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| 3. |
- Ahsan, Muhammad, et al.
(författare)
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Genetic analysis and replication of QTL effects on chicken body weight using a multi-locus introgression line
- 2013
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Ingår i: Journal of Data Mining in Genomics and Proteomics. - 2153-0602. ; 4, s. 83-83
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Quantitative Trait Loci (QTL) mapping is a useful initial step to dissect the geneticarchitecture of complex biological traits. Intercrosses between divergently selected lines ofanimals is a powerful approach to map loci that affect such traits individually or throughinteractions. The drawback with the approach is a low mapping resolution and consequentlyfurther fine mapping is needed for detailed studies of the mapped loci. We have earliermapped a network of four interacting loci that through reciprocal epistatic capacitationexplains nearly half of the difference in body weight between the Virginia High WeightSelected (HWS) and Low Weight Selected (LWS) chicken lines that after 50 generationsdisplay a 12-fold difference in weight at 56 days of age. The network has been replicated andfine-mapped in an eight-generation Advance Intercross Line (AIL) and its large effect onweight confirmed. A three-locus introgression line has been bred, where the LWS haplotypesat the three loci in the network with the strongest effects on weight have been simultaneouslyintrogressed into the HWS background. Here we describe the first results from a haplotypebasedassociation analysis in this multi-locus introgression line that again replicate the effectsof the introgressed loci on body-weight in the Virginia chicken lines, but also indicate anallelic heterogeneity at the loci within the founder-lines. Further analyses are in progress toevaluate the epistatic effects of the loci in this population as well as the functionalcontribution of the allelic heterogeneity.
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| 4. |
- Ahsan, Muhammad, et al.
(författare)
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Identification of candidate genes and mutations in QTL regions for chicken growth using bioinformatic analysis of NGS and SNP-ChiP data
- 2013
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Quantitative trait loci (QTL) mapping is a first step to identify chromosomal regions harboring genetic polymorphisms that regulate complex traits. Searching causative mutations for observed effects is sometimes a daunting task as even after fine mapping of the QTL, millions of base pairs including many genes will typically need to be explored. There is thus a great need for efficient bioinformatics strategies to trace the causative mutation(s). Here, we searched for gene transcripts along with mutations regulating body weight at 56 days traits in the Virginia chicken lines – an experimental population comprising two lines that have been divergently selected for 56 days body weight for more than 50 generations. Several QTL regions have been mapped in an F2 intercross between the lines, and the regions have subsequently been replicated and fine mapped using an Advanced Intercross Line (AIL). Candidate transcripts and mutations were here sought in the parts of the QTL regions where the highest genetic divergence between the High-Weight selected (HWS) and Low-Weight selected (LWS) lines was observed. Such regions, 47 Mbp or 35% of the actual QTL regions, were identified by comparing the allele frequencies in the genomes of the HWS and LWS lines using both individual 60K SNP chip genotyping of birds and analysis of read proportions with 12X ABI SOLID genome resequencing of DNA pools. Gene transcripts in the target segments, obtained using the Ensembl genome browser 67, were analyzed with DAVID bioinformatic database to investigate their role in any growth-related functions. Single nucleotide polymorphisms (SNPs) in target segments obtained from resequencing data were analyzed with Variant Effect Predictor (VEP) tool to find their location and functional consequences in gene transcripts. Non-synonymous SNPs (nsSNPs) were scored for their effects on protein function with PASE software (Li et al., submitted). Finally, we present most important candidate gene transcripts from each QTL segment for further functional validation. For example, the cysteine rich transmembrane BMP regulator 1 (chordin-like) gene has growth factor binding and cell growth functions. It carries a nsSNP with high allele frequency difference (0.97) between lines, PASE (0.67) and conservation scores (0.63). Another candidate, glucagon is involved in anorexia and appetite regulation carrying a CpG mutation with high allele frequency difference (0.87) between lines.
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| 5. |
- Ahsan, Muhammad, et al.
(författare)
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Identification of candidate genes and mutations in QTL regions for chicken growth using bioinformatic analysis of NGS and SNP-chip data.
- 2013
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Ingår i: Frontiers in Genetics. - : Frontiers Media SA. - 1664-8021. ; 4
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Tidskriftsartikel (refereegranskat)abstract
- Mapping of chromosomal regions harboring genetic polymorphisms that regulate complex traits is usually followed by a search for the causative mutations underlying the observed effects. This is often a challenging task even after fine mapping, as millions of base pairs including many genes will typically need to be investigated. Thus to trace the causative mutation(s) there is a great need for efficient bioinformatic strategies. Here, we searched for genes and mutations regulating growth in the Virginia chicken lines - an experimental population comprising two lines that have been divergently selected for body weight at 56 days for more than 50 generations. Several quantitative trait loci (QTL) have been mapped in an F2 intercross between the lines, and the regions have subsequently been replicated and fine mapped using an Advanced Intercross Line. We have further analyzed the QTL regions where the largest genetic divergence between the High-Weight selected (HWS) and Low-Weight selected (LWS) lines was observed. Such regions, covering about 37% of the actual QTL regions, were identified by comparing the allele frequencies of the HWS and LWS lines using both individual 60K SNP chip genotyping of birds and analysis of read proportions from genome resequencing of DNA pools. Based on a combination of criteria including significance of the QTL, allele frequency difference of identified mutations between the selected lines, gene information on relevance for growth, and the predicted functional effects of identified mutations we propose here a subset of candidate mutations of highest priority for further evaluation in functional studies. The candidate mutations were identified within the GCG, IGFBP2, GRB14, CRIM1, FGF16, VEGFR-2, ALG11, EDN1, SNX6, and BIRC7 genes. We believe that the proposed method of combining different types of genomic information increases the probability that the genes underlying the observed QTL effects are represented among the candidate mutations identified.
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| 6. |
- Albert, Frank W., et al.
(författare)
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Genetic architecture of tameness in a rat model of animal domestication
- 2009
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Ingår i: Genetics. - : Oxford University Press (OUP). - 0016-6731 .- 1943-2631. ; 182:2, s. 541-554
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Tidskriftsartikel (refereegranskat)abstract
- A common feature of domestic animals is tameness - i.e., they tolerate and are unafraid of human presence and handling. To gain insight into the genetic basis of tameness and aggression, we studied an intercross between two lines of rats (Rattus norvegicus) selected over >60 generations for increased tameness and increased aggression against humans, respectively. We measured 45 traits, including tameness and aggression, anxiety-related traits, organ weights, and levels of serum components in >700 rats from an intercross population. Using 201 genetic markers, we identified two significant quantitative trait loci (QTL) for tameness. These loci overlap with QTL for adrenal gland weight and for anxiety-related traits and are part of a five-locus epistatic network influencing tameness. An additional QTL influences the occurrence of white coat spots, but shows no significant effect on tameness. The loci described here are important starting points for finding the genes that cause tameness in these rats and potentially in domestic animals in general.
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| 7. |
- Albert, F. W., et al.
(författare)
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Targeted resequencing of a genomic region influencing tameness and aggression reveals multiple signals of positive selection
- 2011
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Ingår i: Heredity. - : Springer Science and Business Media LLC. - 0018-067X .- 1365-2540. ; 107:3, s. 205-214
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Tidskriftsartikel (refereegranskat)abstract
- The identification of the causative genetic variants in quantitative trait loci (QTL) influencing phenotypic traits is challenging, especially in crosses between outbred strains. We have previously identified several QTL influencing tameness and aggression in a cross between two lines of wild-derived, outbred rats (Rattus norvegicus) selected for their behavior towards humans. Here, we use targeted sequence capture and massively parallel sequencing of all genes in the strongest QTL in the founder animals of the cross. We identify many novel sequence variants, several of which are potentially functionally relevant. The QTL contains several regions where either the tame or the aggressive founders contain no sequence variation, and two regions where alternative haplotypes are fixed between the founders. A re-analysis of the QTL signal showed that the causative site is likely to be fixed among the tame founder animals, but that several causative alleles may segregate among the aggressive founder animals. Using a formal test for the detection of positive selection, we find 10 putative positively selected regions, some of which are close to genes known to influence behavior. Together, these results show that the QTL is probably not caused by a single selected site, but may instead represent the joint effects of several sites that were targets of polygenic selection.
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| 8. |
- Alexander, Michelle, et al.
(författare)
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Mitogenomic analysis of a 50-generation chicken pedigree reveals a rapid rate of mitochondrial evolution and evidence for paternal mtDNA inheritance
- 2015
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Ingår i: Biology Letters. - : The Royal Society. - 1744-9561 .- 1744-957X. ; 11:10
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Tidskriftsartikel (refereegranskat)abstract
- Mitochondrial genomes represent a valuable source of data for evolutionary research, but studies of their short-term evolution have typically been limited to invertebrates, humans and laboratory organisms. Here we present a detailed study of 12 mitochondrial genomes that span a total of 385 transmissions in a well-documented 50-generation pedigree in which two lineages of chickens were selected for low and high juvenile body weight. These data allowed us to test the hypothesis of time-dependent evolutionary rates and the assumption of strict maternal mitochondrial transmission, and to investigate the role of mitochondrial mutations in determining phenotype. The identification of a non-synonymous mutation in ND4L and a synonymous mutation in CYTB, both novel mutations in Gallus, allowed us to estimate a molecular rate of 3.13 x 10(-7) mutations/site/year (95% confidence interval 3.75 x 10(-8)-1.12 x 10(-6)). This is substantially higher than avian rate estimates based upon fossil calibrations. Ascertaining which of the two novel mutations was present in an additional 49 individuals also revealed an instance of paternal inheritance of mtDNA. Lastly, an association analysis demonstrated that neither of the point mutations was strongly associated with the phenotypic differences between the two selection lines. Together, these observations reveal the highly dynamic nature of mitochondrial evolution over short time periods.
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| 10. |
- Alvarez-Castro, Jose, et al.
(författare)
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Estimation and interpretation of genetic effects with epistasis using the NOIA model.
- 2012
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Ingår i: Methods in Molecular Biology. - Totowa, NJ : Humana Press. - 1064-3745 .- 1940-6029. ; 871, s. 191-204
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Tidskriftsartikel (refereegranskat)abstract
- We introduce this communication with a brief outline of the historical landmarks in genetic modeling, especially concerning epistasis. Then, we present methods for the use of genetic modeling in QTL analyses. In particular, we summarize the essential expressions of the natural and orthogonal interactions (NOIA) model of genetic effects. Our motivation for reviewing that theory here is twofold. First, this review presents a digest of the expressions for the application of the NOIA model, which are often mixed with intermediate and additional formulae in the original articles. Second, we make the required theory handy for the reader to relate the genetic concepts to the particular mathematical expressions underlying them. We illustrate those relations by providing graphical interpretations and a diagram summarizing the key features for applying genetic modeling with epistasis in comprehensive QTL analyses. Finally, we briefly review some examples of the application of NOIA to real data and the way it improves the interpretability of the results.
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| 11. |
- Álvarez-Castro, José M., et al.
(författare)
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A unified model for functional and statistical epistasis and its application in quantitative trait loci analysis
- 2007
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Ingår i: Genetics. - : Oxford University Press (OUP). - 0016-6731 .- 1943-2631. ; 176:2, s. 1151-1167
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Tidskriftsartikel (refereegranskat)abstract
- Interaction between genes, or epistasis, is found to be common and it is a key, concept for understanding adaptation and evolution of natural populations, response to selection in breeding programs, and determination of complex disease. Current]),, two independent classes of models are used to study epistasis. Statistical models focus on maintaining desired statistical properties for detection and estimation of genetic effects and for the decomposition of genetic variance using average effects of allele Substitutions in populations as parameters. Functional models focus on the evolutionary consequences of the attributes of the genotype-phenotype map using natural effects of allele substitutions as parameters. Here we provide a new, general and unified model framework: the natural and orthogonal interactions (NOIA) model. NOIA implements tools for transforming genetic effects measured in One Population to the ones of other populations (e.g., between two experimental designs for QTL) and parameters of statistical and functional epistasis into each other (thus enabling us to obtain functional estimates of QTL), as demonstrated numerically. We develop graphical interpretations of functional and statistical models as regressions of the genotypic values on the gene content, which illustrates the difference between the models-the constraint on the slope of the functional regression-and when the models are equivalent. Furthermore, we use our theoretical foundations to conceptually clarify functional and statistical epistasis, discuss the advantages of NOIA over previous theory, and stress the importance of linking functional and statistical models.
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| 12. |
- Alvarez-Castro, Jose M., et al.
(författare)
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How to perform meaningful estimates of genetic effects
- 2008
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Ingår i: PLoS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 4:5, s. e1000062-
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Tidskriftsartikel (refereegranskat)abstract
- Although the genotype-phenotype map plays a central role both in Quantitative and Evolutionary Genetics, the formalization of a completely general and satisfactory model of genetic effects, particularly accounting for epistasis, remains a theoretical challenge. Here, we use a two-locus genetic system in simulated populations with epistasis to show the convenience of using a recently developed model, NOIA, to perform estimates of genetic effects and the decomposition of the genetic variance that are orthogonal even under deviations from the Hardy-Weinberg proportions. We develop the theory for how to use this model in interval mapping of quantitative trait loci using Halley-Knott regressions, and we analyze a real data set to illustrate the advantage of using this approach in practice. In this example, we show that departures from the Hardy-Weinberg proportions that are expected by sampling alone substantially alter the orthogonal estimates of genetic effects when other statistical models, like F-2 or G2A, are used instead of NOIA. Finally, for the first time from real data, we provide estimates of functional genetic effects as sets of effects of natural allele substitutions in a particular genotype, which enriches the debate on the interpretation of genetic effects as implemented both in functional and in statistical models. We also discuss further implementations leading to a completely general genotype-phenotype map.
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| 13. |
- Alvarez-Castro, Jose, et al.
(författare)
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Modelling of genetic interactions improves prediction of hybrid patterns : a case study in domestic fowl
- 2012
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Ingår i: Genetical Research. - 0016-6723 .- 1469-5073. ; 94:5, s. 255-266
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Tidskriftsartikel (refereegranskat)abstract
- Summary A major challenge in complex trait genetics is to unravel how multiple loci and environmental factors together cause phenotypic diversity. Both first (F1) and second (F2) generation hybrids often display phenotypes that deviate from what is expected under intermediate inheritance. We have here studied two chicken F2 populations generated by crossing divergent chicken lines to assess how epistatic loci, identified in earlier quantitative trait locus (QTL) studies, contribute to hybrid deviations from the mid-parent phenotype. Empirical evidence suggests that the average phenotypes of the intercross birds tend to be lower than the midpoint between the parental means in both crosses. Our results confirm that epistatic interactions, despite a relatively small contribution to the phenotypic variance, play an important role in the deviation of hybrid phenotypes from the mid-parent values (i.e. multi-locus hybrid genotypes lead to lower rather than higher body weights). To a lesser extent, dominance also appears to contribute to the mid-parent deviation, at least in one of the crosses. This observation coincides with the hypothesis that hybridization tends to break up co-adapted gene complexes, i.e. generate Bateson-Dobzhansky-Muller incompatibilities.
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| 16. |
- Besnier, Francois, 1980-, et al.
(författare)
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A general and efficient method for estimating continuous IBD functions for use in genome scans for QTL
- 2007
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Ingår i: BMC Bioinformatics. - : Springer Science and Business Media LLC. - 1471-2105. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Background: Identity by descent (IBD) matrix estimation is a central component in mapping of Quantitative Trait Loci (QTL) using variance component models. A large number of algorithms have been developed for estimation of IBD between individuals in populations at discrete locations in the genome for use in genome scans to detect QTL affecting various traits of interest in experimental animal, human and agricultural pedigrees. Here, we propose a new approach to estimate IBD as continuous functions rather than as discrete values. Results: Estimation of IBD functions improved the computational efficiency and memory usage in genome scanning for QTL. We have explored two approaches to obtain continuous marker-bracket IBD-functions. By re-implementing an existing and fast deterministic IBD-estimation method, we show that this approach results in IBD functions that produces the exact same IBD as the original algorithm, but with a greater than 2-fold improvement of the computational efficiency and a considerably lower memory requirement for storing the resulting genome-wide IBD. By developing a general IBD function approximation algorithm, we show that it is possible to estimate marker-bracket IBD functions from IBD matrices estimated at marker locations by any existing IBD estimation algorithm. The general algorithm provides approximations that lead to QTL variance component estimates that even in worst-case scenarios are very similar to the true values. The approach of storing IBD as polynomial IBD-function was also shown to reduce the amount of memory required in genome scans for QTL. Conclusion: In addition to direct improvements in computational and memory efficiency, estimation of IBD-functions is a fundamental step needed to develop and implement new efficient optimization algorithms for high precision localization of QTL. Here, we discuss and test two approaches for estimating IBD functions based on existing IBD estimation algorithms. Our approaches provide immediately useful techniques for use in single QTL analyses in the variance component QTL mapping framework. They will, however, be particularly useful in genome scans for multiple interacting QTL, where the improvements in both computational and memory efficiency are the key for successful development of efficient optimization algorithms to allow widespread use of this methodology.
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| 17. |
- Besnier, Francois, et al.
(författare)
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A genetic algorithm based method for stringent haplotyping of family data
- 2009
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Ingår i: BMC Genetics. - : Springer Science and Business Media LLC. - 1471-2156. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Background: The linkage phase, or haplotype, is an extra level of information that in addition to genotype and pedigree can be useful for reconstructing the inheritance pattern of the alleles in a pedigree, and computing for example Identity By Descent probabilities. If a haplotype is provided, the precision of estimated IBD probabilities increases, as long as the haplotype is estimated without errors. It is therefore important to only use haplotypes that are strongly supported by the available data for IBD estimation, to avoid introducing new errors due to erroneous linkage phases.Results: We propose a genetic algorithm based method for haplotype estimation in family data that includes a stringency parameter. This allows the user to decide the error tolerance level when inferring parental origin of the alleles. This is a novel feature compared to existing methods for haplotype estimation. We show that using a high stringency produces haplotype data with few errors, whereas a low stringency provides haplotype estimates in most situations, but with an increased number of errors.Conclusion: By including a stringency criterion in our haplotyping method, the user is able to maintain the error rate at a suitable level for the particular study; one can select anything from haplotyped data with very small proportion of errors and a higher proportion of non-inferred haplotypes, to data with phase estimates for every marker, when haplotype errors are tolerable. Giving this choice makes the method more flexible and useful in a wide range of applications as it is able to fulfil different requirements regarding the tolerance for haplotype errors, or uncertain marker-phases.
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| 18. |
- Besnier, Francois, et al.
(författare)
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Fine mapping and replication of QTL in outbred chicken advanced intercross lines
- 2011
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Ingår i: Genetics Selection Evolution. - Paris : Springer Science and Business Media LLC. - 0999-193X .- 1297-9686. ; 43, s. 3-
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Tidskriftsartikel (refereegranskat)abstract
- 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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| 21. |
- Brady, Siobhan M, et al.
(författare)
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Reassess the t Test : Interact with All Your Data via ANOVA.
- 2015
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Ingår i: The Plant Cell. - : Oxford University Press (OUP). - 1040-4651 .- 1532-298X. ; 27:8
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Tidskriftsartikel (refereegranskat)abstract
- Plant biology is rapidly entering an era where we have the ability to conduct intricate studies that investigate how a plant interacts with the entirety of its environment. This requires complex, large studies to measure how plant genotypes simultaneously interact with a diverse array of environmental stimuli. Successful interpretation of the results from these studies requires us to transition away from the traditional standard of conducting an array of pairwise t tests toward more general linear modeling structures, such as those provided by the extendable ANOVA framework. In this Perspective, we present arguments for making this transition and illustrate how it will help to avoid incorrect conclusions in factorial interaction studies (genotype × genotype, genotype × treatment, and treatment × treatment, or higher levels of interaction) that are becoming more prevalent in this new era of plant biology.
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| 22. |
- Brandt, Monika, et al.
(författare)
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Imputation-Based Fine-Mapping Suggests That Most QTL in an Outbred Chicken Advanced Intercross Body Weight Line Are Due to Multiple, Linked Loci
- 2017
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Ingår i: G3. - : Oxford University Press (OUP). - 2160-1836. ; 7:1, s. 119-128
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Tidskriftsartikel (refereegranskat)abstract
- The Virginia chicken lines have been divergently selected for juvenile body weight for more than 50 generations. Today, the high- and low-weight lines show a >12-fold difference for the selected trait, 56-d body weight. These lines provide unique opportunities to study the genetic architecture of long-term, single-trait selection. Previously, several quantitative trait loci (QTL) contributing to weight differences between the lines were mapped in an F2-cross between them, and these were later replicated and fine-mapped in a nine-generation advanced intercross of them. Here, we explore the possibility to further increase the fine-mapping resolution of these QTL via a pedigree-based imputation strategy that aims to better capture the genetic diversity in the divergently selected, but outbred, founder lines. The founders of the intercross were high-density genotyped, and then pedigree-based imputation was used to assign genotypes throughout the pedigree. Imputation increased the marker density 20-fold in the selected QTL, providing 6911 markers for the subsequent analysis. Both single-marker association and multi-marker backward-elimination analyses were used to explore regions associated with 56-d body weight. The approach revealed several statistically and population structure independent associations and increased the mapping resolution. Further, most QTL were also found to contain multiple independent associations to markers that were not fixed in the founder populations, implying a complex underlying architecture due to the combined effects of multiple, linked loci perhaps located on independent haplotypes that still segregate in the selected lines.
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| 23. |
- Carlborg, Örjan, et al.
(författare)
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A global search reveals epistatic interaction between QTL for early growth in the chicken.
- 2003
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Ingår i: Genome Research. - : Cold Spring Harbor Laboratory. - 1088-9051 .- 1549-5469. ; 13:3
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Tidskriftsartikel (refereegranskat)abstract
- We have identified quantitative trait loci (QTL) explaining a large proportion of the variation in body weights at different ages and growth between chronological ages in an F(2) intercross between red junglefowl and White Leghorn chickens. QTL were mapped using forward selection for loci with significant marginal genetic effects and with a simultaneous search for epistatic QTL pairs. We found 22 significant loci contributing to these traits, nine of these were only found by the simultaneous two-dimensional search, which demonstrates the power of this approach for detecting loci affecting complex traits. We have also estimated the relative contribution of additive, dominance, and epistasis effects to growth and the contribution of epistasis was more pronounced prior to 46 days of age, whereas additive genetic effects explained the major portion of the genetic variance later in life. Several of the detected loci affected either early or late growth but not both. Very few loci affected the entire growth process, which points out that early and late growth, at least to some extent, have different genetic regulation.
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