Browsing by Author "Besnier, Francois"

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    Fine mapping and replication of QTL in outbred chicken advanced intercross lines
    Besnier, Francois; Wahlberg, Per; Rönnegård, Lars; Ek, Weronica; Andersson, Leif; Siegel, Paul B.; Carlborg, Örjan (2011-01-17)
    Background Linkage mapping is used to identify genomic regions affecting the expression of complex traits. However, when experimental crosses such as F2 populations or backcrosses are used to map regions containing a Quantitative Trait Locus (QTL), the size of the regions identified remains quite large, i.e. 10 or more Mb. Thus, other experimental strategies are needed to refine the QTL locations. Advanced Intercross Lines (AIL) are produced by repeated intercrossing of F2 animals and successive generations, which decrease linkage disequilibrium in a controlled manner. Although this approach is seen as promising, both to replicate QTL analyses and fine-map QTL, only a few AIL datasets, all originating from inbred founders, have been reported in the literature. Methods We have produced a nine-generation AIL pedigree (n = 1529) from two outbred chicken lines divergently selected for body weight at eight weeks of age. All animals were weighed at eight weeks of age and genotyped for SNP located in nine genomic regions where significant or suggestive QTL had previously been detected in the F2 population. In parallel, we have developed a novel strategy to analyse the data that uses both genotype and pedigree information of all AIL individuals to replicate the detection of and fine-map QTL affecting juvenile body weight. Results Five of the nine QTL detected with the original F2 population were confirmed and fine-mapped with the AIL, while for the remaining four, only suggestive evidence of their existence was obtained. All original QTL were confirmed as a single locus, except for one, which split into two linked QTL. Conclusions Our results indicate that many of the QTL, which are genome-wide significant or suggestive in the analyses of large intercross populations, are true effects that can be replicated and fine-mapped using AIL. Key factors for success are the use of large populations and powerful statistical tools. Moreover, we believe that the statistical methods we have developed to efficiently study outbred AIL populations will increase the number of organisms for which in-depth complex traits can be analyzed.
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    Replication and Explorations of High-Order Epistasis Using a Large Advanced Intercross Line Pedigree
    Pettersson, Mats E.; Besnier, Francois; Siegel, Paul B.; Carlborg, Örjan (PLoS, 2011-07)
    Dissection of the genetic architecture of complex traits persists as a major challenge in biology; despite considerable efforts, much remains unclear including the role and importance of genetic interactions. This study provides empirical evidence for a strong and persistent contribution of both second- and third-order epistatic interactions to long-term selection response for body weight in two divergently selected chicken lines. We earlier reported a network of interacting loci with large effects on body weight in an F-2 intercross between these high-and low-body weight lines. Here, most pair-wise interactions in the network are replicated in an independent eight-generation advanced intercross line (AIL). The original report showed an important contribution of capacitating epistasis to growth, meaning that the genotype at a hub in the network releases the effects of one or several peripheral loci. After fine-mapping of the loci in the AIL, we show that these interactions were persistent over time. The replication of five of six originally reported epistatic loci, as well as the capacitating epistasis, provides strong empirical evidence that the originally observed epistasis is of biological importance and is a contributor in the genetic architecture of this population. The stability of genetic interaction mechanisms over time indicates a non-transient role of epistasis on phenotypic change. Third-order epistasis was for the first time examined in this study and was shown to make an important contribution to growth, which suggests that the genetic architecture of growth is more complex than can be explained by two-locus interactions only. Our results illustrate the importance of designing studies that facilitate exploration of epistasis in populations for obtaining a comprehensive understanding of the genetics underlying a complex trait.