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Genome Biology

, 14:R100

First Online: 12 September 2013Received: 31 May 2013Accepted: 12 September 2013


BackgroundHaplotypes are important for assessing genealogy and disease susceptibility of individual genomes, but are difficult to obtain with routine sequencing approaches. Experimental haplotype reconstruction based on assembling fragments of individual chromosomes is promising, but with variable yields due to incompletely understood parameter choices.

ResultsWe parameterize the clone-based haplotyping problem in order to provide theoretical and empirical assessments of the impact of different parameters on haplotype assembly. We confirm the intuition that long clones help link together heterozygous variants and thus improve haplotype length. Furthermore, given the length of the clones, we address how to choose the other parameters, including number of pools, clone coverage and sequencing coverage, so as to maximize haplotype length. We model the problem theoretically and show empirically the benefits of using larger clones with moderate number of pools and sequencing coverage. In particular, using 140 kb BAC clones, we construct haplotypes for a personal genome and assemble haplotypes with N50 values greater than 2.6 Mb. These assembled haplotypes are longer and at least as accurate as haplotypes of existing clone-based strategies, whether in vivo or in vitro.

ConclusionsOur results provide practical guidelines for the development and design of clone-based methods to achieve long range, high-resolution and accurate haplotypes.

AbbreviationsBACBacterial artificial chromosome

CGIComplete Genomics Institute

HLAHuman leukocyte antigen

LClone length

LFRLong fragment read

MECMinimum error correction

MESMinimum edit score

nNumber of clones per pool

pNumber of pools

PGPPersonal Genome Project

WGSWhole genome sequencing.

Electronic supplementary materialThe online version of this article doi:10.1186-gb-2013-14-9-r100 contains supplementary material, which is available to authorized users.

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Autor: Christine Lo - Rui Liu - Jehyuk Lee - Kimberly Robasky - Susan Byrne - Carolina Lucchesi - John Aach - George Church - Vin

Fuente: https://link.springer.com/

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