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An Improved Method for Quantitative Trait Loci Detection and Identification of Within-Line Segregation in F2 Intercross Designs
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics.
2008 (English)In: Genetics, ISSN 0016-6731, E-ISSN 1943-2631, Vol. 178, no 4, p. 2315-2326Article in journal (Refereed) Published
Abstract [en]

We present a new flexible, simple, and power ful genome-scan method (flexible intercross analysis, FIA) for detecting quantitative trait loci (QTL) in experimental line crosses. The method is based on a pure random-effects model that simultaneously models between- and within-line QTL variation for single as well as epistatic QTL. It utilizes the score statistic and thereby facilitates computationally efficient significance testing based on empirical significance thresholds obtained by means of permutations. The properties of the method are explored using simulations and analyses of experimental data. The simulations showed that the power of FIA was as good as, or better than, Haley–Knott regression and that FIA was rather insensitive to the level of allelic fixation in the founders, especially for pedigrees with few founders. A chromosome scan was conducted for a meat quality trait in an F2 intercross in pigs where a mutation in the halothane (Ryanodine receptor, RYR1) gene with a large effect on meat quality was known to segregate in one founder line. FIA obtained significant support for the halothane-associated QTL and identified the base generation allele with the mutated allele. A genome scan was also performed in a previously analyzed chicken F2 intercross. In the chicken intercross analysis, four previously detected QTL were confirmed at a 5% genomewide significance level, and FIA gave strong evidence (P , 0.01) for two of these QTL to be segregating within the founder lines. FIA was also extended to account for epistasis and using simulations we show that the method provides good estimates of epistatic QTL variance even for segregating QTL. Extensions of FIA and its applications on other intercross populations including backcrosses, advanced intercross lines, and heterogeneous stocks are also discussed.

Place, publisher, year, edition, pages
2008. Vol. 178, no 4, p. 2315-2326
National Category
Genetics
Research subject
Genetics
Identifiers
URN: urn:nbn:se:uu:diva-101358DOI: 10.1534/genetics.107.083162ISI: 000255239600039PubMedID: 18430952OAI: oai:DiVA.org:uu-101358DiVA, id: diva2:212729
Available from: 2009-05-06 Created: 2009-04-23 Last updated: 2017-12-13Bibliographically approved
In thesis
1. Development of Variance Component Methods for Genetic Dissection of Complex Traits
Open this publication in new window or tab >>Development of Variance Component Methods for Genetic Dissection of Complex Traits
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis presents several developments on Variance component (VC) approach for Quantitative Trait Locus (QTL) mapping.

The first part consists of methodological improvements: a new fast and efficient method for estimating IBD matrices, have been developed. The new method makes a better use of the computer resources in terms of computational power and storage memory, facilitating further improvements by resolving methodological bottlenecks in algorithms to scan multiple QTL. A new VC model have also been developed in order to consider and evaluate the correlation of the allelic effects within parental lines origin in experimental outbred crosses. The method was tested on simulated and experimental data and revealed a higher or similar power to detect QTL than linear regression based QTL mapping.

The second part focused on the prospect to analyze multi-generational pedigrees by VC approach. The IBD estimation algorithm was extended to include haplotype information in addition to genotype and pedigree to improve the accuracy of the IBD estimates, and a new haplotyping algorithm was developed for limiting the risk of haplotyping errors in multigenerational pedigrees. Those newly developed methods where subsequently applied for the analysis of a nine generations AIL pedigree obtained after crossing two chicken lines divergently selected for body weight. Nine QTL described in a F2 population were replicated in the AIL pedigree, and our strategy to use both genotype and phenotype information from all individuals in the entire pedigree clearly made efficient use of the available genotype information provided in AIL.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2009. p. 32
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 646
National Category
Bioinformatics and Systems Biology
Research subject
Genetics
Identifiers
urn:nbn:se:uu:diva-101399 (URN)978-91-554-7534-5 (ISBN)
Public defence
2009-06-12, C8:305, BMC, Husargatan 3, Uppsala, 09:00 (English)
Opponent
Supervisors
Available from: 2009-05-20 Created: 2009-04-24 Last updated: 2011-03-08Bibliographically approved

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Rönnegård, LarsBesnier, FrancoisCarlborg, Örjan

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