uu.seUppsala University Publications
Change search
Link to record
Permanent link

Direct link
BETA
Lindblad-Toh, KerstinORCID iD iconorcid.org/0000-0001-8338-0253
Alternative names
Publications (10 of 152) Show all publications
Chen, J., Swofford, R., Johnson, J., Cummings, B. B., Rogel, N., Lindblad-Toh, K., . . . Regev, A. (2019). A quantitative framework for characterizing the evolutionary history of mammalian gene expression. Genome Research, 29(1), 53-63
Open this publication in new window or tab >>A quantitative framework for characterizing the evolutionary history of mammalian gene expression
Show others...
2019 (English)In: Genome Research, ISSN 1088-9051, E-ISSN 1549-5469, Vol. 29, no 1, p. 53-63Article in journal (Refereed) Published
Abstract [en]

The evolutionary history of a gene helps predict its function and relationship to phenotypic traits. Although sequence conservation is commonly used to decipher gene function and assess medical relevance, methods for functional inference from comparative expression data are lacking. Here, we use RNA-seq across seven tissues from 17 mammalian species to show that expression evolution across mammals is accurately modeled by the Ornstein-Uhlenbeck process, a commonly proposed model of continuous trait evolution. We apply this model to identify expression pathways under neutral, stabilizing, and directional selection. We further demonstrate novel applications of this model to quantify the extent of stabilizing selection on a gene's expression, parameterize the distribution of each gene's optimal expression level, and detect deleterious expression levels in expression data from individual patients. Our work provides a statistical framework for interpreting expression data across species and in disease.

National Category
Genetics
Identifiers
urn:nbn:se:uu:diva-374111 (URN)10.1101/gr.237636.118 (DOI)000454707900005 ()30552105 (PubMedID)
Funder
Swedish Research Council
Available from: 2019-01-23 Created: 2019-01-23 Last updated: 2019-01-23Bibliographically approved
Farias, F. H. G., Dahlqvist, J., Kozyrev, S. V., Leonard, D., Wilbe, M., Abramov, S., . . . Lindblad-Toh, K. (2019). A rare regulatory variant in the MEF2D gene affects gene regulation and splicing and is associated with a SLE sub-phenotype in Swedish cohorts. European Journal of Human Genetics, 27, 432-441
Open this publication in new window or tab >>A rare regulatory variant in the MEF2D gene affects gene regulation and splicing and is associated with a SLE sub-phenotype in Swedish cohorts
Show others...
2019 (English)In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 27, p. 432-441Article in journal (Refereed) Published
Abstract [en]

Systemic lupus erythematosus (SLE) is an autoimmune disorder with heterogeneous clinical presentation and complex etiology involving the interplay between genetic, epigenetic, environmental and hormonal factors. Many common SNPs identified by genome wide-association studies (GWAS) explain only a small part of the disease heritability suggesting the contribution from rare genetic variants, undetectable in GWAS, and complex epistatic interactions. Using targeted re-sequencing of coding and conserved regulatory regions within and around 215 candidate genes selected on the basis of their known role in autoimmunity and genes associated with canine immune-mediated diseases, we identified a rare regulatory variant rs200395694:G > T located in intron 4 of the MEF2D gene encoding the myocyte-specific enhancer factor 2D transcription factor and associated with SLE in Swedish cohorts (504 SLE patients and 839 healthy controls, p = 0.014, CI = 1.1-10). Fisher's exact test revealed an association between the genetic variant and a triad of disease manifestations including Raynaud, anti-U1-ribonucleoprotein (anti-RNP), and anti-Smith (anti-Sm) antibodies (p = 0.00037) among the patients. The DNA-binding activity of the allele was further studied by EMSA, reporter assays, and minigenes. The region has properties of an active cell-specific enhancer, differentially affected by the alleles of rs200395694:G > T. In addition, the risk allele exerts an inhibitory effect on the splicing of the alternative tissue-specific isoform, and thus may modify the target gene set regulated by this isoform. These findings emphasize the potential of dissecting traits of complex diseases and correlating them with rare risk alleles with strong biological effects.

National Category
Medical Genetics
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-368313 (URN)10.1038/s41431-018-0297-x (DOI)000458626500013 ()30459414 (PubMedID)
Funder
Swedish Research CouncilSwedish Research Council FormasSwedish Rheumatism AssociationKnut and Alice Wallenberg Foundation
Note

These authors contributed equally: Johanna Dahlqvist, Sergey V. Kozyrev, Dag Leonard, Maria Wilbe

Available from: 2018-12-04 Created: 2018-12-04 Last updated: 2019-03-11Bibliographically approved
Biasoli, D., Compston-Garnett, L., Ricketts, S. L., Birand, Z., Courtay-Cahen, C., Fineberg, E., . . . Starkey, M. (2019). A synonymous germline variant in a gene encoding a cell adhesion molecule is associated with cutaneous mast cell tumour development in Labrador and Golden Retrievers. PLoS Genetics, 15(3), Article ID e1007967.
Open this publication in new window or tab >>A synonymous germline variant in a gene encoding a cell adhesion molecule is associated with cutaneous mast cell tumour development in Labrador and Golden Retrievers
Show others...
2019 (English)In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 15, no 3, article id e1007967Article in journal (Refereed) Published
Abstract [en]

Mast cell tumours are the most common type of skin cancer in dogs, representing a significant concern in canine health. The molecular pathogenesis is largely unknown, but breed-predisposition for mast cell tumour development suggests the involvement of inherited genetic risk factors in some breeds. In this study, we aimed to identify germline risk factors associated with the development of mast cell tumours in Labrador Retrievers, a breed with an elevated risk of mast cell tumour development. Using a methodological approach that combined a genome-wide association study, targeted next generation sequencing, and TaqMan genotyping, we identified a synonymous variant in the DSCAM gene on canine chromosome 31 that is associated with mast cell tumours in Labrador Retrievers. DSCAM encodes a cell-adhesion molecule. We showed that the variant has no effect on the DSCAM mRNA level but is associated with a significant reduction in the level of the DSCAM protein, suggesting that the variant affects the dynamics of DSCAM mRNA translation. Furthermore, we showed that the variant is also associated with mast cell tumours in Golden Retrievers, a breed that is closely related to Labrador Retrievers and that also has a predilection for mast cell tumour development. The variant is common in both Labradors and Golden Retrievers and consequently is likely to be a significant genetic contributor to the increased susceptibility of both breeds to develop mast cell tumours. The results presented here not only represent an important contribution to the understanding of mast cell tumour development in dogs, as they highlight the role of cell adhesion in mast cell tumour tumourigenesis, but they also emphasise the potential importance of the effects of synonymous variants in complex diseases such as cancer. Author summary The combination of various genetic and environmental risk factors makes the understanding of the molecular circuitry behind complex diseases, like cancer, a major challenge. The homogeneous nature of pedigree dog breed genomes makes these dogs ideal for the identification of both simple disease-causing genetic variants and genetic risk factors for complex diseases. Mast cell tumours are the most common type of canine skin cancer, and one of the most common cancers affecting dogs of most breeds. Several breeds, including Labrador Retrievers (which represent one of the most popular dog breeds), have an elevated risk of mast cell tumour development. Here, by using a methodological approach that combined different techniques, we identified a common inherited synonymous variant, that predisposes Labrador Retrievers to mast cell tumour development. Interestingly, we showed that this variant, despite its synonymous nature, appears to have an effect on translation dynamics as it is associated with reduced levels of DSCAM, a cell adhesion molecule. The results presented here reveal dysregulation of cell adhesion to be an important factor in mast cell tumour pathogenesis, and also highlight the important role that synonymous variants can play in complex diseases.

Place, publisher, year, edition, pages
PUBLIC LIBRARY SCIENCE, 2019
National Category
Immunology
Identifiers
urn:nbn:se:uu:diva-382472 (URN)10.1371/journal.pgen.1007967 (DOI)000462994900012 ()30901340 (PubMedID)
Available from: 2019-05-02 Created: 2019-05-02 Last updated: 2019-05-02Bibliographically approved
Megquier, K., Genereux, D. P., Hekman, J., Swofford, R., Turner-Maier, J., Johnson, J., . . . Karlsson, E. K. (2019). BarkBase: Epigenomic Annotation of Canine Genomes. Genes, 10(6), Article ID 433.
Open this publication in new window or tab >>BarkBase: Epigenomic Annotation of Canine Genomes
Show others...
2019 (English)In: Genes, ISSN 2073-4425, E-ISSN 2073-4425, Vol. 10, no 6, article id 433Article in journal (Refereed) Published
Abstract [en]

Dogs are an unparalleled natural model for investigating the genetics of health and disease, particularly for complex diseases like cancer. Comprehensive genomic annotation of regulatory elements active in healthy canine tissues is crucial both for identifying candidate causal variants and for designing functional studies needed to translate genetic associations into disease insight. Currently, canine geneticists rely primarily on annotations of the human or mouse genome that have been remapped to dog, an approach that misses dog-specific features. Here, we describe BarkBase, a canine epigenomic resource available at barkbase.org. BarkBase hosts data for 27 adult tissue types, with biological replicates, and for one sample of up to five tissues sampled at each of four carefully staged embryonic time points. RNA sequencing is complemented with whole genome sequencing and with assay for transposase-accessible chromatin using sequencing (ATAC-seq), which identifies open chromatin regions. By including replicates, we can more confidently discern tissue-specific transcripts and assess differential gene expression between tissues and timepoints. By offering data in easy-to-use file formats, through a visual browser modeled on similar genomic resources for human, BarkBase introduces a powerful new resource to support comparative studies in dogs and humans.

Place, publisher, year, edition, pages
MDPI, 2019
Keywords
dog, expression, genome, annotation, ATAC-seq, RNA-seq, epigenomic, canine, comparative
National Category
Genetics
Identifiers
urn:nbn:se:uu:diva-390646 (URN)10.3390/genes10060433 (DOI)000473797000028 ()31181663 (PubMedID)
Funder
NIH (National Institute of Health), 5R24OD018250
Available from: 2019-08-19 Created: 2019-08-19 Last updated: 2019-08-19Bibliographically approved
Hitte, C., Le Beguec, C., Cadieu, E., Wucher, V., Primot, A., Prouteau, P., . . . Derrien, T. (2019). Genome-Wide Analysis of Long Non-Coding RNA Profiles in Canine Oral Melanomas. Genes, 10(6), Article ID 477.
Open this publication in new window or tab >>Genome-Wide Analysis of Long Non-Coding RNA Profiles in Canine Oral Melanomas
Show others...
2019 (English)In: Genes, ISSN 2073-4425, E-ISSN 2073-4425, Vol. 10, no 6, article id 477Article in journal (Refereed) Published
Abstract [en]

Mucosal melanomas (MM) are rare aggressive cancers in humans, and one of the most common forms of oral cancers in dogs. Similar biological and histological features are shared between MM in both species, making dogs a powerful model for comparative oncology studies of melanomas. Although exome sequencing recently identified recurrent coding mutations in canine MM, little is known about changes in non-coding gene expression, and more particularly, in canine long non-coding RNAs (lncRNAs), which are commonly dysregulated in human cancers. Here, we sampled a large cohort (n = 52) of canine normal/tumor oral MM from three predisposed breeds (poodles, Labrador retrievers, and golden retrievers), and used deep transcriptome sequencing to identify more than 400 differentially expressed (DE) lncRNAs. We further prioritized candidate lncRNAs by comparative genomic analysis to pinpoint 26 dog-human conserved DE lncRNAs, including SOX21-AS, ZEB2-AS, and CASC15 lncRNAs. Using unsupervised co-expression network analysis with coding genes, we inferred the potential functions of the DE lncRNAs, suggesting associations with cancer-related genes, cell cycle, and carbohydrate metabolism Gene Ontology (GO) terms. Finally, we exploited our multi-breed design to identify DE lncRNAs within breeds. This study provides a unique transcriptomic resource for studying oral melanoma in dogs, and highlights lncRNAs that may potentially be diagnostic or therapeutic targets for human and veterinary medicine.

Place, publisher, year, edition, pages
MDPI, 2019
Keywords
mucosal melanoma, dogs, transcriptome sequencing, long non-coding RNAs (lncRNAs)
National Category
Genetics
Identifiers
urn:nbn:se:uu:diva-390645 (URN)10.3390/genes10060477 (DOI)000473797000072 ()31234577 (PubMedID)
Available from: 2019-08-19 Created: 2019-08-19 Last updated: 2019-08-19Bibliographically approved
Hindle, A. G., Allen, K. N., Batten, A. J., Huckastadt, L. A., Turner-Maier, J., Schulberg, S. A., . . . Buys, E. S. (2019). Low guanylyl cyclase activity in Weddell seals: implications for peripheral vasoconstriction and perfusion of the brain during diving. American Journal of Physiology. Regulatory Integrative and Comparative Physiology, 316(6), R704-R715
Open this publication in new window or tab >>Low guanylyl cyclase activity in Weddell seals: implications for peripheral vasoconstriction and perfusion of the brain during diving
Show others...
2019 (English)In: American Journal of Physiology. Regulatory Integrative and Comparative Physiology, ISSN 0363-6119, E-ISSN 1522-1490, Vol. 316, no 6, p. R704-R715Article in journal (Refereed) Published
Abstract [en]

Nitric oxide (NO) is a potent vasodilator, which improves perfusion and oxygen delivery during tissue hypoxia in terrestrial animals. The vertebrate dive response involves vasoconstriction in select tissues. which persists despite profound hypoxia. Using tissues collected from Weddell seals at necropsy, we investigated whether vasoconstriction is aided by downregulation of local hypoxia signaling mechanisms. We focused on NO-soluble guanylyl cyclasc (GC)-cGMP signaling, a well-known vasodilatory transduction pathway. Seals have a lower GC protein abundance. activity, and capacity to respond to NO stimulation than do terrestrial mammals. In seal lung homogenates, GC produced less cGMP (20.1 +/- 3.7 pmol.mg protein(-1).min(-1)) than the lungs of dogs (-80 +/- 144 pmol.mg protein(-1).min(-1) less than seals), sheep (-472 +/- 96), rats (-664 +/- 104) or mice ( -1,160 +/- 104, P < 0.0001). Amino acid sequences of the GC enzyme alpha-subunits differed between seals and terrestrial mammals, potentially affecting their structure and function. Vasoconstriction in diving Weddell seals is not consistent across tissues; perfusion is maintained in the brain and heart but decreased in other organs such as the kidney. A NO donor increased median GC activity 49.5-fold in the seal brain but only 27.4-fold in the kidney. consistent with the priority of cerebral perfusion during diving. Nos3 expression was high in the seal brain, which could improve NO production and vasodilatory potential. Conversely, Pde5a expression was high in the seal renal artery, which may increase cGMP breakdown and vasoconstriction in the kidney. Taken together, the results of this study suggest that alterations in the NO-cGMP pathway facilitate the diving response.

Place, publisher, year, edition, pages
AMER PHYSIOLOGICAL SOC, 2019
Keywords
dive response, NO-cGMP signaling, pinniped, soluble guanylate cyclase
National Category
Physiology
Identifiers
urn:nbn:se:uu:diva-386431 (URN)10.1152/ajpregu.00283.2018 (DOI)000469020400002 ()30892912 (PubMedID)
Available from: 2019-06-26 Created: 2019-06-26 Last updated: 2019-06-26Bibliographically approved
Palkopoulou, E., Lipson, M., Mallick, S., Nielsen, S., Rohland, N., Baleka, S., . . . Reich, D. (2018). A comprehensive genomic history of extinct and living elephants. Proceedings of the National Academy of Sciences of the United States of America, 115(11), E2566-E2574
Open this publication in new window or tab >>A comprehensive genomic history of extinct and living elephants
Show others...
2018 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 115, no 11, p. E2566-E2574Article in journal (Refereed) Published
Abstract [en]

Elephantids are the world's most iconic megafaunal family, yet there is no comprehensive genomic assessment of their relationships. We report a total of 14 genomes, including 2 from the American mastodon, which is an extinct elephantid relative, and 12 spanning all three extant and three extinct elephantid species including an similar to 120,000-y-old straight-tusked elephant, a Columbian mammoth, and woolly mammoths. Earlier genetic studies modeled elephantid evolution via simple bifurcating trees, but here we show that interspecies hybridization has been a recurrent feature of elephantid evolution. We found that the genetic makeup of the straight-tusked elephant, previously placed as a sister group to African forest elephants based on lower coverage data, in fact comprises three major components. Most of the straight-tusked elephant's ancestry derives from a lineage related to the ancestor of African elephants while its remaining ancestry consists of a large contribution from a lineage related to forest elephants and another related to mammoths. Columbian and woolly mammoths also showed evidence of interbreeding, likely following a latitudinal cline across North America. While hybridization events have shaped elephantid history in profound ways, isolation also appears to have played an important role. Our data reveal nearly complete isolation between the ancestors of the African forest and savanna elephants for similar to 500,000 y, providing compelling justification for the conservation of forest and savanna elephants as separate species.

Place, publisher, year, edition, pages
NATL ACAD SCIENCES, 2018
Keywords
paleogenomics, elephantid evolution, mammoth, admixture, species divergence
National Category
Evolutionary Biology
Identifiers
urn:nbn:se:uu:diva-350613 (URN)10.1073/pnas.1720554115 (DOI)000427245400014 ()29483247 (PubMedID)
Available from: 2018-05-23 Created: 2018-05-23 Last updated: 2018-05-23Bibliographically approved
Eriksson, D., Bianchi, M., Landegren, N., Dalin, F., Skov, J., Hultin-Rosenberg, L., . . . Kampe, O. (2018). Common genetic variation in the autoimmune regulator (AIRE) locus is associated with autoimmune Addison's disease in Sweden. Scientific Reports, 8, Article ID 8395.
Open this publication in new window or tab >>Common genetic variation in the autoimmune regulator (AIRE) locus is associated with autoimmune Addison's disease in Sweden
Show others...
2018 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 8395Article in journal (Refereed) Published
Abstract [en]

Autoimmune Addison's disease (AAD) is the predominating cause of primary adrenal failure. Despite its high heritability, the rarity of disease has long made candidate-gene studies the only feasible methodology for genetic studies. Here we conducted a comprehensive reinvestigation of suggested AAD risk loci and more than 1800 candidate genes with associated regulatory elements in 479 patients with AAD and 2394 controls. Our analysis enabled us to replicate many risk variants, but several other previously suggested risk variants failed confirmation. By exploring the full set of 1800 candidate genes, we further identified common variation in the autoimmune regulator (AIRE) as a novel risk locus associated to sporadic AAD in our study. Our findings not only confirm that multiple loci are associated with disease risk, but also show to what extent the multiple risk loci jointly associate to AAD. In total, risk loci discovered to date only explain about 7% of variance in liability to AAD in our study population.

National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-357556 (URN)10.1038/s41598-018-26842-2 (DOI)000433538800022 ()29849176 (PubMedID)
Funder
Swedish Research CouncilEU, FP7, Seventh Framework Programme, 201167Swedish Research Council FormasKnut and Alice Wallenberg FoundationRagnar Söderbergs stiftelseTorsten Söderbergs stiftelseNovo NordiskMarianne and Marcus Wallenberg FoundationTore Nilsons Stiftelse för medicinsk forskningÅke Wiberg FoundationSwedish Rheumatism AssociationSwedish Society of Medicine
Available from: 2018-08-20 Created: 2018-08-20 Last updated: 2018-08-20Bibliographically approved
Eriksson, D., Dalin, F., Eriksson, G. N., Landegren, N., Bianchi, M., Hallgren, Å., . . . Kämpe, O. (2018). Cytokine Autoantibody Screening in the Swedish Addison Registry Identifies Patients With Undiagnosed APS1. Journal of Clinical Endocrinology and Metabolism, 103(1), 179-186
Open this publication in new window or tab >>Cytokine Autoantibody Screening in the Swedish Addison Registry Identifies Patients With Undiagnosed APS1
Show others...
2018 (English)In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 103, no 1, p. 179-186Article in journal (Refereed) Published
Abstract [en]

Context: Autoimmune polyendocrine syndrome type 1 (APS1) is a monogenic disorder that features autoimmune Addison disease as a major component. Although APS1 accounts for only a small fraction of all patients with Addison disease, early identification of these individuals is vital to prevent the potentially lethal complications of APS1.

Objective: To determine whether available serological and genetic markers are valuable screening tools for the identification of APS1 among patients diagnosed with Addison disease.

Design: We systematically screened 677 patients with Addison disease enrolled in the Swedish Addison Registry for autoantibodies against interleukin-22 and interferon-α4. Autoantibody-positive patients were investigated for clinical manifestations of APS1, additional APS1-specific autoantibodies, and DNA sequence and copy number variations of AIRE.

Results: In total, 17 patients (2.5%) displayed autoantibodies against interleukin-22 and/or interferon-α4, of which nine were known APS1 cases. Four patients previously undiagnosed with APS1 fulfilled clinical, genetic, and serological criteria. Hence, we identified four patients with undiagnosed APS1 with this screening procedure.

Conclusion: We propose that patients with Addison disease should be routinely screened for cytokine autoantibodies. Clinical or serological support for APS1 should warrant DNA sequencing and copy number analysis of AIRE to enable early diagnosis and prevention of lethal complications.

National Category
Endocrinology and Diabetes Immunology in the medical area Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:uu:diva-343355 (URN)10.1210/jc.2017-01957 (DOI)000424934300021 ()29069385 (PubMedID)
Funder
Swedish Research CouncilRagnar Söderbergs stiftelseTorsten Söderbergs stiftelseEU, FP7, Seventh Framework Programme, 201167Stockholm County CouncilSwedish Society for Medical Research (SSMF)Swedish Society of MedicineNovo NordiskÅke Wiberg Foundation
Available from: 2018-02-26 Created: 2018-02-26 Last updated: 2018-04-24Bibliographically approved
Thorlacius, G. E., Hultin-Rosenberg, L., Sandling, J. K., Imgenberg-Kreuz, J., Theander, E., Kvarnstrom, M., . . . Nordmark, G. (2018). Genetic basis and clinical evidence for two variants of primary Sjögren's syndrome with distinct outcomes. Clinical and Experimental Rheumatology, 36(3), S246-S247
Open this publication in new window or tab >>Genetic basis and clinical evidence for two variants of primary Sjögren's syndrome with distinct outcomes
Show others...
2018 (English)In: Clinical and Experimental Rheumatology, ISSN 0392-856X, E-ISSN 1593-098X, Vol. 36, no 3, p. S246-S247Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
CLINICAL & EXPER RHEUMATOLOGY, 2018
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:uu:diva-369087 (URN)000446486100047 ()
Available from: 2018-12-11 Created: 2018-12-11 Last updated: 2018-12-11Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0001-8338-0253

Search in DiVA

Show all publications