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  • 1.
    Forsberg, Simon
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Complex Trait Genetics: Beyond Additivity2016Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    The link between the genotype and the phenotype of an organism is immensely complex. Despite this it can, to a great extent, be captured using models that assume that gene variants combine their effects in an additive manner. This thesis explores aspects of genetics that cannot be fully captured using such additive models. Using experimental data from three different model organisms, I study two phenomena that fall outside of the additive paradigm: genetic interactions and genetic variance heterogeneity.

    Using the model plant Arabidopsis thaliana, we show how important biological insights can be reached by exploring loci that display genetic variance heterogeneity. In the first study, this approach identified alleles in the gene CMT2 associated with the climate at sampling locations, suggesting a role in climate adaption. These alleles affected the genome wide methylation pattern, and a complete knock down of this gene increased the plants heat tolerance. In the second study, we demonstrate how the observed genetic variance heterogeneity was the result of the partial linkage of many functional alleles near the gene MOT1, all contributing to Molybdenum levels in the leaves.

    Further, we explore genetic interactions using data from dogs and budding yeast (Saccharomyces cerevisiae). In the dog population, two interacting loci were associated with fructosamine levels, a biomarker used to monitor blood glucose. One of the loci displayed the pattern of a selective sweep in some of the studied breeds, suggesting that the interaction is important for the phenotypic breed-differences.

    In a cross between two strains of yeast, with the advantage of large population size and nearly equal allele frequencies, we identified large epistatic networks. The networks were largely centered on a number of hub-loci and altogether involved hundreds of genetic interactions. Most network hubs had the ability to either suppress or uncover the phenotypic effects of other loci. Many multi-locus allele combinations resulted in phenotypes that deviated significantly from the expectations, had the loci acted in an additive manner.

    Critically, this thesis demonstrates that non-additive genetic mechanisms often need to be considered in order to fully understand the genetics of complex traits. 

    Delarbeid
    1. Accounting for genetic interactions improves modeling of individual quantitative trait phenotypes in yeast
    Åpne denne publikasjonen i ny fane eller vindu >>Accounting for genetic interactions improves modeling of individual quantitative trait phenotypes in yeast
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Experiments in model organisms report abundant genetic interactions underlying biologically important traits, whereas quantitative genetics theory predicts, and data support, that most genetic variance in populations is additive. Here we describe networks of capacitating genetic interactions that contribute to quantitative trait variation in a large yeast intercross population. The additive variance explained by individual loci in a network is highly dependent on the allele frequencies of the interacting loci. Modeling of phenotypes for multi-locus genotype classes in the epistatic networks is often improved by accounting for the interactions. We discuss the implications of these results for attempts to dissect genetic architectures and to predict individual phenotypes and long-term responses to selection.

    Emneord
    genetic interactions, epistasis, yeast, QTL, epistatic networks
    HSV kategori
    Forskningsprogram
    Genetik
    Identifikatorer
    urn:nbn:se:uu:diva-307821 (URN)10.1101/059485 (DOI)
    Tilgjengelig fra: 2016-11-22 Laget: 2016-11-22 Sist oppdatert: 2016-11-30
    2. The Multi-allelic Genetic Architecture of a Variance-Heterogeneity Locus for Molybdenum Concentration in Leaves Acts as a Source of Unexplained Additive Genetic Variance.
    Åpne denne publikasjonen i ny fane eller vindu >>The Multi-allelic Genetic Architecture of a Variance-Heterogeneity Locus for Molybdenum Concentration in Leaves Acts as a Source of Unexplained Additive Genetic Variance.
    Vise andre…
    2015 (engelsk)Inngår i: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 11, nr 11Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Genome-wide association (GWA) analyses have generally been used to detect individual loci contributing to the phenotypic diversity in a population by the effects of these loci on the trait mean. More rarely, loci have also been detected based on variance differences between genotypes. Several hypotheses have been proposed to explain the possible genetic mechanisms leading to such variance signals. However, little is known about what causes these signals, or whether this genetic variance-heterogeneity reflects mechanisms of importance in natural populations. Previously, we identified a variance-heterogeneity GWA (vGWA) signal for leaf molybdenum concentrations in Arabidopsis thaliana. Here, fine-mapping of this association reveals that the vGWA emerges from the effects of three independent genetic polymorphisms that all are in strong LD with the markers displaying the genetic variance-heterogeneity. By revealing the genetic architecture underlying this vGWA signal, we uncovered the molecular source of a significant amount of hidden additive genetic variation or "missing heritability". Two of the three polymorphisms underlying the genetic variance-heterogeneity are promoter variants for Molybdate transporter 1 (MOT1), and the third a variant located ~25 kb downstream of this gene. A fourth independent association was also detected ~600 kb upstream of MOT1. Use of a T-DNA knockout allele highlights Copper Transporter 6; COPT6 (AT2G26975) as a strong candidate gene for this association. Our results show that an extended LD across a complex locus including multiple functional alleles can lead to a variance-heterogeneity between genotypes in natural populations. Further, they provide novel insights into the genetic regulation of ion homeostasis in A. thaliana, and empirically confirm that variance-heterogeneity based GWA methods are a valuable tool to detect novel associations of biological importance in natural populations.

    HSV kategori
    Forskningsprogram
    Genetik
    Identifikatorer
    urn:nbn:se:uu:diva-294195 (URN)10.1371/journal.pgen.1005648 (DOI)26599497 (PubMedID)
    Tilgjengelig fra: 2016-05-18 Laget: 2016-05-18 Sist oppdatert: 2017-11-30
    3. The Shepherds' Tale: A Genome-Wide Study across 9 Dog Breeds Implicates Two Loci in the Regulation of Fructosamine Serum Concentration in Belgian Shepherds
    Åpne denne publikasjonen i ny fane eller vindu >>The Shepherds' Tale: A Genome-Wide Study across 9 Dog Breeds Implicates Two Loci in the Regulation of Fructosamine Serum Concentration in Belgian Shepherds
    Vise andre…
    2015 (engelsk)Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, nr 5, artikkel-id e0123173Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Diabetes mellitus is a serious health problem in both dogs and humans. Certain dog breeds show high prevalence of the disease, whereas other breeds are at low risk. Fructosamine and glycated haemoglobin (HbA1c) are two major biomarkers of glycaemia, where serum concentrations reflect glucose turnover over the past few weeks to months. In this study, we searched for genetic factors influencing variation in serum fructosamine concentration in healthy dogs using data from nine dog breeds. Considering all breeds together, we did not find any genome-wide significant associations to fructosamine serum concentration. However, by performing breed-specific analyses we revealed an association on chromosome 3 (rho(corrected) approximate to 1:68 x 10(-6)) in Belgian shepherd dogs of the Malinois subtype. The associated region and its close neighbourhood harbours interesting candidate genes such as LETM1 and GAPDH that are important in glucose metabolism and have previously been implicated in the aetiology of diabetes mellitus. To further explore the genetics of this breed specificity, we screened the genome for reduced heterozygosity stretches private to the Belgian shepherd breed. This revealed a region with reduced heterozygosity that shows a statistically significant interaction (rho = 0.025) with the association region on chromosome 3. This region also harbours some interesting candidate genes and regulatory regions but the exact mechanisms underlying the interaction are still unknown. Nevertheless, this finding provides a plausible explanation for breed-specific genetic effects for complex traits in dogs. Shepherd breeds are at low risk of developing diabetes mellitus. The findings in Belgian shepherds could be connected to a protective mechanism against the disease. Further insight into the regulation of glucose metabolism could improve diagnostic and therapeutic methods for diabetes mellitus.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-256241 (URN)10.1371/journal.pone.0123173 (DOI)000354544200009 ()25970163 (PubMedID)
    Tilgjengelig fra: 2015-06-24 Laget: 2015-06-22 Sist oppdatert: 2017-12-04bibliografisk kontrollert
    4. Natural CMT2 variation is associated with genome-wide methylation changes and temperature seasonality.
    Åpne denne publikasjonen i ny fane eller vindu >>Natural CMT2 variation is associated with genome-wide methylation changes and temperature seasonality.
    Vise andre…
    2014 (engelsk)Inngår i: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 10, nr 12Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    As Arabidopsis thaliana has colonized a wide range of habitats across the world it is an attractive model for studying the genetic mechanisms underlying environmental adaptation. Here, we used public data from two collections of A. thaliana accessions to associate genetic variability at individual loci with differences in climates at the sampling sites. We use a novel method to screen the genome for plastic alleles that tolerate a broader climate range than the major allele. This approach reduces confounding with population structure and increases power compared to standard genome-wide association methods. Sixteen novel loci were found, including an association between Chromomethylase 2 (CMT2) and temperature seasonality where the genome-wide CHH methylation was different for the group of accessions carrying the plastic allele. Cmt2 mutants were shown to be more tolerant to heat-stress, suggesting genetic regulation of epigenetic modifications as a likely mechanism underlying natural adaptation to variable temperatures, potentially through differential allelic plasticity to temperature-stress.

    HSV kategori
    Forskningsprogram
    Bioinformatik
    Identifikatorer
    urn:nbn:se:uu:diva-294203 (URN)10.1371/journal.pgen.1004842 (DOI)25503602 (PubMedID)
    Tilgjengelig fra: 2016-05-18 Laget: 2016-05-18 Sist oppdatert: 2017-11-30
  • 2.
    Forsberg, Simon K G
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Accounting for genetic interactions improves modeling of individual quantitative trait phenotypes in yeastManuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Experiments in model organisms report abundant genetic interactions underlying biologically important traits, whereas quantitative genetics theory predicts, and data support, that most genetic variance in populations is additive. Here we describe networks of capacitating genetic interactions that contribute to quantitative trait variation in a large yeast intercross population. The additive variance explained by individual loci in a network is highly dependent on the allele frequencies of the interacting loci. Modeling of phenotypes for multi-locus genotype classes in the epistatic networks is often improved by accounting for the interactions. We discuss the implications of these results for attempts to dissect genetic architectures and to predict individual phenotypes and long-term responses to selection.

  • 3.
    Forsberg, Simon K. G.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Bloom, Joshua S.
    Univ Calif Los Angeles, Dept Human Genet, Los Angeles, CA USA.; Univ Calif Los Angeles, Howard Hughes Med Inst, Los Angeles, CA 90024 USA.; Univ Calif Los Angeles, Dept Biol Chem, Los Angeles, CA 90024 USA..
    Sadhu, Meru J.
    Univ Calif Los Angeles, Dept Human Genet, Los Angeles, CA USA.; Univ Calif Los Angeles, Howard Hughes Med Inst, Los Angeles, CA 90024 USA.; Univ Calif Los Angeles, Dept Biol Chem, Los Angeles, CA 90024 USA..
    Kruglyak, Leonid
    Univ Calif Los Angeles, Dept Human Genet, Los Angeles, CA USA.; Univ Calif Los Angeles, Howard Hughes Med Inst, Los Angeles, CA 90024 USA.; Univ Calif Los Angeles, Dept Biol Chem, Los Angeles, CA 90024 USA..
    Carlborg, Örjan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Accounting for genetic interactions improves modeling of individual quantitative trait phenotypes in yeast2017Inngår i: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 49, nr 4, s. 497-503Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Experiments in model organisms report abundant genetic interactions underlying biologically important traits, whereas quantitative genetics theory predicts, and data support, the notion that most genetic variance in populations is additive. Here we describe networks of capacitating genetic interactions that contribute to quantitative trait variation in a large yeast intercross population. The additive variance explained by individual loci in a network is highly dependent on the allele frequencies of the interacting loci. Modeling of phenotypes for multilocus genotype classes in the epistatic networks is often improved by accounting for the interactions. We discuss the implications of these results for attempts to dissect genetic architectures and to predict individual phenotypes and long-term responses to selection.

  • 4.
    Forsberg, Simon K. G.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Carlborg, Örjan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    On the relationship between epistasis and genetic variance heterogeneity.2017Inngår i: Journal of Experimental Botany, ISSN 0022-0957, E-ISSN 1460-2431, Vol. 68, nr 20, s. 5431-5438Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Epistasis and genetic variance heterogeneity are two non-additive genetic inheritance patterns that are often, but not always, related. Here we use theoretical examples and empirical results from earlier analyses of experimental data to illustrate the connection between the two. This includes an introduction to the relationship between epistatic gene action, statistical epistasis, and genetic variance heterogeneity, and a brief discussion about how genetic processes other than epistasis can also give rise to genetic variance heterogeneity.

  • 5.
    Zan, Yanjun
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Forsberg, Simon K. G.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi. Princeton Univ, Ecol & Evolutionary Biol Dept, Lewis Sigler Inst Integrat Genom, Princeton, NJ 08540 USA.
    Carlborg, Örjan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    On the Relationship Between High-Order Linkage Disequilibrium and Epistasis2018Inngår i: G3: Genes, Genomes, Genetics, ISSN 2160-1836, E-ISSN 2160-1836, Vol. 8, nr 8, s. 2817-2824Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A plausible explanation for statistical epistasis revealed in genome wide association analyses is the presence of high order linkage disequilibrium (LD) between the genotyped markers tested for interactions and unobserved functional polymorphisms. Based on findings in experimental data, it has been suggested that high order LD might be a common explanation for statistical epistasis inferred between local polymorphisms in the same genomic region. Here, we empirically evaluate how prevalent high order LD is between local, as well as distal, polymorphisms in the genome. This could provide insights into whether we should account for this when interpreting results from genome wide scans for statistical epistasis. An extensive and strong genome wide high order LD was revealed between pairs of markers on the high density 250k SNP-chip and individual markers revealed by whole genome sequencing in the Arabidopsis thaliana 1001-genomes collection. The high order LD was found to be more prevalent in smaller populations, but present also in samples including several hundred individuals. An empirical example illustrates that high order LD might be an even greater challenge in cases when the genetic architecture is more complex than the common assumption of bi-allelic loci. The example shows how significant statistical epistasis is detected for a pair of markers in high order LD with a complex multi allelic locus. Overall, our study illustrates the importance of considering also other explanations than functional genetic interactions when genome wide statistical epistasis is detected, in particular when the results are obtained in small populations of inbred individuals.

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