C. This data can partially substitute for having parental short read data, and this study compares the results to the Triocanu approach.

Technical Abstract: Haplotype-resolved genome assemblies are important for understanding how combinations of variants impact phenotypes. These assemblies can be created in various ways, such as use of tissues that contain single-haplotype (haploid) genomes, or by co-sequencing of parental genomes, but these approaches can be impractical in many situations. We present FALCON Phase, which integrates long-read sequencing data and ultra-long-range Hi-C chromatin interaction data of a diploid individual to create high-quality, phased diploid genome assemblies. The method was evaluated by application to three datasets, including human, cattle, and zebra finch, for which high-quality, fully haplotype resolved assemblies were available for benchmarking. Phasing algorithm accuracy was affected by heterozygosity of the individual sequenced, with higher accuracy for cattle and zebra finch (>97%) compared to human (82%). In addition, scaffolding with the same Hi-C chromatin contact data resulted in phased chromosome scale scaffolds.