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Osterman, Pia
Publications (10 of 15) Show all publications
Rentoft, M., Svensson, D., Sjödin, A., Olason, P. I., Sjöström, O., Nylander, C., . . . Johansson, E. (2019). A geographically matched control population efficiently limits the number of candidate disease-causing variants in an unbiased whole-genome analysis. PLoS ONE, 14(3), Article ID e0213350.
Open this publication in new window or tab >>A geographically matched control population efficiently limits the number of candidate disease-causing variants in an unbiased whole-genome analysis
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2019 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 14, no 3, article id e0213350Article in journal (Refereed) Published
Abstract [en]

Whole-genome sequencing is a promising approach for human autosomal dominant disease studies. However, the vast number of genetic variants observed by this method constitutes a challenge when trying to identify the causal variants. This is often handled by restricting disease studies to the most damaging variants, e.g. those found in coding regions, and overlooking the remaining genetic variation. Such a biased approach explains in part why the genetic causes of many families with dominantly inherited diseases, in spite of being included in whole-genome sequencing studies, are left unsolved today. Here we explore the use of a geographically matched control population to minimize the number of candidate disease-causing variants without excluding variants based on assumptions on genomic position or functional predictions. To exemplify the benefit of the geographically matched control population we apply a typical disease variant filtering strategy in a family with an autosomal dominant form of colorectal cancer. With the use of the geographically matched control population we end up with 26 candidate variants genome wide. This is in contrast to the tens of thousands of candidates left when only making use of available public variant datasets. The effect of the local control population is dual, it (1) reduces the total number of candidate variants shared between affected individuals, and more importantly (2) increases the rate by which the number of candidate variants are reduced as additional affected family members are included in the filtering strategy. We demonstrate that the application of a geographically matched control population effectively limits the number of candidate disease-causing variants and may provide the means by which variants suitable for functional studies are identified genome wide.

Place, publisher, year, edition, pages
Public Library of Science, 2019
National Category
Medical Genetics
Identifiers
urn:nbn:se:umu:diva-158021 (URN)10.1371/journal.pone.0213350 (DOI)000462465800028 ()30917156 (PubMedID)
Funder
Knut and Alice Wallenberg Foundation, 2011.0042
Available from: 2019-04-10 Created: 2019-04-10 Last updated: 2019-04-12Bibliographically approved
ter Beek, J., Parkash, V., Bylund, G., Osterman, P., Sauer-Eriksson, A. E. & Johansson, E. (2019). Structural evidence for an essential Fe–S cluster in the catalytic core domain of DNA polymerase ϵ. Nucleic Acids Research, 47(11), 5712-5722
Open this publication in new window or tab >>Structural evidence for an essential Fe–S cluster in the catalytic core domain of DNA polymerase ϵ
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2019 (English)In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 47, no 11, p. 5712-5722Article in journal (Refereed) Published
Abstract [en]

DNA polymerase ϵ (Pol ϵ), the major leading-strand DNA polymerase in eukaryotes, has a catalytic subunit (Pol2) and three non-catalytic subunits. The N-terminal half of Pol2 (Pol2CORE) exhibits both polymerase and exonuclease activity. It has been suggested that both the non-catalytic C-terminal domain of Pol2 (with the two cysteine motifs CysA and CysB) and Pol2CORE (with the CysX cysteine motif) are likely to coordinate an Fe–S cluster. Here, we present two new crystal structures of Pol2CORE with an Fe–S cluster bound to the CysX motif, supported by an anomalous signal at that position. Furthermore we show that purified four-subunit Pol ϵ, Pol ϵ CysAMUT (C2111S/C2133S), and Pol ϵ CysBMUT (C2167S/C2181S) all have an Fe–S cluster that is not present in Pol ϵ CysXMUT (C665S/C668S). Pol ϵ CysAMUT and Pol ϵ CysBMUT behave similarly to wild-type Pol ϵ in in vitro assays, but Pol ϵ CysXMUT has severely compromised DNA polymerase activity that is not the result of an excessive exonuclease activity. Tetrad analyses show that haploid yeast strains carrying CysXMUT are inviable. In conclusion, Pol ϵ has a single Fe–S cluster bound at the base of the P-domain, and this Fe–S cluster is essential for cell viability and polymerase activity.

Place, publisher, year, edition, pages
Oxford University Press, 2019
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-161925 (URN)10.1093/nar/gkz248 (DOI)000475702000027 ()30968138 (PubMedID)2-s2.0-85068487970 (Scopus ID)
Available from: 2019-08-06 Created: 2019-08-06 Last updated: 2019-08-06Bibliographically approved
Ganai, R. A., Osterman, P. & Johansson, E. (2015). Yeast DNA Polymerase epsilon Catalytic Core and Holoenzyme Have Comparable Catalytic Rates. Journal of Biological Chemistry, 290(6), 3825-3835
Open this publication in new window or tab >>Yeast DNA Polymerase epsilon Catalytic Core and Holoenzyme Have Comparable Catalytic Rates
2015 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 290, no 6, p. 3825-3835Article in journal (Refereed) Published
Abstract [en]

The holoenzyme of yeast DNApolymerase ε (Pol ε) consists of four subunits– Pol2, Dpb2, Dpb3, and Dpb4. A proteasesensitivesite results in a N-terminalproteolytic fragment of Pol2, called Pol2core,that consists of the catalytic core of Pol ε andretains both polymerase and exonucleaseactivities. Pre-steady-state kinetics showedthat the exonuclease rates on single-stranded,double-stranded, and mismatched DNA werecomparable between Pol ε and Pol2core. Singleturnover pre-steady-state kinetics alsoshowed that the kpol of Pol ε and Pol2core werecomparable when pre-loading the polymeraseonto the primer-template before adding Mg2+and dTTP. However, a global fit of the dataover six sequential nucleotide incorporationsrevealed that the overall polymerization rateand processivity was higher for Pol ε than forPol2core. The largest difference was observedwhen challenged for the formation of aternary complex and incorporation of thefirst nucleotide. Pol ε needed less than asecond to incorporate a nucleotide, butseveral seconds passed before Pol2coreincorporated detectable levels of the firstnucleotide. We conclude that the accessorysubunits and the C-terminus of Pol2 do notinfluence the catalytic rate of Pol ε butfacilitate the loading and incorporation of thefirst nucleotide by Pol ε.

Place, publisher, year, edition, pages
USA: , 2015
Keywords
DNA polymerase, DNA repair, DNA replication, enzyme catalysis, enzyme kinetics
National Category
Biochemistry and Molecular Biology
Research subject
Biochemistry
Identifiers
urn:nbn:se:umu:diva-97692 (URN)10.1074/jbc.M114.615278 (DOI)000349456000053 ()25538242 (PubMedID)
Available from: 2015-01-08 Created: 2015-01-05 Last updated: 2018-06-07Bibliographically approved
Hogg, M., Osterman, P., Bylund, G., Ganai, R. A., Lundström, E.-B., Sauer-Eriksson, E. & Johansson, E. (2014). Structural basis for processive DNA synthesis by yeast DNA polymerase ε. Nature Structural & Molecular Biology, 21(1), 49-56
Open this publication in new window or tab >>Structural basis for processive DNA synthesis by yeast DNA polymerase ε
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2014 (English)In: Nature Structural & Molecular Biology, ISSN 1545-9993, E-ISSN 1545-9985, Vol. 21, no 1, p. 49-56Article in journal (Refereed) Published
Abstract [en]

DNA polymerase ε (Pol ε) is a high-fidelity polymerase that has been shown to participate in leading-strand synthesis during DNA replication in eukaryotic cells. We present here a ternary structure of the catalytic core of Pol ε (142 kDa) from Saccharomyces cerevisiae in complex with DNA and an incoming nucleotide. This structure provides information about the selection of the correct nucleotide and the positions of amino acids that might be critical for proofreading activity. Pol ε has the highest fidelity among B-family polymerases despite the absence of an extended b-hairpin loop that is required for high-fidelity replication by other B-family polymerases. Moreover, the catalytic core has a new domain that allows Pol ε to encircle the nascent doublestranded DNA. Altogether, the structure provides an explanation for the high processivity and high fidelity of leading-strand DNA synthesis in eukaryotes

Place, publisher, year, edition, pages
Nature Publishing Group, 2014
National Category
Biochemistry and Molecular Biology
Research subject
Biochemistry
Identifiers
urn:nbn:se:umu:diva-97700 (URN)10.1038/nsmb.2712 (DOI)000329290700014 ()24292646 (PubMedID)
Available from: 2015-01-08 Created: 2015-01-05 Last updated: 2018-06-07Bibliographically approved
Svenson, U., Nordfjäll, K., Baird, D., Roger, L., Osterman, P., Hellenius, M.-L. & Roos, G. (2011). Blood cell telomere length is a dynamic feature. PLoS ONE, 6(6), e21485
Open this publication in new window or tab >>Blood cell telomere length is a dynamic feature
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2011 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 6, p. e21485-Article in journal (Refereed) Published
Abstract [en]

There is a considerable heterogeneity in blood cell telomere length (TL) for individuals of similar age and recent studies have revealed that TL changes by time are dependent on TL at baseline. TL is partly inherited, but results from several studies indicate that e.g. life style and/or environmental factors can affect TL during life. Collectively, these studies imply that blood cell TL might fluctuate during a life time and that the actual TL at a defined time point is the result of potential regulatory mechanism(s) and environmental factors. We analyzed relative TL (RTL) in subsequent blood samples taken six months apart from 50 individuals and found significant associations between RTL changes and RTL at baseline. Individual RTL changes per month were more pronounced than the changes recorded in a previously studied population analyzed after 10 years' follow up. The data argues for an oscillating TL pattern which levels out at longer follow up times. In a separate group of five blood donors, a marked telomere loss was demonstrated within a six month period for one donor where after TL was stabilized. PCR determined RTL changes were verified by Southern blotting and STELA (single telomere elongation length analysis). The STELA demonstrated that for the donor with a marked telomere loss, the heterogeneity of the telomere distribution decreased considerably, with a noteworthy loss of the largest telomeres. In summary, the collected data support the concept that individual blood cell telomere length is a dynamic feature and this will be important to recognize in future studies of human telomere biology.

Place, publisher, year, edition, pages
San Francisco: Public Library of Science, 2011
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:umu:diva-57221 (URN)10.1371/journal.pone.0021485 (DOI)21720548 (PubMedID)
Available from: 2012-07-10 Created: 2012-07-10 Last updated: 2018-06-08Bibliographically approved
Ekblom, K., Marklund, S. L., Jansson, J.-H., Osterman, P., Hallmans, G., Weinehall, L. & Hultdin, J. (2011). Response to letter regarding article "Plasma bilirubin and UGT1A1*28 are not protective factors against first-time myocardial infarction in a prospective nested case-referent setting". Circulation: Cardiovascular Genetics, 4(1), e2
Open this publication in new window or tab >>Response to letter regarding article "Plasma bilirubin and UGT1A1*28 are not protective factors against first-time myocardial infarction in a prospective nested case-referent setting"
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2011 (English)In: Circulation: Cardiovascular Genetics, ISSN 1942-325X, E-ISSN 1942-3268, Vol. 4, no 1, p. e2-Article in journal (Refereed) Published
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-41157 (URN)10.1161/CIRCGENETICS.110.958603 (DOI)21325153 (PubMedID)
Available from: 2011-03-18 Created: 2011-03-18 Last updated: 2018-06-08Bibliographically approved
Ekblom, K., Marklund, S. L., Johansson, L., Osterman, P., Hallmans, G., Weinehall, L., . . . Hultdin, J. (2010). Bilirubin and UGT1A1*28 are not associated with lower risk for ischemic stroke in a prospective nested case-referent setting.. Cerebrovascular Diseases, 30(6), 590-596
Open this publication in new window or tab >>Bilirubin and UGT1A1*28 are not associated with lower risk for ischemic stroke in a prospective nested case-referent setting.
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2010 (English)In: Cerebrovascular Diseases, ISSN 1015-9770, E-ISSN 1421-9786, Vol. 30, no 6, p. 590-596Article in journal (Refereed) Published
Abstract [en]

Background: Bilirubin, an antioxidant, has been associated with reduced cardiovascular disease risk. A major cause of elevated plasma bilirubin is the common UGT1A1*28 promoter polymorphism in the gene of the bilirubin-conjugating enzyme UDP-glucuronosyltransferase 1A1, which reduces transcription by 70%. Earlier studies reporting a protective effect of bilirubin on stroke have not included analysis of UGT1A1*28. The purpose of this study is to investigate if bilirubin and UGT1A1*28 are protective against ischemic stroke in a prospective case-referent setting. Methods: Cases with first-ever ischemic stroke (n = 231; median lag time 4.9 years) and 462 matched referents from the Northern Sweden Health and Disease Study Cohort were included. Plasma bilirubin was measured and UGT1A1*28 was analyzed by fragment analysis. Results: Plasma bilirubin was lower in cases than in referents, but the difference reached significance only for women. The UGT1A1*28 polymorphism (allele frequency 30%) showed a strong gene-dose relationship with bilirubin levels both among cases and referents, but was not associated with risk for stroke. Among multiple other variables analyzed, the strongest correlation with bilirubin was found for plasma iron. Conclusions: There was no evidence for a protective effect of the UGT1A1*28 polymorphism against stroke and consequently neither for bilirubin. The findings suggest that other factors influencing the risk for stroke might also affect bilirubin levels.

Place, publisher, year, edition, pages
Karger, 2010
Keywords
Acute ischemic stroke, epidemiology, Risk factor, Bilirubin, UGT1A1*28 polymorphism
National Category
Medical and Health Sciences
Research subject
Medicine
Identifiers
urn:nbn:se:umu:diva-39369 (URN)10.1159/000319778 (DOI)000284642400008 ()20948202 (PubMedID)
Available from: 2011-01-25 Created: 2011-01-25 Last updated: 2018-06-08Bibliographically approved
Ekblom, K., Marklund, S. L., Jansson, J.-H., Osterman, P., Hallmans, G., Weinehall, L. & Hultdin, J. (2010). Plasma Bilirubin and UGT1A1*28 Are Not Protective Factors Against First-Time Myocardial Infarction in a Prospective, Nested Case–Referent Setting. Circulation: Cardiovascular Genetics (3), 340-347
Open this publication in new window or tab >>Plasma Bilirubin and UGT1A1*28 Are Not Protective Factors Against First-Time Myocardial Infarction in a Prospective, Nested Case–Referent Setting
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2010 (English)In: Circulation: Cardiovascular Genetics, ISSN 1942-325X, E-ISSN 1942-3268, no 3, p. 340-347Article in journal (Refereed) Published
Abstract [en]

Background: Bilirubin, an effective antioxidant, shows a large variation in levels between individuals and has been positively associated with reduced cardiovascular disease risk. A major reason for the variability is a common promoter polymorphism, UGT1A1*28, which reduces the transcription of the enzyme that conjugates bilirubin, UDP-glucuronosyltransferase 1A1. The aim of the study was to evaluate a possible protective effect of plasma bilirubin and the UGT1A1*28 polymorphism against myocardial infarction in a prospective case-referent setting.

Methods and Results: 618 subjects with a first-ever myocardial infarction (median event age 60.5 years, median lag time 3.5 years) and 1184 matched referents were studied. Plasma bilirubin was lower in cases vs. referents. Despite a strong gene-dosage effect on bilirubin levels in both cases and referents, the UGT1A1*28 polymorphism did not influence the risk of myocardial infarction. Among multiple other variables, serum iron showed one of the strongest associations with bilirubin levels.

Conclusion: We found no evidence for a protective effect of the UGT1A1*28 polymorphism against myocardial infarction and consequently neither for bilirubin. The lower bilirubin levels in cases might be caused by decreased production, increased degradation or increased elimination.

Place, publisher, year, edition, pages
Philadelphia, PA: Lippincott Williams & Wilkins, 2010
Keywords
bilirubin, myocardial infarction, risk factors, epidemiology
National Category
Public Health, Global Health, Social Medicine and Epidemiology Cardiac and Cardiovascular Systems
Research subject
Clinical Chemistry
Identifiers
urn:nbn:se:umu:diva-33747 (URN)10.1161/CIRCGENETICS.109.861773 (DOI)000281006600006 ()20562445 (PubMedID)
Available from: 2010-05-05 Created: 2010-05-05 Last updated: 2018-12-04Bibliographically approved
Degerman, S., Siwicki, J. K., Osterman, P., Lafferty-Whyte, K., Keith, W. N. & Roos, G. (2010). Telomerase upregulation is a postcrisis event during senescence bypass and immortalization of two Nijmegen breakage syndrome T cell cultures. Aging Cell, 9, 220-235
Open this publication in new window or tab >>Telomerase upregulation is a postcrisis event during senescence bypass and immortalization of two Nijmegen breakage syndrome T cell cultures
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2010 (English)In: Aging Cell, ISSN 1474-9718, E-ISSN 1474-9726, Vol. 9, p. 220-235Article in journal (Refereed) Published
Abstract [en]

Summary Our knowledge on immortalization and telomere biology is mainly based on genetically manipulated cells analyzed before and many population doublings post growth crisis. The general view is that growth crisis is telomere length (TL) dependent and that escape from crisis is coupled to increased expression of the telomerase reverse transcriptase (hTERT) gene, telomerase activity upregulation and TL stabilization. Here we have analyzed the process of spontaneous immortalization of human T cells, regarding pathways involved in senescence and telomerase regulation. Two Nijmegen breakage syndrome (NBS) T cell cultures (S3R and S4) showed gradual telomere attrition until a period of growth crisis followed by the outgrowth of immortalized cells. Whole genome expression analysis indicated differences between pre-, early post- and late postcrisis cells. Early postcrisis cells demonstrated a logarithmic growth curve, very short telomeres and, notably, no increase in hTERT or telomerase activity despite downregulation of several negative hTERT regulators (e.g. FOS, JUN D, SMAD3, RUNX2, TNF-alpha and TGFbeta-R2). Thereafter, cMYC mRNA increased in parallel with increased hTERT expression, telomerase activity and elongation of short telomeres, indicating a step-wise activation of hTERT transcription involving reduction of negative regulators followed by activation of positive regulator(s). Gene expression analysis indicated that cells escaped growth crisis by deregulated DNA damage response and senescence controlling genes, including downregulation of ATM, CDKN1B (p27), CDKN2D (p19) and ASF1A and upregulation of CDK4, TWIST1, TP73L (p63) and SYK. Telomerase upregulation was thus found to be uncoupled to escape of growth crisis but rather a later event in the immortalization process of NBS T cell cultures.

Place, publisher, year, edition, pages
John Wiley & Sons, 2010
Keywords
hTERT, immortalization, senescence, T cell, telomerase, telomere
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-33450 (URN)10.1111/j.1474-9726.2010.00550.x (DOI)000275677000010 ()20089118 (PubMedID)
Available from: 2010-04-26 Created: 2010-04-26 Last updated: 2018-06-08Bibliographically approved
Roos, G. & Osterman, P. (2010). [The Nobel Prize on the protective function of telomeres can be very useful clinically. Several research targets ahead: not only new cancer therapies]. Läkartidningen, 107(4), 190-193
Open this publication in new window or tab >>[The Nobel Prize on the protective function of telomeres can be very useful clinically. Several research targets ahead: not only new cancer therapies]
2010 (English)In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 107, no 4, p. 190-193Article in journal (Refereed) Published
Keywords
Nobelpris, Telomer, Telomeras, 1900-talshistoria, Biomedicinsk forskning, Tumörer
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-39266 (URN)20333974 (PubMedID)
Available from: 2011-01-19 Created: 2011-01-19 Last updated: 2018-06-08Bibliographically approved
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