| 1. |
- Engervall, K, et al.
(författare)
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Borreliosis as a cause of peripheral facial palsy: a multi-center study
- 1995
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Ingår i: ORL. - 0301-1569. ; 57:4, s. 202-206
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Tidskriftsartikel (refereegranskat)abstract
- Borreliosis is known to be a common cause of peripheral facial palsy in Stockholm and its vicinity. The aim of the present study was to investigate the frequency and characteristics of borreliosis among patients with peripheral facial palsy in different parts of Sweden. All serological tests were performed in one laboratory. Ten Swedish Ear Nose and Throat clinics participated in a prospective 1-year study of patients seeking medical attention for acute peripheral facial palsy. Twenty-eight (6%) out of totally 446 patients fulfilled the criteria for the diagnosis of borreliosis. The frequency varied between 1 and 16% and was highest along the southeast coast of Sweden whereas no case was reported from the northern part of the country. Borreliosis was more common among children with facial palsy than among adults. The infection occurred during all seasons although it appears to be less frequent during the spring months. Only a minority of the borrelial patients had a history of a preceding tick bite or erythema migrans. The fairly low overall frequency of this secondary stage of borreliosis in the study may be a result of better knowledge of the disease and earlier treatment of its early manifestations. In Sweden's endemic areas borreliosis is a common cause of peripheral facial palsy, and therefore all patients with facial palsy in these regions should be examined for borrelial infection.
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| 2. |
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| 3. |
- Tideholm, B, et al.
(författare)
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Continuous 24-hour measurement of middle ear pressure
- 1996
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Ingår i: Acta Oto-Laryngologica. - 1651-2251. ; 116:4, s. 581-588
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Tidskriftsartikel (refereegranskat)abstract
- A new method was developed for continuous measurement of the middle ear pressure during a 24-h period. The equipment consisted of a piezo-electric pressure device and a digital memory. To allow continuous pressure recordings during normal every-day activities the equipment was made light and portable. The measurement accuracy of the equipment as well as the base-line and temperature stability were tested and found to meet to our requirements satisfactorily. In 4 volunteers with different middle ear conditions, a small perforation was made through the tympanic membrane. A rubber stopper containing a small polyethylene tube was fitted into the external ear canal. Tubal function tests were made to establish the equipment's ability to monitor fast pressure changes. The tests were well in accordance with other methods of direct pressure measurements. The equipment was carried by the volunteers for 24 h to monitor any slow or rapid dynamic pressure changes in the middle ear. Four continuous 24-h measurements are presented. The method was found to be suitable for valid measurements of dynamic pressure changes in the middle ear during normal every-day activities. It may become a useful instrument in the search for a better understanding of the development of chronic middle ear disease.
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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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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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| 5. |
- 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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| 6. |
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| 7. |
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| 8. |
- 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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| 9. |
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| 10. |
- Carlborg, Örjan, et al.
(författare)
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The use of a genetic algorithm for simultaneous mapping of multiple interacting quantitative trait loci.
- 2000
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Ingår i: Genetics. - 0016-6731 .- 1943-2631. ; 155:4
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Tidskriftsartikel (refereegranskat)abstract
- Here we describe a general method for improving computational efficiency in simultaneous mapping of multiple interacting quantitative trait loci (QTL). The method uses a genetic algorithm to search for QTL in the genome instead of an exhaustive enumerative ("step-by-step") search. It can be used together with any method of QTL mapping based on a genomic search, since it only provides a more efficient way to search the genome for QTL. The computational demand decreases by a factor of approximately 130 when using genetic algorithm-based mapping instead of an exhaustive enumerative search for two QTL in a genome size of 2000 cM using a resolution of 1 cM. The advantage of using a genetic algorithm increases further for larger genomes, higher resolutions, and searches for more QTL. We show that a genetic algorithm-based search has efficiency higher than or equal to a search method conditioned on previously identified QTL for all epistatic models tested and that this efficiency is comparable to that of an exhaustive search for multiple QTL. The genetic algorithm is thus a powerful and computationally tractable alternative to the exhaustive enumerative search for simultaneous mapping of multiple interacting QTL. The use of genetic algorithms for simultaneous mapping of more than two QTL and for determining empirical significance thresholds using permutation tests is also discussed.
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| 11. |
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| 12. |
- Gjuvsland, Arne B., et al.
(författare)
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Statistical epistasis is a generic feature of gene regulatory networks
- 2007
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Ingår i: Genetics. - : Oxford University Press (OUP). - 0016-6731 .- 1943-2631. ; 175:1, s. 411-420
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Tidskriftsartikel (refereegranskat)abstract
- Functional dependencies between genes are a defining characteristic of gene networks underlying quantitative traits. However, recent studies show that the proportion of the genetic variation that can be attributed to statistical epistasis varies from almost zero to very high. It is thus of fundamental as well as instrumental importance to better understand whether different functional dependency patterns among polymorphic genes give rise to distinct statistical interaction patterns or not. Here we address this issue by combining a quantitative genetic model approach with genotype-phenotype models capable of translating allelic variation and regulatory principles into phenotypic variation at the level of gene expression. We show that gene regulatory networks with and without feedback motifs can exhibit a wide range of possible statistical genetic architectures with regard to both type of effect explaining phenotypic variance and number of apparent loci underlying the observed phenotypic effect. Although all motifs are capable of harboring significant interactions, positive feedback gives rise to higher amounts and more types of statistical epistasis. The results also suggest that the inclusion of statistical interaction terms in genetic models will increase the chance to detect additional QTL as well as functional dependencies between genetic loci over a broad range of regulatory regimes. This article illustrates how statistical genetic methods can fruitfully be combined with nonlinear systems dynamics to elucidate biological issues beyond reach of each methodology in isolation.
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| 13. |
- Guo, Ying, et al.
(författare)
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A genomic inference of the White Plymouth Rock genealogy
- 2019
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Ingår i: Poultry Science. - : Elsevier BV. - 0032-5791 .- 1525-3171. ; 98:11, s. 5272-5280
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Tidskriftsartikel (refereegranskat)abstract
- Crossing of populations has been, and still is, a central component in domestication and breed and variety formation. It is a way for breeders to utilize heterosis and to introduce new genetic variation into existing plant and livestock populations. During the mid-19th century, several chicken breeds that had been introduced to America from Europe and Asia became the founders for those formed in the USA. Historical records about the genealogy of these populations are often unclear and inconsistent. Here, we used genomics in an attempt to describe the ancestry of the White Plymouth Rock (WPR) chicken. In total, 150 chickens from the WPR and 8 other stocks that historical records suggested contributed to its formation were whole-genome re-sequenced. The admixture analyses of the autosomal and sex chromosomes showed that the WPR was likely founded as a cross between a paternal lineage that was primarily Dominique, and a maternal lineage where Black Java and Cochin contributed in essentially equal proportions. These results were consistent and provided quantification with the historical records that they were the main contributors to the WPR. The genomic analyses also revealed genome-wide contributions (<10% each) by Brahma, Langshan, and Black Minorca. When viewed on an individual chromosomal basis, contributions varied considerably among stocks.
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| 14. |
- Gylfason, Kristinn B., 1978-, et al.
(författare)
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A packaged optical slot-waveguide ring resonator sensor array for multiplex assays in labs-on-chip
- 2009
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Ingår i: Proceedings of Conference, MicroTAS 2009 - The 13th International Conference on Miniaturized Systems for Chemistry and Life Sciences. - : Chemical and Biological Microsystems Society. - 9780979806421 ; , s. 2004-2006
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Konferensbidrag (refereegranskat)abstract
- We present the design, fabrication, and characterization of a packaged array of individually addressable slot-waveguide ring resonator sensors in a compact cartridge for sensitive, label-free, multiplex assays. The novel use of a dual surfaceenergy adhesive film enables simple generic packaging method for multiple sensors in a single cartridge. The use of optical slot-waveguides, and drift compensation by on-chip light splitting to reference sensors, gives the best refractive-index limit of detection reported for planar ring resonator sensors.
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| 15. |
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| 16. |
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| 17. |
- Hill, Daniel, et al.
(författare)
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Microfluidic and Transducer Technologies for Lab on a Chip Applications
- 2010
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Ingår i: 2010 ANNUAL INTERNATIONAL CONFERENCE OF THE IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY (EMBC). - : IEEE conference proceedings. - 9781424441242 ; , s. 305-307
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Konferensbidrag (refereegranskat)abstract
- Point-of-care diagnostic devices typically require six distinct qualities: they must deliver at least the same sensitivity and selectivity, and for a cost per assay no greater than that of today's central lab technologies, deliver results in a short period of time (<15 min at GP; <2h in hospital), be portable or at least small in scale, and require no or extremely little sample preparation. State-of-the-art devices deliver information of several markers in the same measurement.
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| 18. |
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| 19. |
- Johansson, Anna Maria, et al.
(författare)
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Genome-Wide Effects of Long-Term Divergent Selection
- 2010
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Ingår i: PLoS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 6:11, s. e1001188-
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Tidskriftsartikel (refereegranskat)abstract
- To understand the genetic mechanisms leading to phenotypic differentiation, it is important to identify genomic regions under selection. We scanned the genome of two chicken lines from a single trait selection experiment, where 50 generations of selection have resulted in a 9-fold difference in body weight. Analyses of nearly 60,000 SNP markers showed that the effects of selection on the genome are dramatic. The lines were fixed for alternative alleles in more than 50 regions as a result of selection. Another 10 regions displayed strong evidence for ongoing differentiation during the last 10 generations. Many more regions across the genome showed large differences in allele frequency between the lines, indicating that the phenotypic evolution in the lines in 50 generations is the result of an exploitation of standing genetic variation at 100s of loci across the genome.
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| 20. |
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| 21. |
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| 22. |
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| 23. |
- Le Rouzic, Arnaud, et al.
(författare)
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Phenotypic evolution from genetic polymorphisms in a radial network architecture
- 2007
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Ingår i: BMC Biology. - : Springer Science and Business Media LLC. - 1741-7007. ; 5, s. 50-
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Tidskriftsartikel (refereegranskat)abstract
- Background: The genetic architecture of a quantitative trait influences the phenotypic response to natural or artificial selection. One of the main objectives of genetic mapping studies is to identify the genetic factors underlying complex traits and understand how they contribute to phenotypic expression. Presently, we are good at identifying and locating individual loci with large effects, but there is a void in describing more complex genetic architectures. Although large networks of connected genes have been reported, there is an almost complete lack of information on how polymorphisms in these networks contribute to phenotypic variation and change. To date, most of our understanding comes from theoretical, model-based studies, and it remains difficult to assess how realistic their conclusions are as they lack empirical support. Results: A previous study provided evidence that nearly half of the difference in eight-week body weight between two divergently selected lines of chickens was a result of four loci organized in a 'radial' network (one central locus interacting with three 'radial' loci that, in turn, only interacted with the central locus). Here, we study the relationship between phenotypic change and genetic polymorphism in this empirically detected network. We use a model-free approach to study, through individual-based simulations, the dynamic properties of this polymorphic and epistatic genetic architecture. The study provides new insights to how epistasis can modify the selection response, buffer and reveal effects of major loci leading to a progressive release of genetic variation. We also illustrate the difficulty of predicting genetic architecture from observed selection response, and discuss mechanisms that might lead to misleading conclusions on underlying genetic architectures from quantitative trait locus (QTL) experiments in selected populations. Conclusion: Considering both molecular (QTL) and phenotypic (selection response) data, as suggested in this work, provides additional insights into the genetic mechanisms involved in the response to selection. Such dissection of genetic architectures and in-depth studies of their ability to contribute to short-or long-term selection response represents an important step towards a better understanding of the genetic bases of complex traits and, consequently, of the evolutionary properties of populations.
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| 24. |
- Lillie, Mette, et al.
(författare)
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Bidirectional Selection for Body Weight on Standing Genetic Variation in a Chicken Model
- 2019
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Ingår i: G3. - : Oxford University Press (OUP). - 2160-1836. ; 9:4, s. 1165-1173
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Tidskriftsartikel (refereegranskat)abstract
- Experimental populations of model organisms provide valuable opportunities to unravel the genomic impact of selection in a controlled system. The Virginia body weight chicken lines represent a unique resource to investigate signatures of selection in a system where long-term, single-trait, bidirectional selection has been carried out for more than 60 generations. At 55 generations of divergent selection, earlier analyses of pooled genome resequencing data from these lines revealed that 14.2% of the genome showed extreme differentiation between the selected lines, contained within 395 genomic regions. Here, we report more detailed analyses of these data exploring the regions displaying within- and between-line genomic signatures of the bidirectional selection applied in these lines. Despite the strict selection regime for opposite extremes in body weight, this did not result in opposite genomic signatures between the lines. The lines often displayed a duality of the sweep signatures, where an extended region of homozygosity in one line, in contrast to mosaic pattern of heterozygosity in the other line. These haplotype mosaics consisted of short, distinct haploblocks of variable between-line divergence, likely the results of a complex demographic history involving bottlenecks, introgressions and moderate inbreeding. We demonstrate this using the example of complex haplotype mosaicism in the growth1 QTL. These mosaics represent the standing genetic variation available at the onset of selection in the founder population. Selection on standing genetic variation can thus result in different signatures depending on the intensity and direction of selection.
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| 25. |
- Lillie, Mette, et al.
(författare)
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Genome-wide standing variation facilitates long-term response to bidirectional selection for antibody response in chickens
- 2017
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Ingår i: BMC Genomics. - : Springer Science and Business Media LLC. - 1471-2164. ; 18
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Long-term selection experiments provide a powerful approach to gain empirical insights into adaptation, allowing researchers to uncover the targets of selection and infer their contributions to the mode and tempo of adaptation. Here we implement a pooled genome re-sequencing approach to investigate the consequences of 39 generations of bidirectional selection in White Leghorn chickens on a humoral immune trait: antibody response to sheep red blood cells.RESULTS: We observed wide genome involvement in response to this selection regime. Many genomic regions were highly differentiated resulting from this experimental selection regime, an involvement of up to 20% of the chicken genome (208.8 Mb). While genetic drift has certainly contributed to this, we implement gene ontology, association analysis and population simulations to increase our confidence in candidate selective sweeps. Three strong candidate genes, MHC, SEMA5A and TGFBR2, are also presented.CONCLUSIONS: The extensive genomic changes highlight the polygenic genetic architecture of antibody response in these chicken populations, which are derived from a common founder population, demonstrating the extent of standing immunogenetic variation available at the onset of selection.
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| 26. |
- Lindh, A. U., et al.
(författare)
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Predicting suicide: A comparison between clinical suicide risk assessment and the Suicide Intent Scale
- 2020
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Ingår i: Journal of Affective Disorders. - : Elsevier BV. - 0165-0327 .- 1573-2517. ; 263, s. 445-449
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Tidskriftsartikel (refereegranskat)abstract
- Background: How suicide risk should be assessed is under discussion with arguments for both actuarial and clinical approaches. The aim of the present study was to compare the predictive accuracy of a clinical suicide risk assessment to that of the Suicide Intent Scale (SIS) in predicting suicide within one year of an episode of self-harm with or without suicidal intent. Methods: Prospective clinical study of 479 persons assessed in a psychiatric emergency department after an episode of self-harm. The clinical risk assessment and the SIS rating were made independently of each other. Suicides within one year were identified in the National Cause of Death Register. Receiver operating characteristic (ROC) curves were constructed, optimal cut-offs were identified and accuracy statistics were calculated. Results: Of 479 participants, 329 (68.7%) were women. The age range was 18-95 years. During one-year follow up, 14 participants died by suicide. The area under the curve (AUC) for the clinical risk assessment and the SIS score were very similar, as were the accuracy statistic measures at the optimal cut-offs of the respective methods. The positive predictive value (PPV) of each assessment method was 6%. Limitations: The clinical suicide risk assessment is not standardized. The number of suicides is small, not allowing for stratification by e.g. gender or diagnosis. Conclusion: Predictive accuracy was similar for a clinical risk assessment and the SIS, and insufficient to guide treatment allocation.
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| 27. |
- Ou, Jen-Hsiang, et al.
(författare)
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Complex genetic architecture of the chicken Growth1 QTL region
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- The genetic complexity of polygenic traits represents a captivating and intricate facet of biological inheritance. Unlike Mendelian traits controlled by a single gene, polygenic traits are influenced by multiple genetic loci, each exerting a modest effect on the trait. This cumulative impact of numerous genes, interactions among them, environmental factors, and epigenetic modifications results in a multifaceted architecture of genetic contributions to complex traits.Given the well-characterized genome, diverse traits, and range of genetic resources, chicken (Gallus gallus) was employed as a model organism to dissect the intricate genetic makeup of a previously identified major Quantitative Trait Loci (QTL) for body weight on chromosome 1.A multigenerational advanced intercross line (AIL) of 3215 chickens whose genomes had been sequenced to an average of 0.4x was analyzed using genome-wide association study (GWAS) and variance-heterogeneity GWAS (vGWAS) to identify markers associated with 8-week body weight. Additionally, epistatic interactions were studied using the natural and orthogonal interaction (NOIA) model.Six genetic modules, two from GWAS and four from vGWAS, were strongly associated with the studied trait. We found evidence of both additive- and non-additive interactions between these modules and constructed a putative local epistasis network for the region. Our screens for functional alleles revealed a missense variant in the gene ribonuclease H2 subunit B (RNASEH2B), which has previously been associated with growth-related traits in chickens and Darwin’s finches. In addition, one of the most strongly associated SNPs identified is located in a non-coding region upstream of the long non-coding RNA, ENSGALG00000053256, previously suggested as a candidate gene for regulating chicken body weight. By studying large numbers of individuals from a family material using approaches to capture both additive and non-additive effects, this study advances our understanding of genetic complexities in a highly polygenic trait and has practical implications for poultry breeding and agriculture.
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| 28. |
- Park, H B, et al.
(författare)
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Melanocortin-4 receptor (MC4R) genotypes have no major effect on fatness in a Large White x Wild Boar intercross.
- 2002
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Ingår i: Animal Genetics. - 0268-9146 .- 1365-2052. ; 33:2
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Tidskriftsartikel (refereegranskat)abstract
- The melanocortin-4 receptor (MC4R), a G-protein coupled receptor, is implicated in mediating the effect of leptin on food intake and energy balance. A previous candidate gene study reported an association between an MC4R missense mutation (Asp298Asn) and fatness, growth and feed intake in pigs. To assess this association further, we analysed the segregation of this missense mutation in relation to variation in fatness traits using a Wild Boar x Large White intercross. The Wild Boar and Large White founders were homozygous for different MC4R alleles. The MC4R was assigned to the expected region on pig chromosome 1. The statistical evaluation did not reveal any indication of a significant effect on fatness related traits in this pedigree.
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| 29. |
- Pettersson, Mats, et al.
(författare)
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Dynamics of adaptive alleles in divergently selected body weight lines of chickens.
- 2013
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Ingår i: G3. - : Oxford University Press (OUP). - 2160-1836. ; 3:12
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Tidskriftsartikel (refereegranskat)abstract
- By studying genomic changes over time in populations subjected to strong artificial directional selection, we can gain insights to the dynamics of beneficial alleles originating from the founder population or emerging as novel mutations undergoing ongoing selection. The Virginia lines are a chicken resource population generated by long-term bi-directional, single-trait selection for juvenile body weight. We studied genome-wide allele frequency changes from generation 40 to 53 using genome-wide genotypes from directional and relaxed selection lines. Overall, there were small changes in allele frequencies at individual loci over the studied time period; but, on average, the changes were greater in lines with larger phenotypic changes. This is consistent with previous findings that much of the response to selection over the first 40 years of selection was attributable to utilization of standing genetic variation at many loci in the genome, indicating a mostly polygenic architecture for body weight. Over the course of the selection experiment, the largest phenotypic response to selection was observed in the high-weight selected line, and in this line we detected a single locus where the allele frequency changed rapidly during a late stage of the experiment. This locus likely contains a novel, beneficial mutation that appeared between generations 40 and 45 and was driven to fixation in 5 to 10 generations. This result illustrates the dependence of continued long-term selection response on standing genetic variation at many loci as well as strong, novel, beneficial mutations.
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| 30. |
- Pettersson, Mats, et al.
(författare)
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Replication and Explorations of High-Order Epistasis Using a Large Advanced Intercross Line Pedigree
- 2011
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Ingår i: PLoS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 7:7, s. e1002180-
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 31. |
- Rubin, Carl-Johan, et al.
(författare)
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Strong signatures of selection in the domestic pig genome
- 2012
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 109:48, s. 19529-19536
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Tidskriftsartikel (refereegranskat)abstract
- Domestication of wild boar (Sus scrofa) and subsequent selection have resulted in dramatic phenotypic changes in domestic pigs for a number of traits, including behavior, body composition, reproduction, and coat color. Here we have used whole-genome resequencing to reveal some of the loci that underlie phenotypic evolution in European domestic pigs. Selective sweep analyses revealed strong signatures of selection at three loci harboring quantitative trait loci that explain a considerable part of one of the most characteristic morphological changes in the domestic pig - the elongation of the back and an increased number of vertebrae. The three loci were associated with the NR6A1, PLAG1, and LCORL genes. The latter two have repeatedly been associated with loci controlling stature in other domestic animals and in humans. Most European domestic pigs are homozygous for the same haplotype at these three loci. We found an excess of derived nonsynonymous substitutions in domestic pigs, most likely reflecting both positive selection and relaxed purifying selection after domestication. Our analysis of structural variation revealed four duplications at the KIT locus that were exclusively present in white or white-spotted pigs, carrying the Dominant white, Patch, or Belt alleles. This discovery illustrates how structural changes have contributed to rapid phenotypic evolution in domestic animals and how alleles in domestic animals may evolve by the accumulation of multiple causative mutations as a response to strong directional selection.
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| 32. |
- Rönneburg, Tilman, et al.
(författare)
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Low-coverage sequencing in a deep intercross of the Virginia body weight lines provides insight to the polygenic genetic architecture of growth : novel loci revealed by increased power and improved genome-coverage
- 2023
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Ingår i: Poultry Science. - : Elsevier. - 0032-5791 .- 1525-3171. ; 102:5
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Tidskriftsartikel (refereegranskat)abstract
- Genetic dissection of highly polygenic traits is a challenge, in part due to the power necessary to confidently identify loci with minor effects. Experimental crosses are valuable resources for mapping such traits. Traditionally, genome-wide analyses of experimental crosses have targeted major loci using data from a single generation (often the F2) with individuals from later generations being generated for replication and fine-mapping. Here, we aim to confidently identify minor-effect loci contributing to the highly polygenic basis of the long-term, bi-directional selection responses for 56-d body weight in the Virginia body weight chicken lines. To achieve this, a strategy was developed to make use of data from all generations (F2–F18) of the advanced intercross line, developed by crossing the low and high selected lines after 40 generations of selection. A cost-efficient low-coverage sequencing based approach was used to obtain high-confidence genotypes in 1Mb bins across 99.3% of the chicken genome for >3,300 intercross individuals. In total, 12 genome-wide significant, and 30 additional suggestive QTL reaching a 10% FDR threshold, were mapped for 56-d body weight. Only 2 of these QTL reached genome-wide significance in earlier analyses of the F2 generation. The minor-effect QTL mapped here were generally due to an overall increase in power by integrating data across generations, with contributions from increased genome-coverage and improved marker information content. The 12 significant QTL explain >37% of the difference between the parental lines, three times more than 2 previously reported significant QTL. The 42 significant and suggestive QTL together explain >80%. Making integrated use of all available samples from multiple generations in experimental crosses are economically feasible using the low-cost, sequencing-based genotyping strategies outlined here. Our empirical results illustrate the value of this strategy for mapping novel minor-effect loci contributing to complex traits to provide a more confident, comprehensive view of the individual loci that form the genetic basis of the highly polygenic, long-term selection responses for 56-d body weight in the Virginia body weight chicken lines.
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| 33. |
- Rönneburg, Tilman, et al.
(författare)
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Mapping and dissecting capacitating epistasis in a population subjected to long-term, directional selection
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Dissection of the genetic mechanisms that constitute quantitative traits is challenging, especially when the underlying biology is complex, and dependent on the interaction of multiple genes and environmental factors. Unexplained phenotypic variance or missing heritability in studies of quantitative traits has often been explained by a high polygenicity of the trait, i.e. many small effect loci, as well as epistasis. The ability to detect both phenomenons has so far been limited by the significantly increased power and resolution required, with studies often failing to explain a majority of the heritability or phenotypic variance of the trait investigated. Here, we use low-coverage, whole-genome sequencing data of a large (n>3300), 18-generation advanced intercross line formed from generation 41 of the Virginia body weight lines, which originated from an outbred common stock of chickens and are bi-directionally selected for 8-week body weight. this study attempts to use this large and powerful population to explore the role of capacitating epistasis in the long-term selection responses in the Virginia chicken lines. Using a mix of stratification and vQTL analysis, we Identify 6 potential capacitor hubs of varying strength, which together capacitate an effect of 259g. Furthermore, the higher resolution enabled a dissection of a previously identified epistatic interaction between QTL on chromosome 4 and 7 into a network where two capacitors on Chromosome 4 and 7 release an effect for two capacitated loci on chromosome 4, explaining more than twice the effect of the purely additive model when accounting for the interaction ( 136.9g vs 331.5g). This provides not only a better estimate for how genetic components correspond to the selection response observed, but also a mechanistic example of how higher resolution and power enabled the dissection of previously large, additive QTL into a complex network of multiple smaller, interacting QTL, coherent with previous assumptions about the polygenicity and complexity of a highly polygenic trait.
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| 34. |
- Rönneburg, Tilman, et al.
(författare)
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Within-line segregation as contributors to long-term, single-trait selection-responses in the Virginia chicken lines
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Populations display a remarkable capability to adapt under natural or artificial selection, even far beyond the original phenotype range, given intense single trait selection. The genetic mechanisms to facilitate this however, are still unclear. Here we use an Advanced Intercross Line, generated after 40 generations of intense bi-directional selection from a common outbred founder population. in an attempt to quantify the contribution of still segregating variants to the selection response.While the selection response of the founding lines has been extensively profiled within this population, this has been done under the assumption that the most important regions were fixed for divergent alleles between the lines. Investigating beyond this paradigm has been previously hampered due to requirements in power, marker density and number of recombination events. Here we use a large low-coverage sequencing dataset that has been imputed to both founder-line haplotypes as well as dense marker coverage using high-quality, deep coverage sequenced founders. Utilizing this dataset for a multi-locus GWAS approach to contrast with a more traditional cross-QTL methodology, the aim of this study is to identify novel regions that contribute to the phenotype, and assess as to whether and how they contribute to the selection response. Out of 40 (a=890g, 23% of total phenotypic variance) Loci retained in the model, 24 (a=557.5g, 15% of total phenotypic variance) do not overlap known QTL. While some freely segregate between lines, 14 (a=346.6g, 9.3% of total phenotypic variance) of them are fixed in at least one founding line, and likely contribute a significant fraction of the selection response.
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| 35. |
- Rönneburg, Tilman, et al.
(författare)
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Within-line segregation as contributors to long-term, single-trait selection responses in the Virginia chicken lines
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Populations display a remarkable capability to adapt under natural or artificial selection, even far beyond the original phenotype range, given intense single trait selection. The genetic mechanisms to facilitate this however, are still unclear. Here we use an Advanced Intercross Line, generated after 40 generations of intense bi-directional selection from a common outbred founder population, in an attempt to quantify the contribution of still segregating variants to the selection response.While the selection response of the founding lines has been extensively profiled within this population, this has been done under the assumption that the most important regions were fixed for divergent alleles between the lines. Investigating beyond this paradigm has been previously hampered due to requirements in power, marker density, and number of recombination events. Here we use a large low-coverage sequencing dataset that has been imputed to both founder-line haplotypes as well as dense marker coverage using high-quality, deep-coverage sequenced founders. Utilizing this dataset for a multi-locus GWAS approach to contrast with a more traditional cross-QTL methodology, the aim of this study is to identify novel regions that contribute to the phenotype and assess whether and how they contribute to the selection response. Out of 40 (a=890g, 23.9% of total phenotypic variance) Loci retained in the multilocus model, 24 (a=557.5g, 15% of total phenotypic variance) do not overlap known QTL. While some freely segregate between lines, 14 (a=346.6g, 9.3% of total phenotypic variance) of them are fixed in at least one founding line, and likely contribute a significant fraction of the selection response.The variance effect prediction result provides a functional view of markers. The RNASEH2B and TBXAS1 genes were considered as candidates, with previous research supporting body weight-related functions. For GALNT7, ENSGALG00000049347, TOM1, ENSGALG00000013583, ENSGALG00000039245, CHD7, and CNTNAP5 genes, the high conservation score provides a clue of being important for biological functions. However, the mechanism by which these genes regulate body weight still remains limited.
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| 36. |
- Sandström, Niklas, 1981-, et al.
(författare)
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Lab-on-a-chip microsystems for point-of-care diagnostics
- 2010
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Ingår i: 1st International scientific conference on Microfluidics in bioanalytical research and diagnostics. ; , s. 34-35
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)
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| 37. |
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| 38. |
- Sheng, Zheya, et al.
(författare)
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Standing genetic variation as a major contributor to adaptation in the Virginia chicken lines selection experiment.
- 2015
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Ingår i: Genome Biology. - : Springer Science and Business Media LLC. - 1465-6906 .- 1474-760X .- 1474-7596. ; 16
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Artificial selection provides a powerful approach to study the genetics of adaptation. Using selective-sweep mapping, it is possible to identify genomic regions where allele-frequencies have diverged during selection. To avoid false positive signatures of selection, it is necessary to show that a sweep affects a selected trait before it can be considered adaptive. Here, we confirm candidate, genome-wide distributed selective sweeps originating from the standing genetic variation in a long-term selection experiment on high and low body weight of chickens.RESULTS: Using an intercross between the two divergent chicken lines, 16 adaptive selective sweeps were confirmed based on their association with the body weight at 56 days of age. Although individual additive effects were small, the fixation for alternative alleles across the loci contributed at least 40 % of the phenotypic difference for the selected trait between these lines. The sweeps contributed about half of the additive genetic variance present within and between the lines after 40 generations of selection, corresponding to a considerable portion of the additive genetic variance of the base population.CONCLUSIONS: Long-term, single-trait, bi-directional selection in the Virginia chicken lines has resulted in a gradual response to selection for extreme phenotypes without a drastic reduction in the genetic variation. We find that fixation of several standing genetic variants across a highly polygenic genetic architecture made a considerable contribution to long-term selection response. This provides new fundamental insights into the dynamics of standing genetic variation during long-term selection and adaptation.
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| 39. |
- Wahlberg, Per, et al.
(författare)
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Genetic analysis of an F2 intercross between two chicken lines divergently selected for body-weight
- 2009
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Ingår i: BMC Genomics. - : Springer Science and Business Media LLC. - 1471-2164. ; 10, s. 248-
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: We have performed Quantitative Trait Loci (QTL) analysis of an F(2) intercross between two chicken lines divergently selected for juvenile body-weight. In a previous study 13 identified loci with effects on body-weight, only explained a small proportion of the large variation in the F(2) population. Epistatic interaction analysis however, indicated that a network of interacting loci with large effect contributed to the difference in body-weight of the parental lines. This previous analysis was, however, based on a sparse microsatellite linkage map and the limited coverage could have affected the main conclusions. Here we present a revised QTL analysis based on a high-density linkage map that provided a more complete coverage of the chicken genome. Furthermore, we utilized genotype data from ~13,000 SNPs to search the genome for potential selective sweeps that have occurred in the selected lines. RESULTS: We constructed a linkage map comprising 434 genetic markers, covering 31 chromosomes but leaving seven microchromosomes uncovered. The analysis showed that seven regions harbor QTL that influence growth. The pair-wise interaction analysis identified 15 unique QTL pairs and notable is that nine of those involved interactions with a locus on chromosome 7, forming a network of interacting loci. The analysis of ~13,000 SNPs showed that a substantial proportion of the genetic variation present in the founder population has been lost in either of the two selected lines since ~60% of the SNPs polymorphic among lines showed fixation in one of the lines. With the current marker coverage and QTL map resolution we did not observe clear signs of selective sweeps within QTL intervals. CONCLUSION: The results from the QTL analysis using the new improved linkage map are to a large extent in concordance with our previous analysis of this pedigree. The difference in body-weight between the parental chicken lines is caused by many QTL each with a small individual effect. Although the increased chromosomal marker coverage did not lead to the identification of additional QTL, we were able to refine the localization of QTL. The importance of epistatic interaction as a mechanism contributing significantly to the remarkable selection response was further strengthened because additional pairs of interacting loci were detected with the improved map.
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| 40. |
- Yang, Yunzhou, et al.
(författare)
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Haplotype Purging after Relaxation of Selection in Lines of Chickens That Had Undergone Long-Term Selection for High and Low Body Weight
- 2020
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Ingår i: Genes. - : MDPI. - 2073-4425. ; 11:6
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Tidskriftsartikel (refereegranskat)abstract
- Bi-directional selection for increased and decreased 56-day body weights (BW56) has been applied to two lines of White Plymouth Rock chickens-the Virginia high (HWS) and low (LWS) body weight lines. Correlated responses have been observed, including negative effects on traits related to fitness. Here, we use high and low body weight as proxies for fitness. On a genome-wide level, relaxed lines (HWR, LWR) bred from HWS and LWS purged some genetic variants in the selected lines. Whole-genome re-sequencing was here used to identify individual loci where alleles that accumulated during directional selection were purged when selection was relaxed. In total, 11 loci with significant purging signals were identified, five in the low (LW) and six in the high (HW) body weight lineages. Associations between purged haplotypes in these loci and BW56 were tested in an advanced intercross line (AIL). Two loci with purging signals and haplotype associations to BW56 are particularly interesting for further functional characterization, one locus on chromosome 6 in the LW covering the sour-taste receptor genePKD2L1, a functional candidate gene for the decreased appetite observed in the LWS and a locus on chromosome 20 in the HW containing a skeletal muscle hypertrophy gene,DNTTIP1.
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| 41. |
- Zan, Yanjun, et al.
(författare)
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Artificial selection response due to polygenic adaptation from a multilocus, multiallelic genetic architecture
- 2017
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Ingår i: Molecular biology and evolution. - : Oxford University Press (OUP). - 0737-4038 .- 1537-1719. ; 34:10, s. 2678-2689
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Tidskriftsartikel (refereegranskat)abstract
- The ability of a population to adapt to changes in their living conditions, whether in nature or captivity, often depends on polymorphisms in multiple genes across the genome. In-depth studies of such polygenic adaptations are difficult in natural populations, but can be approached using the resources provided by artificial selection experiments. Here, we dissect the genetic mechanisms involved in long-term selection responses of the Virginia chicken lines, populations that after 40 generations of divergent selection for 56-day body weight display a 9-fold difference in the selected trait. In the F15 generation of an intercross between the divergent lines, 20 loci explained >60% of the additive genetic variance for the selected trait. We focused particularly on fine-mapping seven major QTL that replicated in this population and found that only two fine-mapped to single, bi-allelic loci; the other five contained linked loci, multiple alleles or were epistatic. This detailed dissection of the polygenic adaptations in the Virginia lines provides a deeper understanding of the range of different genome-wide mechanisms that have been involved in these long-term selection responses. The results illustrate that the genetic architecture of a highly polygenic trait can involve a broad range of genetic mechanisms, and that this can be the case even in a small population bred from founders with limited genetic diversity.
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| 42. |
- Zan, Yanjun, et al.
(författare)
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Genotyping by low-coverage whole-genome sequencing in intercross pedigrees from outbred founders : a cost-efficient approach
- 2019
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Ingår i: Genetics Selection Evolution. - : BMC. - 0999-193X .- 1297-9686. ; 51:1
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Tidskriftsartikel (refereegranskat)abstract
- Background Experimental intercrosses between outbred founder populations are powerful resources for mapping loci that contribute to complex traits i.e. quantitative trait loci (QTL). Here, we present an approach and its accompanying software for high-resolution reconstruction of founder mosaic genotypes in the intercross offspring from such populations using whole-genome high-coverage sequence data on founder individuals (similar to 30x) and very low-coverage sequence data on intercross individuals (< 0.5x). Sets of founder-line informative markers were selected for each full-sib family and used to infer the founder mosaic genotypes of the intercross individuals. The application of this approach and the quality of the estimated genome-wide genotypes are illustrated in a large F-2 pedigree between two divergently selected lines of chickens. Results We describe how we obtained whole-genome genotype data for hundreds of individuals in a cost- and time-efficient manner by using a Tn5-based library preparation protocol and an imputation algorithm that was optimized for this application. In total, 7.6 million markers segregated in this pedigree and, within each full-sib family, between 10.0 and 13.7% of these were fully informative, i.e. fixed for alternative alleles in the founders from the divergent lines, and were used for reconstruction of the offspring mosaic genotypes. The genotypes that were estimated based on the low-coverage sequence data were highly consistent (> 95% agreement) with those obtained using individual single nucleotide polymorphism (SNP) genotyping. The estimated resolution of the inferred recombination breakpoints was relatively high, with 50% of them being defined on regions shorter than 10 kb. Conclusions A method and software for inferring founder mosaic genotypes in intercross offspring from low-coverage whole-genome sequencing in pedigrees from heterozygous founders are described. They provide high-quality, high-resolution genotypes in a time- and cost-efficient manner. The software is freely available at https://github.com/CarlborgGenomics/Stripes..
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