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PoolHap: Inferring Haplotype Frequencies from Pooled Samples by Next Generation Sequencing

Long, QA; Jeffares, DC; Zhang, QR; Ye, K; Nizhynska, V; Ning, ZM; Tyler-Smith, C; (2011) PoolHap: Inferring Haplotype Frequencies from Pooled Samples by Next Generation Sequencing. PLOS ONE , 6 (1) , Article e15292. 10.1371/journal.pone.0015292. Green open access

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Abstract

With the advance of next-generation sequencing (NGS) technologies, increasingly ambitious applications are becoming feasible. A particularly powerful one is the sequencing of polymorphic, pooled samples. The pool can be naturally occurring, as in the case of multiple pathogen strains in a blood sample, multiple types of cells in a cancerous tissue sample, or multiple isoforms of mRNA in a cell. In these cases, it's difficult or impossible to partition the subtypes experimentally before sequencing, and those subtype frequencies must hence be inferred. In addition, investigators may occasionally want to artificially pool the sample of a large number of individuals for reasons of cost-efficiency, e. g., when carrying out genetic mapping using bulked segregant analysis. Here we describe PoolHap, a computational tool for inferring haplotype frequencies from pooled samples when haplotypes are known. The key insight into why PoolHap works is that the large number of SNPs that come with genome-wide coverage can compensate for the uneven coverage across the genome. The performance of PoolHap is illustrated and discussed using simulated and real data. We show that PoolHap is able to accurately estimate the proportions of haplotypes with less than 2% error for 34-strain mixtures with 2X total coverage Arabidopsis thaliana whole genome polymorphism data. This method should facilitate greater biological insight into heterogeneous samples that are difficult or impossible to isolate experimentally. Software and users manual are freely available at http://arabidopsis.gmi.oeaw.ac.at/quan/poolhap/.

Type: Article
Title: PoolHap: Inferring Haplotype Frequencies from Pooled Samples by Next Generation Sequencing
Open access status: An open access version is available from UCL Discovery
DOI: 10.1371/journal.pone.0015292
Publisher version: http:dx/doi.org/10.1371/journal.pone.0015292
Language: English
Additional information: © 2011 Long et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Austrian Academy of Science (http://www.oeaw.ac.at/english/home.html), the Wellcome Trust (grant 085775/Z/08/Z) (http://www.wellcome.ac.uk/) and National Natural Science Foundation of China (No. 30700442, 30730057) (http://www.nsfc.gov.cn/Portal0/default10​6.htm). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Keywords: CELLS, IDENTIFICATION, ISOFORMS
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
URI: https://discovery.ucl.ac.uk/id/eprint/763514
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