Population genomics of the Viking world.

The maritime expansion of Scandinavian populations during the Viking Age (about AD 750-1050) was a far-flung transformation in world history1,2. Here we sequenced the genomes of 442 humans from archaeological sites across Europe and Greenland (to a median depth of about 1×) to understand the global influence of this expansion. We find the Viking period involved gene flow into Scandinavia from the south and east. We observe genetic structure within Scandinavia, with diversity hotspots in the south and restricted gene flow within Scandinavia. We find evidence for a major influx of Danish ancestry into England; a Swedish influx into the Baltic; and Norwegian influx into Ireland, Iceland and Greenland. Additionally, we see substantial ancestry from elsewhere in Europe entering Scandinavia during the Viking Age. Our ancient DNA analysis also revealed that a Viking expedition included close family members. By comparing with modern populations, we find that pigmentation-associated loci have undergone strong population differentiation during the past millennium, and trace positively selected loci-including the lactase-persistence allele of LCT and alleles of ANKA that are associated with the immune response-in detail. We conclude that the Viking diaspora was characterized by substantial transregional engagement: distinct populations influenced the genomic makeup of different regions of Europe, and Scandinavia experienced increased contact with the rest of the continent

Performance of simultaneous emission-transmission systems for attenuation-corrected SPEct: a method for validation applied to two camera systems

Several commercially available systems for attenuation correction in single photon emission computed tomography (SPECT) based on a transmission scan have been introduced that vary in performance. A test procedure for attenuation correction in SPECT is described and applied to two principally different gamma camera systems (the Siemens Multispect 3 triple-headed system [3HS] and the ADAC Genesys Vertex double-headed system [2HS]). The test procedure was based on geometrically well-defined phantoms. A torso phantom was used to illustrate the attenuation correction methods. The test procedure can be used without detailed knowledge of or access to the algorithms used for attenuation correction. The influence on the transmission measurement of radioactivity in a phantom was higher for the 2HS than for the 3HS. The 3HS produced satisfactory attenuation maps and corrected emission count rates to a constant value independent of phantom density and size. With the 2HS, there was a progressive decrease in the correction of emission count rates with increasing phantom density, and about 30% lower corrected count rates in the large compared with the small phantom. A decrease in measured attenuation coefficients in the vicinity of an emission source was demonstrated in large but not small phantoms. A likely explanation is erroneous correction of downscatter into the transmission energy window. This study demonstrates the need for independent evaluation of systems for attenuation correction in SPECT

Kinetics of lung clearance of 99mTc-DTPA in smoking patients with sarcoidosis compared to healthy smokers.

Investigation of lung clearance of 99mTc-labelled diethylene triamine penta-acetic acid (DTPA) in smoking sarcoid patients has been impeded by difficulties to differ between pathology of clearance kinetics caused by sarcoidosis and by smoking. This study explores the kinetics of lung clearance of 99mTc-DTPA in 15 current smokers with intrathoracic sarcoidosis. The results are compared with findings from 16 healthy smokers. Measurements of lung clearance over 180 min, i.e. longer than usual, revealed in II of the sarcoid patients a bi-exponential lung clearance course, which is pathologic. All healthy smokers also showed a bi-exponential lung clearance. In the analysis of the bi-exponential curve an initial fast, and a slow clearance component could be separated. The smokers with sarcoidosis had a significantly higher elimination rate of the slow component than the healthy smokers. Thus, analysis of the late part of the lung clearance curve may be rewarding in smoking sarcoid patients. The study shows that lung clearance of 99mTc-DTPA may be a method useful also in smoking patients with sarcoidosis

234th ENMC International Workshop: Chaperone dysfunction in muscle disease Naarden, The Netherlands, 8\u201310 December 2017

No Abstract Availabl

Digenic inheritance involving a muscle-specific protein kinase and the giant titin protein causes a skeletal muscle myopathy.

Acknowledgements: We acknowledge H. Luque, L. Phillips, J. Casement, O. Magnuson, D. Nguyen and Y. Hu for technical support; R. García-Tercero and C. Díaz for sample collection; E. Zorio, M.E. Leach, D. Bharucha-Goebel, J. Dastgir and C. Konersman for clinical expertise and M. Gautel for helpful advice. We also thank CureCMD for their help in patient recruitment and the patients for donating their samples. The research leading to these results has received funding from the European Community’s Seventh Framework Program (FP7/2007-2013; 2012-305121) ‘Integrated European—omics research project for diagnosis and therapy in rare neuromuscular and neurodegenerative diseases (NEUROMICS)’ (to A. Töpf, V.S., I.T.Z. and F.M.); the European Union’s Horizon 2020 research and innovation program (Solve-RD project; 779257 to A. Töpf); Muscular Dystrophy UK and Muscular Dystrophy Association US (mda577346 to F.M.); Päulon Säätiö (to M. Savarese); Academy of Finland, Sigrid Juselius Foundation (to B.U.); core funding to the Sanger Institute by the Wellcome Trust (098051 and 206194 to E.M.B.-N., J.P. and N.W.); EURO-NMD and Fundación Gemio (to J.J.V., N.M. and P.M.); Intramural Research Grant (2-5, 29-4) for Neurological and Psychiatric Disorders of NCNP and AMED (JP20ek0109490h0001 to I.N.); Inserm, CNRS, University of Strasbourg, Labex INRT (ANR-10-LABX-0030 and ANR-10-IDEX-0002-02), France Génomique (ANR-10-INBS-09) and Fondation Maladies Rares for the ‘Myocapture’ sequencing project, AFM-Téléthon (22734), the European Joint program (EJPRD2019-126 IDOLS-G and ANR-19-RAR4-0002 to J.L., X.L. and V.B.); Intramural funds from the NIH National Institute of Neurological Disorders and Stroke (to C.G.B.); the Dutch Princess Beatrix Muscle Fund and the Dutch Spieren voor Spieren Muscle fund (to C.E.E.); PI16/00316 supported by the Instituto de Salud Carlos III (ISCIII), Madrid and the Generalitat Valenciana (grant PROMETEO/2019/075 to N.M.); Australian NHMRC Neil Hamilton Fairley Early Career Research Fellowship (GNT1090428 to E.C.O.); Starship Foundation A+7340 (to G.L.O.); Early Career Award from the Thrasher Research Fund (to S.S.); U54 HD090255 from the NIH Eunice Kennedy Shriver National Institute of Child Health and Human Development (to A.H.B.); Wellcome Center for Mitochondrial Research (203105/Z/16/Z), the Mitochondrial Disease Patient Cohort (UK; G0800674), the Medical Research Council International Center for Genomic Medicine in Neuromuscular Disease (MR/S005021/1), the Medical Research Council (MR/W019027/1), the Lily Foundation, Mito Foundation, the Pathological Society, the UK NIHR Biomedical Research Center for Ageing and Age-related Disease award to the Newcastle upon Tyne Foundation Hospitals NHS Trust and the UK NHS Highly Specialized Service for Rare Mitochondrial Disorders of Adults and Children (to R.W.T.). MYO–SEQ was funded by Sanofi Genzyme, Ultragenyx, LGMD2I Research Fund, Samantha J Brazzo Foundation, LGMD2D Foundation, Kurt+Peter Foundation, Muscular Dystrophy UK and Coalition to Cure Calpain 3. Sequencing and analysis for relevant families (Supplementary Note) were provided by the Broad Institute of MIT and Harvard Center for Mendelian Genomics (Broad CMG) and were funded by the National Human Genome Research Institute, the National Eye Institute and the National Heart, Lung and Blood Institute under grant UM1 HG008900 and the National Human Genome Research Institute under grants U01HG0011755 and R01 HG009141. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. DNA samples for NeurOmics and MYO–SEQ were provided by the John Walton Muscular Dystrophy Research Center Biobank. This facility is supported by the NIHR Newcastle Biomedical Research Center. Newcastle University’s Electron Microscopy Research Services and equipment Hitachi HT7800 120 kV TEM microscope are funded by BBSRC grant reference BB/R013942/1.Funder: Genzyme (Genzyme Corporation); doi: https://doi.org/10.13039/100004329Funder: Ultragenyx Pharmaceutical (Ultragenyx Pharmaceutical Inc.); doi: https://doi.org/10.13039/100013220Funder: EC | EC Seventh Framework Programm | FP7 Ideas: European Research Council (FP7-IDEAS-ERC - Specific Programme: "Ideas" Implementing the Seventh Framework Programme of the European Community for Research, Technological Development and Demonstration Activities (2007 to 2013)); doi: https://doi.org/10.13039/100011199; Grant(s): 2012-305121In digenic inheritance, pathogenic variants in two genes must be inherited together to cause disease. Only very few examples of digenic inheritance have been described in the neuromuscular disease field. Here we show that predicted deleterious variants in SRPK3, encoding the X-linked serine/argenine protein kinase 3, lead to a progressive early onset skeletal muscle myopathy only when in combination with heterozygous variants in the TTN gene. The co-occurrence of predicted deleterious SRPK3/TTN variants was not seen among 76,702 healthy male individuals, and statistical modeling strongly supported digenic inheritance as the best-fitting model. Furthermore, double-mutant zebrafish (srpk3-/-; ttn.1+/-) replicated the myopathic phenotype and showed myofibrillar disorganization. Transcriptome data suggest that the interaction of srpk3 and ttn.1 in zebrafish occurs at a post-transcriptional level. We propose that digenic inheritance of deleterious changes impacting both the protein kinase SRPK3 and the giant muscle protein titin causes a skeletal myopathy and might serve as a model for other genetic diseases

Digenic inheritance involving a muscle-specific protein kinase and the giant titin protein causes a skeletal muscle myopathy

In digenic inheritance, pathogenic variants in two genes must be inherited together to cause disease. Only very few examples of digenic inheritance have been described in the neuromuscular disease field. Here we show that predicted deleterious variants in SRPK3, encoding the X-linked serine/argenine protein kinase 3, lead to a progressive early onset skeletal muscle myopathy only when in combination with heterozygous variants in the TTN gene. The co-occurrence of predicted deleterious SRPK3/TTN variants was not seen among 76,702 healthy male individuals, and statistical modeling strongly supported digenic inheritance as the best-fitting model. Furthermore, double-mutant zebrafish (srpk3−/−; ttn.1+/−) replicated the myopathic phenotype and showed myofibrillar disorganization. Transcriptome data suggest that the interaction of srpk3 and ttn.1 in zebrafish occurs at a post-transcriptional level. We propose that digenic inheritance of deleterious changes impacting both the protein kinase SRPK3 and the giant muscle protein titin causes a skeletal myopathy and might serve as a model for other genetic diseases.Peer reviewe

Digenic inheritance involving a muscle-specific protein kinase and the giant titin protein causes a skeletal muscle myopathy.

Acknowledgements: We acknowledge H. Luque, L. Phillips, J. Casement, O. Magnuson, D. Nguyen and Y. Hu for technical support; R. García-Tercero and C. Díaz for sample collection; E. Zorio, M.E. Leach, D. Bharucha-Goebel, J. Dastgir and C. Konersman for clinical expertise and M. Gautel for helpful advice. We also thank CureCMD for their help in patient recruitment and the patients for donating their samples. The research leading to these results has received funding from the European Community’s Seventh Framework Program (FP7/2007-2013; 2012-305121) ‘Integrated European—omics research project for diagnosis and therapy in rare neuromuscular and neurodegenerative diseases (NEUROMICS)’ (to A. Töpf, V.S., I.T.Z. and F.M.); the European Union’s Horizon 2020 research and innovation program (Solve-RD project; 779257 to A. Töpf); Muscular Dystrophy UK and Muscular Dystrophy Association US (mda577346 to F.M.); Päulon Säätiö (to M. Savarese); Academy of Finland, Sigrid Juselius Foundation (to B.U.); core funding to the Sanger Institute by the Wellcome Trust (098051 and 206194 to E.M.B.-N., J.P. and N.W.); EURO-NMD and Fundación Gemio (to J.J.V., N.M. and P.M.); Intramural Research Grant (2-5, 29-4) for Neurological and Psychiatric Disorders of NCNP and AMED (JP20ek0109490h0001 to I.N.); Inserm, CNRS, University of Strasbourg, Labex INRT (ANR-10-LABX-0030 and ANR-10-IDEX-0002-02), France Génomique (ANR-10-INBS-09) and Fondation Maladies Rares for the ‘Myocapture’ sequencing project, AFM-Téléthon (22734), the European Joint program (EJPRD2019-126 IDOLS-G and ANR-19-RAR4-0002 to J.L., X.L. and V.B.); Intramural funds from the NIH National Institute of Neurological Disorders and Stroke (to C.G.B.); the Dutch Princess Beatrix Muscle Fund and the Dutch Spieren voor Spieren Muscle fund (to C.E.E.); PI16/00316 supported by the Instituto de Salud Carlos III (ISCIII), Madrid and the Generalitat Valenciana (grant PROMETEO/2019/075 to N.M.); Australian NHMRC Neil Hamilton Fairley Early Career Research Fellowship (GNT1090428 to E.C.O.); Starship Foundation A+7340 (to G.L.O.); Early Career Award from the Thrasher Research Fund (to S.S.); U54 HD090255 from the NIH Eunice Kennedy Shriver National Institute of Child Health and Human Development (to A.H.B.); Wellcome Center for Mitochondrial Research (203105/Z/16/Z), the Mitochondrial Disease Patient Cohort (UK; G0800674), the Medical Research Council International Center for Genomic Medicine in Neuromuscular Disease (MR/S005021/1), the Medical Research Council (MR/W019027/1), the Lily Foundation, Mito Foundation, the Pathological Society, the UK NIHR Biomedical Research Center for Ageing and Age-related Disease award to the Newcastle upon Tyne Foundation Hospitals NHS Trust and the UK NHS Highly Specialized Service for Rare Mitochondrial Disorders of Adults and Children (to R.W.T.). MYO–SEQ was funded by Sanofi Genzyme, Ultragenyx, LGMD2I Research Fund, Samantha J Brazzo Foundation, LGMD2D Foundation, Kurt+Peter Foundation, Muscular Dystrophy UK and Coalition to Cure Calpain 3. Sequencing and analysis for relevant families (Supplementary Note) were provided by the Broad Institute of MIT and Harvard Center for Mendelian Genomics (Broad CMG) and were funded by the National Human Genome Research Institute, the National Eye Institute and the National Heart, Lung and Blood Institute under grant UM1 HG008900 and the National Human Genome Research Institute under grants U01HG0011755 and R01 HG009141. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. DNA samples for NeurOmics and MYO–SEQ were provided by the John Walton Muscular Dystrophy Research Center Biobank. This facility is supported by the NIHR Newcastle Biomedical Research Center. Newcastle University’s Electron Microscopy Research Services and equipment Hitachi HT7800 120 kV TEM microscope are funded by BBSRC grant reference BB/R013942/1.Funder: Genzyme (Genzyme Corporation); doi: https://doi.org/10.13039/100004329Funder: Ultragenyx Pharmaceutical (Ultragenyx Pharmaceutical Inc.); doi: https://doi.org/10.13039/100013220Funder: EC | EC Seventh Framework Programm | FP7 Ideas: European Research Council (FP7-IDEAS-ERC - Specific Programme: "Ideas" Implementing the Seventh Framework Programme of the European Community for Research, Technological Development and Demonstration Activities (2007 to 2013)); doi: https://doi.org/10.13039/100011199; Grant(s): 2012-305121In digenic inheritance, pathogenic variants in two genes must be inherited together to cause disease. Only very few examples of digenic inheritance have been described in the neuromuscular disease field. Here we show that predicted deleterious variants in SRPK3, encoding the X-linked serine/argenine protein kinase 3, lead to a progressive early onset skeletal muscle myopathy only when in combination with heterozygous variants in the TTN gene. The co-occurrence of predicted deleterious SRPK3/TTN variants was not seen among 76,702 healthy male individuals, and statistical modeling strongly supported digenic inheritance as the best-fitting model. Furthermore, double-mutant zebrafish (srpk3-/-; ttn.1+/-) replicated the myopathic phenotype and showed myofibrillar disorganization. Transcriptome data suggest that the interaction of srpk3 and ttn.1 in zebrafish occurs at a post-transcriptional level. We propose that digenic inheritance of deleterious changes impacting both the protein kinase SRPK3 and the giant muscle protein titin causes a skeletal myopathy and might serve as a model for other genetic diseases