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1. WGS-based telomere length analysis in Dutch family trios implicates stronger maternal inheritance and a role for RRM1 gene

Author

Nersisyan, L. (Lilit), Nikoghosyan, M. (Maria), Arakelyan, A. (Arsen), Francioli, L.C. (Laurent), Menelaou, A. (Androniki), Pulit, S.L. (Sara), Elbers, C.C. (Clara), Kloosterman, W.P. (Wigard), Setten, J. (Jessica) van, Nijman, I.J. (Isaac ), Renkens, I. (Ivo), de Bakker, P.I.W. (Paul I. W.), Dijk, F. (Freerk) van, Neerincx, P.B.T. (Pieter B T), Deelen, P. (Patrick), Kanterakis, A. (Alexandros), Dijkstra, M. (Martijn), Byelas, H. (Heorhiy), van der Velde, K.J. (K. Joeri), Platteel, I. (Inge), Swertz, M.A. (Morris A.), Wijmenga, C. (Cisca), Palamara, P.F. (Pier Francesco), Peer, I. (Itsik), Ye, K. (Kai), Lameijer, E.-W. (Eric-Wubbo), Moed, H. (Heleen), Beekman, M. (Marian), Craen, A.J. (Anton) de, Suchiman, H.E.D. (H. Eka D.), Slagboom, P.E. (Eline), Guryev, V. (Victor), Abdellaoui, A. (Abdel), Hottenga, J.J. (Jouke Jan), Kattenberg, V.M. (Mathijs), Willemsen, G.A.H.M. (Gonneke), Boomsma, D.I. (Dorret), van Leeuwen, E.M. (Elisabeth M.), Karssen, L.C. (Lennart), Amin, N. (Najaf), Rivadeneira, F. (Fernando), Isaacs, A.J. (Aaron), Hofman, A. (Albert), Uitterlinden, A.G. (André), Duijn, C.M. (Cornelia) van, Oven, M. (Mannis) van, Kayser, M.H. (Manfred), Vermaat, M. (Martijn), Laros, J.F.J. (Jeroen F.), Dunnen, J.T. (Johan) den, Enckevort, D. (David) van, Mei, S. (Shan), Li, M. (Mingkun), Stoneking, M. (Mark), Schaik, B.D.C. (Barbera) van, Bot, J.J. (Jan), Marschall, T. (Tanja), Schönhuth, A. (Alexander), Hehir-Kwa, J. (Jayne), Handsaker, R.E. (Robert), Polak, P., Sohail, M. (Mashaal), Vuzman, D. (Dana), Estrada Gil, K. (Karol), McCarroll, S.A. (Steve), Sunyaev, S.R. (Shamil), Hormozdiari, F. (Fereydoun), Koval, V. (Vyacheslav), Medina-Gomez, M.C. (Carolina), Oostra, B.A. (Ben), Veldink, J.H. (Jan), Berg, L.H. (Leonard) van den, Pitts, S.J. (Steven J.), Potluri, S. (Shobha), Sundar, P. (Purnima), Cox, D.R. (David), Knijff, P. (Peter) de, Li, Q. (Qibin), Li, Y. (Yingrui), Du, Y. (Yuanping), Chen, R. (Ruoyan), Cao, H. (Hongzhi), Wang, J. (Jun), Li, N. (Ning), Cao, S. (Sujie), Bovenberg, J.A. (Jasper), Ommen, G.J. (Gert) van, Nersisyan, L. (Lilit), Nikoghosyan, M. (Maria), Arakelyan, A. (Arsen), Francioli, L.C. (Laurent), Menelaou, A. (Androniki), Pulit, S.L. (Sara), Elbers, C.C. (Clara), Kloosterman, W.P. (Wigard), Setten, J. (Jessica) van, Nijman, I.J. (Isaac ), Renkens, I. (Ivo), de Bakker, P.I.W. (Paul I. W.), Dijk, F. (Freerk) van, Neerincx, P.B.T. (Pieter B T), Deelen, P. (Patrick), Kanterakis, A. (Alexandros), Dijkstra, M. (Martijn), Byelas, H. (Heorhiy), van der Velde, K.J. (K. Joeri), Platteel, I. (Inge), Swertz, M.A. (Morris A.), Wijmenga, C. (Cisca), Palamara, P.F. (Pier Francesco), Peer, I. (Itsik), Ye, K. (Kai), Lameijer, E.-W. (Eric-Wubbo), Moed, H. (Heleen), Beekman, M. (Marian), Craen, A.J. (Anton) de, Suchiman, H.E.D. (H. Eka D.), Slagboom, P.E. (Eline), Guryev, V. (Victor), Abdellaoui, A. (Abdel), Hottenga, J.J. (Jouke Jan), Kattenberg, V.M. (Mathijs), Willemsen, G.A.H.M. (Gonneke), Boomsma, D.I. (Dorret), van Leeuwen, E.M. (Elisabeth M.), Karssen, L.C. (Lennart), Amin, N. (Najaf), Rivadeneira, F. (Fernando), Isaacs, A.J. (Aaron), Hofman, A. (Albert), Uitterlinden, A.G. (André), Duijn, C.M. (Cornelia) van, Oven, M. (Mannis) van, Kayser, M.H. (Manfred), Vermaat, M. (Martijn), Laros, J.F.J. (Jeroen F.), Dunnen, J.T. (Johan) den, Enckevort, D. (David) van, Mei, S. (Shan), Li, M. (Mingkun), Stoneking, M. (Mark), Schaik, B.D.C. (Barbera) van, Bot, J.J. (Jan), Marschall, T. (Tanja), Schönhuth, A. (Alexander), Hehir-Kwa, J. (Jayne), Handsaker, R.E. (Robert), Polak, P., Sohail, M. (Mashaal), Vuzman, D. (Dana), Estrada Gil, K. (Karol), McCarroll, S.A. (Steve), Sunyaev, S.R. (Shamil), Hormozdiari, F. (Fereydoun), Koval, V. (Vyacheslav), Medina-Gomez, M.C. (Carolina), Oostra, B.A. (Ben), Veldink, J.H. (Jan), Berg, L.H. (Leonard) van den, Pitts, S.J. (Steven J.), Potluri, S. (Shobha), Sundar, P. (Purnima), Cox, D.R. (David), Knijff, P. (Peter) de, Li, Q. (Qibin), Li, Y. (Yingrui), Du, Y. (Yuanping), Chen, R. (Ruoyan), Cao, H. (Hongzhi), Wang, J. (Jun), Li, N. (Ning), Cao, S. (Sujie), Bovenberg, J.A. (Jasper), and Ommen, G.J. (Gert) van

Abstract

Telomere length (TL) regulation is an important factor in ageing, reproduction and cancer development. Genetic, hereditary and environmental factors regulating TL are currently widely investigated, however, their relative contribution to TL variability is still understudied. We have used whole genome sequencing data of 250 family trios from the Genome of the Netherlands project to perform computational measurement of TL and a series of regression and genome-wide association analyses to reveal TL inheritance patterns and associated genetic factors. Our results confirm that TL is a largely heritable trait, primarily with mother’s, and, to a lesser extent, with father’s TL having the strongest influence on the offspring. In this cohort, mother’s, but not father’s age at conception was positively linked to offspring TL. Age-related TL attrition of 40 bp/year had relatively small influence on TL variability. Finally, we have identified TL-associated variations in ribonuclease reductase catalytic subunit M1 (RRM1 gene), which is known to regulate telomere maintenance in yeast. We also highlight the importance of multivariate approach and the limitations of existing tools for the analysis of TL as a polygenic heritable quantitative trait.

Published
2019
Full Text
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2. Dutch genome diagnostic laboratories accelerated and improved variant interpretation and increased accuracy by sharing data

Author

Fokkema, I., Velde, K. (KJoeri) van der, Slofstra, M.K., Ruivenkamp, C.A. (Claudia), Vogel, M.J. (Maartje), Pfundt, R. (Rolph), Blok, M.J.C., Deprez, R.H.L., Waisfisz, Q. (Quinten), Abbott, K.M. (Kristin), Sinke, R.J. (Richard), Rahman, R. (Rosanna), Nijman, I.J. (Isaac ), Koning, B.A.E. (Barbara) de, Thijs, G., Wieskamp, N., Moritz, R.J.G., Charbon, B., Saris, J.J. (Jasper), Dunnen, J.T. (Johan) den, Laros, J.F.J. (Jeroen F.), Bakker, P.I.W. (Paul) de, Gijn, M. (Marielle) van, Fokkema, I., Velde, K. (KJoeri) van der, Slofstra, M.K., Ruivenkamp, C.A. (Claudia), Vogel, M.J. (Maartje), Pfundt, R. (Rolph), Blok, M.J.C., Deprez, R.H.L., Waisfisz, Q. (Quinten), Abbott, K.M. (Kristin), Sinke, R.J. (Richard), Rahman, R. (Rosanna), Nijman, I.J. (Isaac ), Koning, B.A.E. (Barbara) de, Thijs, G., Wieskamp, N., Moritz, R.J.G., Charbon, B., Saris, J.J. (Jasper), Dunnen, J.T. (Johan) den, Laros, J.F.J. (Jeroen F.), Bakker, P.I.W. (Paul) de, and Gijn, M. (Marielle) van

Abstract

Each year diagnostic laboratories in the Netherlands profile thousands of individuals for heritable disease using next‐generation sequencing (NGS). This requires pathogenicity classification of millions of DNA variants on the standard 5‐tier scale. To reduce time spent on data interpretation and increase data quality and reliability, the nine Dutch labs decided to publicly share their classifications. Variant classifications of nearly 100,000 unique variants were catalogued and compared in a centralized MOLGENIS database. Variants classified by more than one center were labeled as “consensus” w

Published
2019
Full Text
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3. WGS-based telomere length analysis in Dutch family trios implicates stronger maternal inheritance and a role for RRM1 gene

Author

Nersisyan, L. (Lilit), Nikoghosyan, M. (Maria), Arakelyan, A. (Arsen), Francioli, L.C. (Laurent), Menelaou, A. (Androniki), Pulit, S.L. (Sara L.), Elbers, C.C. (Clara C.), Kloosterman, W.P. (Wigard), van Setten, J. (Jessica), Nijman, I.J. (Isaac), Renkens, I. (Ivo), de Bakker, P.I.W. (Paul I. W.), Dijk, F. (Freerk) van, Neerincx, P.B.T. (Pieter), Deelen, P. (Patrick), Kanterakis, A. (Alexandros), Dijkstra, M. (Martijn), Byelas, H. (Heorhiy), van der Velde, K.J. (K. Joeri), Platteel, M. (Mathieu), Swertz, M.A. (Morris A.), Wijmenga, C. (Cisca), Palamara, P.F. (Pier Francesco), Pe’er, I. (Itsik), Ye, K. (Kai), Lameijer, E.-W. (Eric-Wubbo), Moed, M.H. (Matthijs H.), Beekman, M. (Marian), Craen, A.J.M. (Anton) de, Suchiman, H.E.D. (H. Eka D.), Slagboom, P.E. (Eline), Guryev, V. (Victor), Abdellaoui, A. (Abdel), Jan Hottenga, J. (Jouke), Kattenberg, M. (Mathijs), Willemsen, G. (Gonneke), Boomsma, D.I. (Dorret), van Leeuwen, E.M. (Elisabeth M.), Karssen, L.C. (Lennart), Amin, N. (Najaf), Rivadeneira, F. (Fernando), Isaacs, A. (Aaron), Hofman, A. (Albert), Uitterlinden, A.G. (André), Duijn, C.M. (Cornelia) van, van Oven, M. (Mannis), Kayser, M. (Manfred), Vermaat, M. (Martijn), Laros, J.F.J. (Jeroen), Dunnen, J.T. (Johan) den, Enckevort, D. (David) van, Mei, H. (Hailiang), Li, M. (Mingkun), Stoneking, M. (Mark), Schaik, B.D.C. (Barbera) van, Bot, J. (Jan), Marschall, T. (Tobias), Schönhuth, A. (Alexander), Hehir-Kwa, J.Y. (Jayne), Handsaker, R.E. (Robert), Polak, P. (Paz), Sohail, M. (Mashaal), Vuzman, D. (Dana), Estrada, K. (Karol), McCarroll, S.A. (Steven A.), Sunyaev, S.R. (Shamil R.), Hormozdiari, F. (Fereydoun), Koval, V. (Vyacheslav), Medina-Gomez, C. (Carolina), Oostra, B. (Ben), Veldink, J. (Jan), van den Berg, L.H. (Leonard H.), Pitts, S.J. (Steven J.), Potluri, S. (Shobha), Sundar, P. (Purnima), Cox, D.R. (David R.), Knijff, P. (Peter) de, Li, Q. (Qibin), Li, Y. (Yingrui), Du, Y. (Yuanping), Chen, R. (Ruoyan), Cao, H. (Hongzhi), Wang, J. (Jun), Li, N. (Ning), Cao, S. (Sujie), Bovenberg, J.A. (Jasper), Ommen, G.-J.B. (Gert-Jan) van, The Genome of the Netherlands Consortium, Nersisyan, L. (Lilit), Nikoghosyan, M. (Maria), Arakelyan, A. (Arsen), Francioli, L.C. (Laurent), Menelaou, A. (Androniki), Pulit, S.L. (Sara L.), Elbers, C.C. (Clara C.), Kloosterman, W.P. (Wigard), van Setten, J. (Jessica), Nijman, I.J. (Isaac), Renkens, I. (Ivo), de Bakker, P.I.W. (Paul I. W.), Dijk, F. (Freerk) van, Neerincx, P.B.T. (Pieter), Deelen, P. (Patrick), Kanterakis, A. (Alexandros), Dijkstra, M. (Martijn), Byelas, H. (Heorhiy), van der Velde, K.J. (K. Joeri), Platteel, M. (Mathieu), Swertz, M.A. (Morris A.), Wijmenga, C. (Cisca), Palamara, P.F. (Pier Francesco), Pe’er, I. (Itsik), Ye, K. (Kai), Lameijer, E.-W. (Eric-Wubbo), Moed, M.H. (Matthijs H.), Beekman, M. (Marian), Craen, A.J.M. (Anton) de, Suchiman, H.E.D. (H. Eka D.), Slagboom, P.E. (Eline), Guryev, V. (Victor), Abdellaoui, A. (Abdel), Jan Hottenga, J. (Jouke), Kattenberg, M. (Mathijs), Willemsen, G. (Gonneke), Boomsma, D.I. (Dorret), van Leeuwen, E.M. (Elisabeth M.), Karssen, L.C. (Lennart), Amin, N. (Najaf), Rivadeneira, F. (Fernando), Isaacs, A. (Aaron), Hofman, A. (Albert), Uitterlinden, A.G. (André), Duijn, C.M. (Cornelia) van, van Oven, M. (Mannis), Kayser, M. (Manfred), Vermaat, M. (Martijn), Laros, J.F.J. (Jeroen), Dunnen, J.T. (Johan) den, Enckevort, D. (David) van, Mei, H. (Hailiang), Li, M. (Mingkun), Stoneking, M. (Mark), Schaik, B.D.C. (Barbera) van, Bot, J. (Jan), Marschall, T. (Tobias), Schönhuth, A. (Alexander), Hehir-Kwa, J.Y. (Jayne), Handsaker, R.E. (Robert), Polak, P. (Paz), Sohail, M. (Mashaal), Vuzman, D. (Dana), Estrada, K. (Karol), McCarroll, S.A. (Steven A.), Sunyaev, S.R. (Shamil R.), Hormozdiari, F. (Fereydoun), Koval, V. (Vyacheslav), Medina-Gomez, C. (Carolina), Oostra, B. (Ben), Veldink, J. (Jan), van den Berg, L.H. (Leonard H.), Pitts, S.J. (Steven J.), Potluri, S. (Shobha), Sundar, P. (Purnima), Cox, D.R. (David R.), Knijff, P. (Peter) de, Li, Q. (Qibin), Li, Y. (Yingrui), Du, Y. (Yuanping), Chen, R. (Ruoyan), Cao, H. (Hongzhi), Wang, J. (Jun), Li, N. (Ning), Cao, S. (Sujie), Bovenberg, J.A. (Jasper), Ommen, G.-J.B. (Gert-Jan) van, and The Genome of the Netherlands Consortium

Abstract

Telomere length (TL) regulation is an important factor in ageing, reproduction and cancer development. Genetic, hereditary and environmental factors regulating TL are currently widely investigated, however, their relative contribution to TL variability is still understudied. We have used whole genome sequencing data of 250 family trios from the Genome of the Netherlands project to perform computational measurement of TL and a series of regression and genome-wide association analyses to reveal TL inheritance patterns and associated genetic factors. Our results confirm that TL is a largely heritable trait, primarily with mother’s, and, to a lesser extent, with father’s TL having the strongest influence on the offspring. In this cohort, mother’s, but not father’s age at conception was positively linked to offspring TL. Age-related TL attrition of 40 bp/year had relatively small influence on TL variability. Finally, we have identified TL-associated variations in ribonuclease reductase catalytic subunit M1 (RRM1 gene), which is known to regulate telomere maintenance in yeast. We also highlight the importance of multivariate approach and the limitations of existing tools for the analysis of TL as a polygenic heritable quantitative trait.

Published
2019
Full Text
View/download PDF

4. WGS-based telomere length analysis in Dutch family trios implicates stronger maternal inheritance and a role for RRM1 gene

Author

Nersisyan, L. (Lilit), Nikoghosyan, M. (Maria), Arakelyan, A. (Arsen), Francioli, L.C. (Laurent), Menelaou, A. (Androniki), Pulit, S.L. (Sara L.), Elbers, C.C. (Clara C.), Kloosterman, W.P. (Wigard), van Setten, J. (Jessica), Nijman, I.J. (Isaac), Renkens, I. (Ivo), de Bakker, P.I.W. (Paul I. W.), Dijk, F. (Freerk) van, Neerincx, P.B.T. (Pieter), Deelen, P. (Patrick), Kanterakis, A. (Alexandros), Dijkstra, M. (Martijn), Byelas, H. (Heorhiy), van der Velde, K.J. (K. Joeri), Platteel, M. (Mathieu), Swertz, M.A. (Morris A.), Wijmenga, C. (Cisca), Palamara, P.F. (Pier Francesco), Pe’er, I. (Itsik), Ye, K. (Kai), Lameijer, E.-W. (Eric-Wubbo), Moed, M.H. (Matthijs H.), Beekman, M. (Marian), Craen, A.J.M. (Anton) de, Suchiman, H.E.D. (H. Eka D.), Slagboom, P.E. (Eline), Guryev, V. (Victor), Abdellaoui, A. (Abdel), Jan Hottenga, J. (Jouke), Kattenberg, M. (Mathijs), Willemsen, G. (Gonneke), Boomsma, D.I. (Dorret), van Leeuwen, E.M. (Elisabeth M.), Karssen, L.C. (Lennart), Amin, N. (Najaf), Rivadeneira, F. (Fernando), Isaacs, A. (Aaron), Hofman, A. (Albert), Uitterlinden, A.G. (André), Duijn, C.M. (Cornelia) van, van Oven, M. (Mannis), Kayser, M. (Manfred), Vermaat, M. (Martijn), Laros, J.F.J. (Jeroen), Dunnen, J.T. (Johan) den, Enckevort, D. (David) van, Mei, H. (Hailiang), Li, M. (Mingkun), Stoneking, M. (Mark), Schaik, B.D.C. (Barbera) van, Bot, J. (Jan), Marschall, T. (Tobias), Schönhuth, A. (Alexander), Hehir-Kwa, J.Y. (Jayne), Handsaker, R.E. (Robert), Polak, P. (Paz), Sohail, M. (Mashaal), Vuzman, D. (Dana), Estrada, K. (Karol), McCarroll, S.A. (Steven A.), Sunyaev, S.R. (Shamil R.), Hormozdiari, F. (Fereydoun), Koval, V. (Vyacheslav), Medina-Gomez, C. (Carolina), Oostra, B. (Ben), Veldink, J. (Jan), van den Berg, L.H. (Leonard H.), Pitts, S.J. (Steven J.), Potluri, S. (Shobha), Sundar, P. (Purnima), Cox, D.R. (David R.), Knijff, P. (Peter) de, Li, Q. (Qibin), Li, Y. (Yingrui), Du, Y. (Yuanping), Chen, R. (Ruoyan), Cao, H. (Hongzhi), Wang, J. (Jun), Li, N. (Ning), Cao, S. (Sujie), Bovenberg, J.A. (Jasper), Ommen, G.-J.B. (Gert-Jan) van, The Genome of the Netherlands Consortium, Nersisyan, L. (Lilit), Nikoghosyan, M. (Maria), Arakelyan, A. (Arsen), Francioli, L.C. (Laurent), Menelaou, A. (Androniki), Pulit, S.L. (Sara L.), Elbers, C.C. (Clara C.), Kloosterman, W.P. (Wigard), van Setten, J. (Jessica), Nijman, I.J. (Isaac), Renkens, I. (Ivo), de Bakker, P.I.W. (Paul I. W.), Dijk, F. (Freerk) van, Neerincx, P.B.T. (Pieter), Deelen, P. (Patrick), Kanterakis, A. (Alexandros), Dijkstra, M. (Martijn), Byelas, H. (Heorhiy), van der Velde, K.J. (K. Joeri), Platteel, M. (Mathieu), Swertz, M.A. (Morris A.), Wijmenga, C. (Cisca), Palamara, P.F. (Pier Francesco), Pe’er, I. (Itsik), Ye, K. (Kai), Lameijer, E.-W. (Eric-Wubbo), Moed, M.H. (Matthijs H.), Beekman, M. (Marian), Craen, A.J.M. (Anton) de, Suchiman, H.E.D. (H. Eka D.), Slagboom, P.E. (Eline), Guryev, V. (Victor), Abdellaoui, A. (Abdel), Jan Hottenga, J. (Jouke), Kattenberg, M. (Mathijs), Willemsen, G. (Gonneke), Boomsma, D.I. (Dorret), van Leeuwen, E.M. (Elisabeth M.), Karssen, L.C. (Lennart), Amin, N. (Najaf), Rivadeneira, F. (Fernando), Isaacs, A. (Aaron), Hofman, A. (Albert), Uitterlinden, A.G. (André), Duijn, C.M. (Cornelia) van, van Oven, M. (Mannis), Kayser, M. (Manfred), Vermaat, M. (Martijn), Laros, J.F.J. (Jeroen), Dunnen, J.T. (Johan) den, Enckevort, D. (David) van, Mei, H. (Hailiang), Li, M. (Mingkun), Stoneking, M. (Mark), Schaik, B.D.C. (Barbera) van, Bot, J. (Jan), Marschall, T. (Tobias), Schönhuth, A. (Alexander), Hehir-Kwa, J.Y. (Jayne), Handsaker, R.E. (Robert), Polak, P. (Paz), Sohail, M. (Mashaal), Vuzman, D. (Dana), Estrada, K. (Karol), McCarroll, S.A. (Steven A.), Sunyaev, S.R. (Shamil R.), Hormozdiari, F. (Fereydoun), Koval, V. (Vyacheslav), Medina-Gomez, C. (Carolina), Oostra, B. (Ben), Veldink, J. (Jan), van den Berg, L.H. (Leonard H.), Pitts, S.J. (Steven J.), Potluri, S. (Shobha), Sundar, P. (Purnima), Cox, D.R. (David R.), Knijff, P. (Peter) de, Li, Q. (Qibin), Li, Y. (Yingrui), Du, Y. (Yuanping), Chen, R. (Ruoyan), Cao, H. (Hongzhi), Wang, J. (Jun), Li, N. (Ning), Cao, S. (Sujie), Bovenberg, J.A. (Jasper), Ommen, G.-J.B. (Gert-Jan) van, and The Genome of the Netherlands Consortium

Abstract

Telomere length (TL) regulation is an important factor in ageing, reproduction and cancer development. Genetic, hereditary and environmental factors regulating TL are currently widely investigated, however, their relative contribution to TL variability is still understudied. We have used whole genome sequencing data of 250 family trios from the Genome of the Netherlands project to perform computational measurement of TL and a series of regression and genome-wide association analyses to reveal TL inheritance patterns and associated genetic factors. Our results confirm that TL is a largely heritable trait, primarily with mother’s, and, to a lesser extent, with father’s TL having the strongest influence on the offspring. In this cohort, mother’s, but not father’s age at conception was positively linked to offspring TL. Age-related TL attrition of 40 bp/year had relatively small influence on TL variability. Finally, we have identified TL-associated variations in ribonuclease reductase catalytic subunit M1 (RRM1 gene), which is known to regulate telomere maintenance in yeast. We also highlight the importance of multivariate approach and the limitations of existing tools for the analysis of TL as a polygenic heritable quantitative trait.

Published
2019
Full Text
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5. Skewed X-inactivation is common in the general female population

Author

Shvetsova, E. (Ekaterina), Sofronova, A. (Alina), Monajemi, R. (Ramin), Gagalova, K. (Kristina), Draisma, G. (Gerrit), White, S.J. (Stefan), Santen, G.W.E. (Gijs), Chuva De Sousa Lopes, S.M. (Susana M.), Heijmans, B.T. (Bastiaan T.), van Meurs, J. (Joyce), Jansen, R. (Rick), Franke, L. (Lude), Kielbasa, S.M. (Szymon M.), Dunnen, J.T. (Johan) den, ‘t Hoen, P.A.C. (Peter A. C.), Heijmans, B.T. (Bastiaan T), Meurs, J.B.J. (Joyce) van, Boomsma, D.I. (Dorret), Pool, R. (Reńe), Dongen, J. (Jenny) van, Hottenga, J.J. (Jouke Jan), Greevenbroek, M.M. van, Stehouwer, C.D. (Coen Da), Kallen, C.J. van der, Schalkwijk, C.G. (Casper), Wijmenga, C. (Cisca), Zhernakova, S. (Sasha), Tigchelaar, E.F. (Ettje F.), Slagboom, P.E. (Eline), Beekman, M. (Marian), Deelen, J. (Joris), Heemst, D. (Diana) van, Veldink, J.H. (Jan), Berg, L.H. (Leonard) van den, Duijn, C.M. (Cornelia) van, Hofman, B.A. (Bert A), Uitterlinden, A.G. (André), Jhamai, P.M. (Mila), Verbiest, M.M.P.J. (Michael), Suchiman, H.E.D. (H Eka D), Verkerk, M. (Marijn), Breggen, R. (Ruud) van der, van Rooij, J. (Jeroen), Lakenberg, N. (Nico), Mei, S. (Shan), Bot, J. (Jan), Zhernakova, D.V. (Dasha V), van ’t Hof, P. (Peter), Deelen, P. (Patrick), Nooren, I. (Irene), Moed, H. (Heleen), Vermaat, M. (Martijn), Luijk, R. (René), Jan Bonder, M. (Marc), Iterson, M. (Maarten) van, van Dijk, F. (Freerk), Van Galen, M. (Michiel), Arindrarto, W. (Wibowo), Swertz, M.A. (Morris A), Zwet, E.W. (Erik) van, Isaacs, A.J. (Aaron), Francioli, L.C. (Laurent), Menelaou, A. (Androniki), Pulit, S.L. (Sara), Dijk, F. (Freerk) van, Palamara, P.F. (Pier Francesco), Elbers, C.C. (Clara), Neerincx, P.B.T. (Pieter B T), Ye, K. (K.), Guryev, V. (Victor), Kloosterman, W. (Wp), Abdellaoui, A. (Abdel), van Leeuwen, E. (Em), Oven, M. (Mannis) van, Li, M. (M.), Laros, J. (Jf), Karssen, L.C. (Lennart), Kanterakis, A. (Alexandros), Amin, N. (Najaf), Hottenga, J. (Jj), Lameijer, E. (Ew), Kattenberg, V.M. (Mathijs), Dijkstra, M. (Martijn), Byelas, H. (Heorhiy), Setten, J. (Jessica) van, van Schaik, B. (Bd), Bot, J.J. (Jan), Nijman, I. (Ij), Renkens, I. (Ivo), Marschall, T. (Tanja), Schönhuth, A. (A.), Hehir-Kwa, J. (Jayne), Handsaker, R.E. (Robert), Polak, P., Sohail, M. (Mashaal), Vuzman, D. (Dana), Hormozdiari, F. (Fereydoun), Enckevort, D. (David) van, Mei, H. (H.), Koval, V. (Vyacheslav), Moed, M. (Mh), van der Velde, K. (Kj), Rivadeneira Ramirez, F. (Fernando), Estrada Gil, K. (Karol), Medina-Gomez, M.C. (Carolina), McCarroll, S. (Sa), de Craen, A. (Aj), Suchiman, H. (He), Hofman, B. (Ba), Oostra, B.A. (Ben), Uitterlinden, A. (Ag), Willemsen, G.A.H.M. (Gonneke), Platteel, I. (Inge), Veldink, J. (Jh), van den Berg, L. (Lh), Pitts, S. (Sj), Potluri, S. (Shobha), Sundar, P. (Purnima), Cox, D. (Dr), Sunyaev, S. (Sr), den Dunnen, J. (Jt), Stoneking, M. (Mark), Knijff, P. (Peter) de, Kayser, M.H. (Manfred), Li, Q. (Q.), Li, Y. (Y.), Du, Y. (Y.), Chen, R. (R.), Cao, H. (H.), Li, N. (N.), Cao, S. (Sherry), Wang, J. (J.), Bovenberg, J.A. (Jasper), Peer, I. (Itsik), Slagboom, P. (Pe), van Duijn, C. (Cm), Boomsma, D. (Di), van Ommen, G. (Gj), de Bakker, P. (Pi), Swertz, M. (Ma), Wijmenga, C. (C.), Shvetsova, E. (Ekaterina), Sofronova, A. (Alina), Monajemi, R. (Ramin), Gagalova, K. (Kristina), Draisma, G. (Gerrit), White, S.J. (Stefan), Santen, G.W.E. (Gijs), Chuva De Sousa Lopes, S.M. (Susana M.), Heijmans, B.T. (Bastiaan T.), van Meurs, J. (Joyce), Jansen, R. (Rick), Franke, L. (Lude), Kielbasa, S.M. (Szymon M.), Dunnen, J.T. (Johan) den, ‘t Hoen, P.A.C. (Peter A. C.), Heijmans, B.T. (Bastiaan T), Meurs, J.B.J. (Joyce) van, Boomsma, D.I. (Dorret), Pool, R. (Reńe), Dongen, J. (Jenny) van, Hottenga, J.J. (Jouke Jan), Greevenbroek, M.M. van, Stehouwer, C.D. (Coen Da), Kallen, C.J. van der, Schalkwijk, C.G. (Casper), Wijmenga, C. (Cisca), Zhernakova, S. (Sasha), Tigchelaar, E.F. (Ettje F.), Slagboom, P.E. (Eline), Beekman, M. (Marian), Deelen, J. (Joris), Heemst, D. (Diana) van, Veldink, J.H. (Jan), Berg, L.H. (Leonard) van den, Duijn, C.M. (Cornelia) van, Hofman, B.A. (Bert A), Uitterlinden, A.G. (André), Jhamai, P.M. (Mila), Verbiest, M.M.P.J. (Michael), Suchiman, H.E.D. (H Eka D), Verkerk, M. (Marijn), Breggen, R. (Ruud) van der, van Rooij, J. (Jeroen), Lakenberg, N. (Nico), Mei, S. (Shan), Bot, J. (Jan), Zhernakova, D.V. (Dasha V), van ’t Hof, P. (Peter), Deelen, P. (Patrick), Nooren, I. (Irene), Moed, H. (Heleen), Vermaat, M. (Martijn), Luijk, R. (René), Jan Bonder, M. (Marc), Iterson, M. (Maarten) van, van Dijk, F. (Freerk), Van Galen, M. (Michiel), Arindrarto, W. (Wibowo), Swertz, M.A. (Morris A), Zwet, E.W. (Erik) van, Isaacs, A.J. (Aaron), Francioli, L.C. (Laurent), Menelaou, A. (Androniki), Pulit, S.L. (Sara), Dijk, F. (Freerk) van, Palamara, P.F. (Pier Francesco), Elbers, C.C. (Clara), Neerincx, P.B.T. (Pieter B T), Ye, K. (K.), Guryev, V. (Victor), Kloosterman, W. (Wp), Abdellaoui, A. (Abdel), van Leeuwen, E. (Em), Oven, M. (Mannis) van, Li, M. (M.), Laros, J. (Jf), Karssen, L.C. (Lennart), Kanterakis, A. (Alexandros), Amin, N. (Najaf), Hottenga, J. (Jj), Lameijer, E. (Ew), Kattenberg, V.M. (Mathijs), Dijkstra, M. (Martijn), Byelas, H. (Heorhiy), Setten, J. (Jessica) van, van Schaik, B. (Bd), Bot, J.J. (Jan), Nijman, I. (Ij), Renkens, I. (Ivo), Marschall, T. (Tanja), Schönhuth, A. (A.), Hehir-Kwa, J. (Jayne), Handsaker, R.E. (Robert), Polak, P., Sohail, M. (Mashaal), Vuzman, D. (Dana), Hormozdiari, F. (Fereydoun), Enckevort, D. (David) van, Mei, H. (H.), Koval, V. (Vyacheslav), Moed, M. (Mh), van der Velde, K. (Kj), Rivadeneira Ramirez, F. (Fernando), Estrada Gil, K. (Karol), Medina-Gomez, M.C. (Carolina), McCarroll, S. (Sa), de Craen, A. (Aj), Suchiman, H. (He), Hofman, B. (Ba), Oostra, B.A. (Ben), Uitterlinden, A. (Ag), Willemsen, G.A.H.M. (Gonneke), Platteel, I. (Inge), Veldink, J. (Jh), van den Berg, L. (Lh), Pitts, S. (Sj), Potluri, S. (Shobha), Sundar, P. (Purnima), Cox, D. (Dr), Sunyaev, S. (Sr), den Dunnen, J. (Jt), Stoneking, M. (Mark), Knijff, P. (Peter) de, Kayser, M.H. (Manfred), Li, Q. (Q.), Li, Y. (Y.), Du, Y. (Y.), Chen, R. (R.), Cao, H. (H.), Li, N. (N.), Cao, S. (Sherry), Wang, J. (J.), Bovenberg, J.A. (Jasper), Peer, I. (Itsik), Slagboom, P. (Pe), van Duijn, C. (Cm), Boomsma, D. (Di), van Ommen, G. (Gj), de Bakker, P. (Pi), Swertz, M. (Ma), and Wijmenga, C. (C.)

Abstract

X-inactivation is a well-established dosage compensation mechanism ensuring that X-chromosomal genes are expressed at comparable levels in males and females. Skewed X-inactivation is often explained by negative selection of one of the alleles. We demonstrate that imbalanced expression of the paternal and maternal X-chromosomes is common in the general population and that the random nature of the X-inactivation mechanism can be sufficient to explain the imbalance. To this end, we analyzed blood-derived RNA and whole-genome sequencing data from 79 female children and their parents from the Genome of the Netherlands project. We calculated the median ratio of the paternal over total counts at all X-chromosomal heterozygous single-nucleotide variants with coverage ≥10. We identified two individuals where the same X-chromosome was inactivated in all cells. Imbalanced expression of the two X-chromosomes (ratios ≤0.35 or ≥0.65) was observed in nearly 50% of the population. The empirically observed skewing is explained by a theoretical model where X-inactivation takes place in an embryonic stage in which eight cells give rise to the hematopoietic compartment. Genes escaping X-inactivation are expressed from both alleles and therefore demonstrate less skewing than inactivated genes. Using this characteristic, we identified three novel escapee genes (SSR4, REPS2, and SEPT6), but did not find support for many previously reported escapee genes in blood. Our collective data suggest that skewed X-inactivation is common in the general population. This may contribute to manifestation of symptoms in carriers of recessive X-linked disorders. We recommend that X-inactivation results should not be used lightly in the interpretation of X-linked variants.

Published
2018
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6. Skewed X-inactivation is common in the general female population

Author

Shvetsova, E. (Ekaterina), Sofronova, A. (Alina), Monajemi, R. (Ramin), Gagalova, K. (Kristina), Draisma, H.H.M. (Harmen), White, S.J. (Stefan), Santen, G.W.E. (Gijs), Chuva de Sousa Lopes, S.M. (Susana), Heijmans, B.T. (Bastiaan), Meurs, J. (Joyce) van, Jansen, R. (Rick), Franke, L. (Lude), Kiełbasa, S.M. (Szymon), Dunnen, J.T. (Johan) den, Hoen, P.A.C. (Peter) ‘t, BIOS consortium, GoNL consortium, Shvetsova, E. (Ekaterina), Sofronova, A. (Alina), Monajemi, R. (Ramin), Gagalova, K. (Kristina), Draisma, H.H.M. (Harmen), White, S.J. (Stefan), Santen, G.W.E. (Gijs), Chuva de Sousa Lopes, S.M. (Susana), Heijmans, B.T. (Bastiaan), Meurs, J. (Joyce) van, Jansen, R. (Rick), Franke, L. (Lude), Kiełbasa, S.M. (Szymon), Dunnen, J.T. (Johan) den, Hoen, P.A.C. (Peter) ‘t, BIOS consortium, and GoNL consortium

Abstract

X-inactivation is a well-established dosage compensation mechanism ensuring that X-chromosomal genes are expressed at comparable levels in males and females. Skewed X-inactivation is often explained by negative selection of one of the alleles. We demonstrate that imbalanced expression of the paternal and maternal X-chromosomes is common in the general population and that the random nature of the X-inactivation mechanism can be sufficient to explain the imbalance. To this end, we analyzed blood-derived RNA and whole-genome sequencing data from 79 female children and their parents from the Genome of the Netherlands project. We calculated the median ratio of the paternal over total counts at all X-chromosomal heterozygous single-nucleotide variants with coverage ≥10. We identified two individuals where the same X-chromosome was inactivated in all cells. Imbalanced expression of the two X-chromosomes (ratios ≤0.35 or ≥0.65) was observed in nearly 50% of the population. The empirically observed skewing is explained by a theoretical model where X-inactivation takes place in an embryonic stage in which eight cells give rise to the hematopoietic compartment. Genes escaping X-inactivation are expressed from both alleles and therefore demonstrate less skewing than inactivated genes. Using this characteristic, we identified three novel escapee genes (SSR4, REPS2, and SEPT6), but did not find support for many previously reported escapee genes in blood. Our collective data suggest that skewed X-inactivation is common in the general population. This may contribute to manifestation of symptoms in carriers of recessive X-linked disorders. We recommend that X-inactivation results should not be used lightly in the interpretation of X-linked variants.

Published
2018
Full Text
View/download PDF

7. Skewed X-inactivation is common in the general female population

Author

Shvetsova, E. (Ekaterina), Sofronova, A. (Alina), Monajemi, R. (Ramin), Gagalova, K. (Kristina), Draisma, H.H.M. (Harmen), White, S.J. (Stefan), Santen, G.W.E. (Gijs), Chuva de Sousa Lopes, S.M. (Susana), Heijmans, B.T. (Bastiaan), Meurs, J. (Joyce) van, Jansen, R. (Rick), Franke, L. (Lude), Kiełbasa, S.M. (Szymon), Dunnen, J.T. (Johan) den, Hoen, P.A.C. (Peter) ‘t, BIOS consortium, GoNL consortium, Shvetsova, E. (Ekaterina), Sofronova, A. (Alina), Monajemi, R. (Ramin), Gagalova, K. (Kristina), Draisma, H.H.M. (Harmen), White, S.J. (Stefan), Santen, G.W.E. (Gijs), Chuva de Sousa Lopes, S.M. (Susana), Heijmans, B.T. (Bastiaan), Meurs, J. (Joyce) van, Jansen, R. (Rick), Franke, L. (Lude), Kiełbasa, S.M. (Szymon), Dunnen, J.T. (Johan) den, Hoen, P.A.C. (Peter) ‘t, BIOS consortium, and GoNL consortium

Abstract

X-inactivation is a well-established dosage compensation mechanism ensuring that X-chromosomal genes are expressed at comparable levels in males and females. Skewed X-inactivation is often explained by negative selection of one of the alleles. We demonstrate that imbalanced expression of the paternal and maternal X-chromosomes is common in the general population and that the random nature of the X-inactivation mechanism can be sufficient to explain the imbalance. To this end, we analyzed blood-derived RNA and whole-genome sequencing data from 79 female children and their parents from the Genome of the Netherlands project. We calculated the median ratio of the paternal over total counts at all X-chromosomal heterozygous single-nucleotide variants with coverage ≥10. We identified two individuals where the same X-chromosome was inactivated in all cells. Imbalanced expression of the two X-chromosomes (ratios ≤0.35 or ≥0.65) was observed in nearly 50% of the population. The empirically observed skewing is explained by a theoretical model where X-inactivation takes place in an embryonic stage in which eight cells give rise to the hematopoietic compartment. Genes escaping X-inactivation are expressed from both alleles and therefore demonstrate less skewing than inactivated genes. Using this characteristic, we identified three novel escapee genes (SSR4, REPS2, and SEPT6), but did not find support for many previously reported escapee genes in blood. Our collective data suggest that skewed X-inactivation is common in the general population. This may contribute to manifestation of symptoms in carriers of recessive X-linked disorders. We recommend that X-inactivation results should not be used lightly in the interpretation of X-linked variants.

Published
2018
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8. The implicitome: A resource for rationalizing gene-disease associations

Author

Hettne, K.M. (Kristina), Thompson, M. (Mark), Haagen, H.H.H.B.M. (Herman) van, Van Der Horst, E. (Eelke), Kaliyaperumal, R. (Rajaram), Mina, E. (Eleni), Tatum, Z. (Zuotian), Laros, J.F.J. (Jeroen F.), Van Mulligen, E.M. (Erik M.), Schuemie, M.J. (Martijn), Emmelien, A. (Aten), Li, T.S. (Tong Shu), Bruskiewich, R. (Richard), Good, B.M. (Benjamin M.), Su, A.I. (Andrew I.), Kors, J.A. (Jan), Dunnen, J.T. (Johan) den, Van Ommen, G.-J.B. (Gert-Jan B.), Roos, M. (Marco), Hoen, P.A.C. (Peter) 't, Mons, B. (Barend), Schultes, E. (Erik), Hettne, K.M. (Kristina), Thompson, M. (Mark), Haagen, H.H.H.B.M. (Herman) van, Van Der Horst, E. (Eelke), Kaliyaperumal, R. (Rajaram), Mina, E. (Eleni), Tatum, Z. (Zuotian), Laros, J.F.J. (Jeroen F.), Van Mulligen, E.M. (Erik M.), Schuemie, M.J. (Martijn), Emmelien, A. (Aten), Li, T.S. (Tong Shu), Bruskiewich, R. (Richard), Good, B.M. (Benjamin M.), Su, A.I. (Andrew I.), Kors, J.A. (Jan), Dunnen, J.T. (Johan) den, Van Ommen, G.-J.B. (Gert-Jan B.), Roos, M. (Marco), Hoen, P.A.C. (Peter) 't, Mons, B. (Barend), and Schultes, E. (Erik)

Abstract

High-throughput experimental methods such as medical sequencing and genome-wide association studies (GWAS) identify increasingly large numbers of potential relations between genetic variants and diseases. Both biological complexity (millions of potential gene-disease associations) and the accelerating rate of data production necessitate computational approaches to prioritize and rationalize potential gene-disease relations. Here, we use concept profile technology to expose from the biomedical literature both explicitly stated gene-disease relations (the explicitome) and a much larger set of implied gene-disease associations (the implicitome). Implicit relations are largely unknown to, or are even unintended by the original authors, but they vastly extend the reach of existing b

Published
2016
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9. A high-quality human reference panel reveals the complexity and distribution of genomic structural variants

Author

Hehir-Kwa, J.Y. (Jayne), Marschall, T. (Tobias), Kloosterman, W.P. (Wigard), Francioli, L.C. (Laurent), Baaijens, J.A. (Jasmijn), Dijkstra, L.J. (Louis), Abdellaoui, A. (Abdel), Koval, V. (Vyacheslav), Thung, (), D.T. (Djie Tjwan), Wardenaar, R. (René), Renkens, I. (Ivo), Coe, B.P. (Bradley), Deelen, P. (Patrick), Ligt, J. (Joep) de, Lameijer, E.-W. (Eric-Wubbo), Dijk, F. (Freerk) van, Hormozdiari, F. (Fereydoun), Uitterlinden, A.G. (André), Duijn, C.M. (Cornelia) van, Eichler, E.E. (Evan), Bakker, P.I.W. (Paul) de, Swertz, M.A. (Morris), Wijmenga, C. (Cisca), Ommen, G.-J.B. (Gert-Jan) van, Slagboom, P.E. (Eline), Boomsma, D.I. (Dorret), Schönhuth, A. (Alexander), Ye, K. (Kai), Guryev, V. (Victor), Bovenberg, J.A. (Jasper), Craen, A.J.M. (Anton) de, Beekman, M. (Marian), Hofman, A. (Albert), Willemsen, G. (Gonneke), Wolffenbuttel, B. (Bruce), Platteel, M. (Mathieu), Du, Y. (Yuanping), Chen, R. (Ruoyan), Cao, H. (Hongzhi), Cao, R. (Rui), Sun, Y. (Yushen), Cao, J.S. (Jeremy Sujie), Neerincx, P.B.T. (Pieter), Dijkstra, M. (Martijn), Byelas, G. (George), Kanterakis, A. (Alexandros), Bot, J. (Jan), Vermaat, M. (Martijn), Laros, J.F.J. (Jeroen), Dunnen, J.T. (Johan) den, Knijff, P. (Peter) de, Karssen, L.C. (Lennart), van Leeuwen, E.M. (Elisa), Amin, N. (Najaf), Rivadeneira, F. (Fernando), Estrada, K. (Karol), Hottenga, J.-J. (Jouke-Jan), Kattenberg, V.M. (Mathijs), Enckevort, D. (David) van, Mei, H. (Hailiang), Santcroos, M. (Mark), Schaik, B.D.C. (Barbera) van, Handsaker, R.E. (Robert), McCarroll, S.A. (Steven), Ko, A. (Arthur), Sudmant, P. (Peter), Nijman, I.J. (Isaac), Hehir-Kwa, J.Y. (Jayne), Marschall, T. (Tobias), Kloosterman, W.P. (Wigard), Francioli, L.C. (Laurent), Baaijens, J.A. (Jasmijn), Dijkstra, L.J. (Louis), Abdellaoui, A. (Abdel), Koval, V. (Vyacheslav), Thung, (), D.T. (Djie Tjwan), Wardenaar, R. (René), Renkens, I. (Ivo), Coe, B.P. (Bradley), Deelen, P. (Patrick), Ligt, J. (Joep) de, Lameijer, E.-W. (Eric-Wubbo), Dijk, F. (Freerk) van, Hormozdiari, F. (Fereydoun), Uitterlinden, A.G. (André), Duijn, C.M. (Cornelia) van, Eichler, E.E. (Evan), Bakker, P.I.W. (Paul) de, Swertz, M.A. (Morris), Wijmenga, C. (Cisca), Ommen, G.-J.B. (Gert-Jan) van, Slagboom, P.E. (Eline), Boomsma, D.I. (Dorret), Schönhuth, A. (Alexander), Ye, K. (Kai), Guryev, V. (Victor), Bovenberg, J.A. (Jasper), Craen, A.J.M. (Anton) de, Beekman, M. (Marian), Hofman, A. (Albert), Willemsen, G. (Gonneke), Wolffenbuttel, B. (Bruce), Platteel, M. (Mathieu), Du, Y. (Yuanping), Chen, R. (Ruoyan), Cao, H. (Hongzhi), Cao, R. (Rui), Sun, Y. (Yushen), Cao, J.S. (Jeremy Sujie), Neerincx, P.B.T. (Pieter), Dijkstra, M. (Martijn), Byelas, G. (George), Kanterakis, A. (Alexandros), Bot, J. (Jan), Vermaat, M. (Martijn), Laros, J.F.J. (Jeroen), Dunnen, J.T. (Johan) den, Knijff, P. (Peter) de, Karssen, L.C. (Lennart), van Leeuwen, E.M. (Elisa), Amin, N. (Najaf), Rivadeneira, F. (Fernando), Estrada, K. (Karol), Hottenga, J.-J. (Jouke-Jan), Kattenberg, V.M. (Mathijs), Enckevort, D. (David) van, Mei, H. (Hailiang), Santcroos, M. (Mark), Schaik, B.D.C. (Barbera) van, Handsaker, R.E. (Robert), McCarroll, S.A. (Steven), Ko, A. (Arthur), Sudmant, P. (Peter), and Nijman, I.J. (Isaac)

Abstract

Structural variation (SV) represents a major source of differences between individual human genomes and has been linked to disease phenotypes. However, the majority of studies provide neither a global view of the full spectrum of these variants nor integrate them into reference panels of genetic variation. Here, we analyse whole genome sequencing data of 769 individuals from 250 Dutch families, and provide a haplotype-resolved map of 1.9 million genome variants across 9 different variant classes, including novel forms of complex indels, and retrotransposition-mediated insertions of mobile elements and processed RNAs. A large proportion are previously under reported variants sized between 21 and 100 bp. We detect 4 megabases of novel sequence, encoding 11 new transcripts. Finally, we show 191 known, trait-associated SNPs to be in strong linkage disequilibrium with SVs and demonstrate that our panel facilitates accurate imputation of SVs in unrelated individuals.

Published
2016
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10. A high-quality human reference panel reveals the complexity and distribution of genomic structural variants

Author

Hehir-Kwa, J.Y. (Jayne), Marschall, T. (Tobias), Kloosterman, W.P. (Wigard), Francioli, L.C. (Laurent), Baaijens, J.A. (Jasmijn), Dijkstra, L.J. (Louis), Abdellaoui, A. (Abdel), Koval, V. (Vyacheslav), Thung, (), D.T. (Djie Tjwan), Wardenaar, R. (René), Renkens, I. (Ivo), Coe, B.P. (Bradley), Deelen, P. (Patrick), Ligt, J. (Joep) de, Lameijer, E.-W. (Eric-Wubbo), Dijk, F. (Freerk) van, Hormozdiari, F. (Fereydoun), Uitterlinden, A.G. (André), Duijn, C.M. (Cornelia) van, Eichler, E.E. (Evan), Bakker, P.I.W. (Paul) de, Swertz, M.A. (Morris), Wijmenga, C. (Cisca), Ommen, G.-J.B. (Gert-Jan) van, Slagboom, P.E. (Eline), Boomsma, D.I. (Dorret), Schönhuth, A. (Alexander), Ye, K. (Kai), Guryev, V. (Victor), Bovenberg, J.A. (Jasper), Craen, A.J.M. (Anton) de, Beekman, M. (Marian), Hofman, A. (Albert), Willemsen, G. (Gonneke), Wolffenbuttel, B. (Bruce), Platteel, M. (Mathieu), Du, Y. (Yuanping), Chen, R. (Ruoyan), Cao, H. (Hongzhi), Cao, R. (Rui), Sun, Y. (Yushen), Cao, J.S. (Jeremy Sujie), Neerincx, P.B.T. (Pieter), Dijkstra, M. (Martijn), Byelas, G. (George), Kanterakis, A. (Alexandros), Bot, J. (Jan), Vermaat, M. (Martijn), Laros, J.F.J. (Jeroen), Dunnen, J.T. (Johan) den, Knijff, P. (Peter) de, Karssen, L.C. (Lennart), van Leeuwen, E.M. (Elisa), Amin, N. (Najaf), Rivadeneira, F. (Fernando), Estrada, K. (Karol), Hottenga, J.-J. (Jouke-Jan), Kattenberg, V.M. (Mathijs), Enckevort, D. (David) van, Mei, H. (Hailiang), Santcroos, M. (Mark), Schaik, B.D.C. (Barbera) van, Handsaker, R.E. (Robert), McCarroll, S.A. (Steven), Ko, A. (Arthur), Sudmant, P. (Peter), Nijman, I.J. (Isaac), Hehir-Kwa, J.Y. (Jayne), Marschall, T. (Tobias), Kloosterman, W.P. (Wigard), Francioli, L.C. (Laurent), Baaijens, J.A. (Jasmijn), Dijkstra, L.J. (Louis), Abdellaoui, A. (Abdel), Koval, V. (Vyacheslav), Thung, (), D.T. (Djie Tjwan), Wardenaar, R. (René), Renkens, I. (Ivo), Coe, B.P. (Bradley), Deelen, P. (Patrick), Ligt, J. (Joep) de, Lameijer, E.-W. (Eric-Wubbo), Dijk, F. (Freerk) van, Hormozdiari, F. (Fereydoun), Uitterlinden, A.G. (André), Duijn, C.M. (Cornelia) van, Eichler, E.E. (Evan), Bakker, P.I.W. (Paul) de, Swertz, M.A. (Morris), Wijmenga, C. (Cisca), Ommen, G.-J.B. (Gert-Jan) van, Slagboom, P.E. (Eline), Boomsma, D.I. (Dorret), Schönhuth, A. (Alexander), Ye, K. (Kai), Guryev, V. (Victor), Bovenberg, J.A. (Jasper), Craen, A.J.M. (Anton) de, Beekman, M. (Marian), Hofman, A. (Albert), Willemsen, G. (Gonneke), Wolffenbuttel, B. (Bruce), Platteel, M. (Mathieu), Du, Y. (Yuanping), Chen, R. (Ruoyan), Cao, H. (Hongzhi), Cao, R. (Rui), Sun, Y. (Yushen), Cao, J.S. (Jeremy Sujie), Neerincx, P.B.T. (Pieter), Dijkstra, M. (Martijn), Byelas, G. (George), Kanterakis, A. (Alexandros), Bot, J. (Jan), Vermaat, M. (Martijn), Laros, J.F.J. (Jeroen), Dunnen, J.T. (Johan) den, Knijff, P. (Peter) de, Karssen, L.C. (Lennart), van Leeuwen, E.M. (Elisa), Amin, N. (Najaf), Rivadeneira, F. (Fernando), Estrada, K. (Karol), Hottenga, J.-J. (Jouke-Jan), Kattenberg, V.M. (Mathijs), Enckevort, D. (David) van, Mei, H. (Hailiang), Santcroos, M. (Mark), Schaik, B.D.C. (Barbera) van, Handsaker, R.E. (Robert), McCarroll, S.A. (Steven), Ko, A. (Arthur), Sudmant, P. (Peter), and Nijman, I.J. (Isaac)

Abstract

Structural variation (SV) represents a major source of differences between individual human genomes and has been linked to disease phenotypes. However, the majority of studies provide neither a global view of the full spectrum of these variants nor integrate them into reference panels of genetic variation. Here, we analyse whole genome sequencing data of 769 individuals from 250 Dutch families, and provide a haplotype-resolved map of 1.9 million genome variants across 9 different variant classes, including novel forms of complex indels, and retrotransposition-mediated insertions of mobile elements and processed RNAs. A large proportion are previously under reported variants sized between 21 and 100 bp. We detect 4 megabases of novel sequence, encoding 11 new transcripts. Finally, we show 191 known, trait-associated SNPs to be in strong linkage disequilibrium with SVs and demonstrate that our panel facilitates accurate imputation of SVs in unrelated individuals.

Published
2016
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11. Mitochondrial Disease Sequence Data Resource (MSeqDR): A global grass-roots consortium to facilitate deposition, curation, annotation, and integrated analysis of genomic data for the mitochondrial disease clinical and research communities

Author

Falk, M.J. (Marni J.), Shen, L. (Lishuang), Gonzalez, M. (Michael), Leipzig, J. (Jeremy), Lott, M.T. (Marie T.), Stassen, A.P.M. (Alphons P.M.), Diroma, M.A. (Maria Angela), Navarro-Gomez, D. (Daniel), Yeske, P. (Philip), Bai, R. (Renkui), Boles, R.G. (Richard G.), Brilhante, V. (Virginia), Ralph, D. (David), DaRe, J.T. (Jeana T.), Shelton, R. (Robert), Terry, S.F. (Sharon), Zhang, Z. (Zhe), Copeland, W.C. (William C.), Oven, M. (Mannis) van, Prokisch, H. (Holger), Wallace, D.C., Attimonelli, M. (Marcella), Krotoski, D. (Danuta), Zuchner, S. (Stephan), Gai, X. (Xiaowu), Bale, S. (Sherri), Bedoyan, J. (Jirair), Behar, D.M. (Doron), Bonnen, P. (Penelope), Brooks, L. (Lisa), Calabrese, C. (Claudia), Calvo, S. (Sarah), Chinnery, P.F. (Patrick), Christodoulou, J. (John), Church, D. (Deanna), Clima, R. (Rosanna), Cohen, B.H. (Bruce H.), Cotton, R.G.H. (Richard), Coo, I.F.M. (René) de, Derbenevoa, O. (Olga), Dunnen, J.T. (Johan) den, Dimmock, D. (David), Enns, G. (Gregory), Gasparre, G. (Giuseppe), Goldstein, A. (Amy), Gonzalez, I. (Iris), Gwinn, K. (Katrina), Hahn, S. (Sihoun), Haas, R.H. (Richard H.), Hakonarson, H. (Hakon), Hirano, M. (Michio), Kerr, D. (Douglas), Li, D. (Dong), Lvova, M. (Maria), Macrae, F. (Finley), Maglott, D. (Donna), McCormick, E. (Elizabeth), Mitchell, G. (Grant), Mootha, V.K. (Vamsi K.), Okazaki, Y. (Yasushi), Pujol, A. (Aurora), Parisi, M. (Melissa), Perin, J.C. (Juan Carlos), Pierce, E.A. (Eric A.), Procaccio, V. (Vincent), Rahman, S. (Shamima), Reddi, H. (Honey), Rehm, H. (Heidi), Riggs, E. (Erin), Rodenburg, R.J.T. (Richard), Rubinstein, Y. (Yaffa), Saneto, R. (Russell), Santorsola, M. (Mariangela), Scharfe, C. (Curt), Sheldon, C. (Claire), Shoubridge, E.A. (Eric), Simone, D. (Domenico), Smeets, B. (Bert), Smeitink, J.A.M. (Jan), Stanley, C. (Christine), Suomalainen, A. (Anu), Tarnopolsky, M.A. (Mark), Thiffault, I. (Isabelle), Thorburn, D.R. (David R.), Hove, J.V. (Johan Van), Wolfe, L. (Lynne), Wong, L.-J. (Lee-Jun), Falk, M.J. (Marni J.), Shen, L. (Lishuang), Gonzalez, M. (Michael), Leipzig, J. (Jeremy), Lott, M.T. (Marie T.), Stassen, A.P.M. (Alphons P.M.), Diroma, M.A. (Maria Angela), Navarro-Gomez, D. (Daniel), Yeske, P. (Philip), Bai, R. (Renkui), Boles, R.G. (Richard G.), Brilhante, V. (Virginia), Ralph, D. (David), DaRe, J.T. (Jeana T.), Shelton, R. (Robert), Terry, S.F. (Sharon), Zhang, Z. (Zhe), Copeland, W.C. (William C.), Oven, M. (Mannis) van, Prokisch, H. (Holger), Wallace, D.C., Attimonelli, M. (Marcella), Krotoski, D. (Danuta), Zuchner, S. (Stephan), Gai, X. (Xiaowu), Bale, S. (Sherri), Bedoyan, J. (Jirair), Behar, D.M. (Doron), Bonnen, P. (Penelope), Brooks, L. (Lisa), Calabrese, C. (Claudia), Calvo, S. (Sarah), Chinnery, P.F. (Patrick), Christodoulou, J. (John), Church, D. (Deanna), Clima, R. (Rosanna), Cohen, B.H. (Bruce H.), Cotton, R.G.H. (Richard), Coo, I.F.M. (René) de, Derbenevoa, O. (Olga), Dunnen, J.T. (Johan) den, Dimmock, D. (David), Enns, G. (Gregory), Gasparre, G. (Giuseppe), Goldstein, A. (Amy), Gonzalez, I. (Iris), Gwinn, K. (Katrina), Hahn, S. (Sihoun), Haas, R.H. (Richard H.), Hakonarson, H. (Hakon), Hirano, M. (Michio), Kerr, D. (Douglas), Li, D. (Dong), Lvova, M. (Maria), Macrae, F. (Finley), Maglott, D. (Donna), McCormick, E. (Elizabeth), Mitchell, G. (Grant), Mootha, V.K. (Vamsi K.), Okazaki, Y. (Yasushi), Pujol, A. (Aurora), Parisi, M. (Melissa), Perin, J.C. (Juan Carlos), Pierce, E.A. (Eric A.), Procaccio, V. (Vincent), Rahman, S. (Shamima), Reddi, H. (Honey), Rehm, H. (Heidi), Riggs, E. (Erin), Rodenburg, R.J.T. (Richard), Rubinstein, Y. (Yaffa), Saneto, R. (Russell), Santorsola, M. (Mariangela), Scharfe, C. (Curt), Sheldon, C. (Claire), Shoubridge, E.A. (Eric), Simone, D. (Domenico), Smeets, B. (Bert), Smeitink, J.A.M. (Jan), Stanley, C. (Christine), Suomalainen, A. (Anu), Tarnopolsky, M.A. (Mark), Thiffault, I. (Isabelle), Thorburn, D.R. (David R.), Hove, J.V. (Johan Van), Wolfe, L. (Lynne), and Wong, L.-J. (Lee-Jun)

Abstract

Success rates for genomic analyses of highly heterogeneous disorders can be greatly improved if a large cohort of patient data is assembled to enhance collective capabilities for accurate sequence variant annotation, analysis, and interpretation. Indeed, molecular diagnostics requires the establishment of robust data resources to enable data sharing that informs accurate understanding of genes, variants, and phenotypes. The "Mitochondrial Disease Sequence Data Resource (MSeqDR) Consortium" is a grass-roots effort facilitated by the United Mitochondrial Disease Foundation to identify and prioritize specific genomic data analysis needs of the global mitochondrial disease clinical and research community. A central Web portal (. https://mseqdr.org) facilitates the coherent compilation, organization, annotation, and analysis of sequence data from both nuclear and mitochondrial genomes of individuals and families with suspected mitochondrial disease. This Web portal provides users with a flexible and expandable suite of resources to enable variant-, gene-, and exome-level sequence analysis in a secure, Web-based, and user-friendly fashion. Users can also elect to share data with other MSeqDR Consortium members, or even the general public, either by custom annotation tracks or through the use of a convenient distributed annotation system (DAS) mechanism. A range of data visualization and analysis tools are provided to facilitate user interrogation and understanding of genomic, and ultimately phenotypic, data of relevance to mitochondrial biology and disease. Currently available tools for nuclear and mitochondrial gene analyses include an MSeqDR GBrowse instance that hosts optimized mitochondrial disease and mitochondrial DNA (mtDNA) specific annotation tracks, as well as an MSeqDR locus-specific database (LSDB) that curates variant data on more than 1300 genes that have been implicated in mitochondrial disease and/or encode mitochondria-localized proteins. MSeqDR is integr

Published
2015
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12. Next-generation sequencing-based genome diagnostics across clinical genetics centers: Implementation choices and their effects

Author

Vrijenhoek, T. (T.), Kraaijeveld, K. (Ken), Elferink, M.G. (Martin), Ligt, J. (Joep) de, Kranendonk, E. (Elcke), Santen, G.W.E. (Gijs), Nijman, I.J. (Isaac ), Butler, D. (Derek), Claes, G. (Godelieve), Costessi, A. (Adalberto), Dorlijn, W. (Wim), Van Eyndhoven, W. (Winfried), Halley, D.J.J. (Dicky), Van Den Hout, M.C.G.N. (Mirjam C.G.N.), Van Hove, S. (Steven), Johansson, L.F. (Lennart F.), Jongbloed, J.D.H. (Jan), Kamps, R. (Rick), Kockx, C. (Christel), De Koning, B. (Bart), Kriek, N. (Nadia), Lekanne Dit Deprez, R.H., Lunstroo, H. (Hans), Mannens, M.M.A.M. (Marcel), Mook, O. (Olaf), Nelen, M.R. (Marcel), Ploem, C. (Corrette), Rijnen, M. (Marco), Saris, J.J. (Jasper), Sinke, R.J. (Richard J), Sistermans, E. (Erik), Slegtenhorst, M.A. (Marjon) van, Sleutels, F. (Frank), Stoep, N. (Nienke) van der, Tienhoven, M. (Marianne) van, Vermaat, M. (Martijn), Vogel, M.J. (Maartje), Waisfisz, Q. (Quinten), Weiss, J.M. (Janneke), Wijngaard, A. (Arthur) van den, Workum, W. (W) van, Ijntema, H. (Helger), Zwaag, B. (Bert) van der, IJcken, W.F.J. (Wilfred) van, Dunnen, J.T. (Johan) den, Veltman, J.A. (Joris), Hennekam, R.C.M. (Raoul), Cuppen, E. (Edwin), Vrijenhoek, T. (T.), Kraaijeveld, K. (Ken), Elferink, M.G. (Martin), Ligt, J. (Joep) de, Kranendonk, E. (Elcke), Santen, G.W.E. (Gijs), Nijman, I.J. (Isaac ), Butler, D. (Derek), Claes, G. (Godelieve), Costessi, A. (Adalberto), Dorlijn, W. (Wim), Van Eyndhoven, W. (Winfried), Halley, D.J.J. (Dicky), Van Den Hout, M.C.G.N. (Mirjam C.G.N.), Van Hove, S. (Steven), Johansson, L.F. (Lennart F.), Jongbloed, J.D.H. (Jan), Kamps, R. (Rick), Kockx, C. (Christel), De Koning, B. (Bart), Kriek, N. (Nadia), Lekanne Dit Deprez, R.H., Lunstroo, H. (Hans), Mannens, M.M.A.M. (Marcel), Mook, O. (Olaf), Nelen, M.R. (Marcel), Ploem, C. (Corrette), Rijnen, M. (Marco), Saris, J.J. (Jasper), Sinke, R.J. (Richard J), Sistermans, E. (Erik), Slegtenhorst, M.A. (Marjon) van, Sleutels, F. (Frank), Stoep, N. (Nienke) van der, Tienhoven, M. (Marianne) van, Vermaat, M. (Martijn), Vogel, M.J. (Maartje), Waisfisz, Q. (Quinten), Weiss, J.M. (Janneke), Wijngaard, A. (Arthur) van den, Workum, W. (W) van, Ijntema, H. (Helger), Zwaag, B. (Bert) van der, IJcken, W.F.J. (Wilfred) van, Dunnen, J.T. (Johan) den, Veltman, J.A. (Joris), Hennekam, R.C.M. (Raoul), and Cuppen, E. (Edwin)

Abstract

Implementation of next-generation DNA sequencing (NGS) technology into routine diagnostic genome care requires strategic choices. Instead of theoretical discussions on the consequences of such choices, we compared NGS-based diagnostic practices in eight clinical genetic centers in the Netherlands, based on genetic testing of nine pre-selected patients with cardiomyopathy. We highlight critical implementation choices, including the specific contributions of laboratory and medical specialists, bioinformaticians and researchers to diagnostic genome care, and how these affect interpretation and reporting of variants. Reported pathogenic mutations were consistent for all but one patient. Of the two centers that were inconsistent in their diagnosis, one reported to have found 'no causal variant', thereby underdiagnosing this patient. The other provided an alternative diagnosis, identifying another variant as causal than the other centers. Ethical and legal analysis showed that informed consent procedures in all centers were generally adequate for diagnostic NGS applications that target a limited set of genes, but not for exome- and genome-based diagnosis. We propose changes to further improve and align these procedures, taking into account the blurring boundary between diagnostics and research, and specific counseling options for exome- and genome-based diagnostics. We conclude that alternative diagnoses may infer a certain level of 'greediness' to come to a positive diagnosis in interpreting sequencing results. Moreover, there is an increasing interdependence of clinic, diagnostics and research departments for comprehensive diagnostic genome care. Therefore, we invite clinical geneticists, physicians, researchers, bioinformatics experts and patients to reconsider their role and position in future diagnostic genome care.

Published
2015
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13. The Genome of the Netherlands: Design, and project goals

Author

Boomsma, D.I. (Dorret), Wijmenga, C. (Cisca), Slagboom, P.E. (Eline), Swertz, M. (Morris), Karssen, L.C. (Lennart), Abdellaoui, A. (Abdel), Ye, K. (Kai), Guryev, V. (Victor), Vermaat, J.S. (Joost), Dijk, F. (Freerk) van, Francioli, L.C. (Laurent), Hottenga, J.J. (Jouke Jan), Laros, J.F.J. (Jeroen F.), Li, Q. (Qibin), Li, Y. (Yingrui), Cao, H. (Hongzhi), Chen, R. (Ruoyan), Du, Y. (Yangchun), Li, N. (Ning), Cao, S. (Sherry), Setten, J. (Jessica) van, Menelaou, A. (Androniki), Pulit, S.L. (Sara), Hehir-Kwa, J. (Jayne), Beekman, M. (Marian), Elbers, C.C. (Clara), Byelas, H. (Heorhiy), Craen, A.J. (Anton) de, Deelen, P. (Patrick), Dijkstra, M. (Martijn), Dunnen, J.T. (Johan) den, Knijff, P. (Peter) de, Houwing-Duistermaat, J.J. (Jeanine), Koval, V. (Vyacheslav), Estrada Gil, K. (Karol), Hofman, A. (Albert), Kanterakis, A. (Alexandros), Enckevort, D. (David) van, Mai, H. (Hailiang), Kattenberg, V.M. (Mathijs), Leeuwen, E.M. (Elisa) van, Neerincx, P.B.T. (Pieter B T), Oostra, B.A. (Ben), Rivadeneira Ramirez, F. (Fernando), Suchiman, H.E.D. (Eka), Uitterlinden, A.G. (André), Willemsen, G.A.H.M. (Gonneke), Wolffenbuttel, B.H.R. (Bruce), Wang, J. (Jinxia), Bakker, P.I.W. (Paul) de, Ommen, G.J. (Gert) van, Duijn, C.M. (Cornelia) van, Boomsma, D.I. (Dorret), Wijmenga, C. (Cisca), Slagboom, P.E. (Eline), Swertz, M. (Morris), Karssen, L.C. (Lennart), Abdellaoui, A. (Abdel), Ye, K. (Kai), Guryev, V. (Victor), Vermaat, J.S. (Joost), Dijk, F. (Freerk) van, Francioli, L.C. (Laurent), Hottenga, J.J. (Jouke Jan), Laros, J.F.J. (Jeroen F.), Li, Q. (Qibin), Li, Y. (Yingrui), Cao, H. (Hongzhi), Chen, R. (Ruoyan), Du, Y. (Yangchun), Li, N. (Ning), Cao, S. (Sherry), Setten, J. (Jessica) van, Menelaou, A. (Androniki), Pulit, S.L. (Sara), Hehir-Kwa, J. (Jayne), Beekman, M. (Marian), Elbers, C.C. (Clara), Byelas, H. (Heorhiy), Craen, A.J. (Anton) de, Deelen, P. (Patrick), Dijkstra, M. (Martijn), Dunnen, J.T. (Johan) den, Knijff, P. (Peter) de, Houwing-Duistermaat, J.J. (Jeanine), Koval, V. (Vyacheslav), Estrada Gil, K. (Karol), Hofman, A. (Albert), Kanterakis, A. (Alexandros), Enckevort, D. (David) van, Mai, H. (Hailiang), Kattenberg, V.M. (Mathijs), Leeuwen, E.M. (Elisa) van, Neerincx, P.B.T. (Pieter B T), Oostra, B.A. (Ben), Rivadeneira Ramirez, F. (Fernando), Suchiman, H.E.D. (Eka), Uitterlinden, A.G. (André), Willemsen, G.A.H.M. (Gonneke), Wolffenbuttel, B.H.R. (Bruce), Wang, J. (Jinxia), Bakker, P.I.W. (Paul) de, Ommen, G.J. (Gert) van, and Duijn, C.M. (Cornelia) van

Abstract

Within the Netherlands a national network of biobanks has been established (Biobanking and Biomolecular Research Infrastructure-Netherlands (BBMRI-NL)) as a national node of the European BBMRI. One of the aims of BBMRI-NL is to enrich biobanks with different types of molecular and phenotype data. Here, we describe the Genome of the Netherlands (GoNL), one of the projects within BBMRI-NL. GoNL is a whole-genome-sequencing project in a representative sample consisting of 250 trio-families from all provinces in the Netherlands, which aims to characterize DNA sequence variation in the Dutch population. The parent-offspring trios include adult individuals ranging in age from 19 to 87 years (mean=53 years; SD=16 years) from birth cohorts 1910-1994. Sequencing was done on blood-derived DNA from uncultured cells and accomplished coverage was 14-15x. The family-based design represents a unique resource to assess the frequency of regional variants, accurately reconstruct haplotypes by family-based phasing, characterize short indels and complex structural variants, and establish the rate of de novo mutational events. GoNL will also serve as a reference panel for imputation in the available genome-wide association studies in Dutch and other cohorts to refine association signals and uncover population-specific variants. GoNL will create a catalog of human genetic variation in this sample that is uniquely characterized with respect to micro-geographic location and a wide range of phenotypes. The resource will be made available to the research and medical community to guide the interpretation of sequencing projects. The present paper summarizes the global characteristics of the project.

Published
2014
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14. Developing a set of ancestry-sensitive DNA markers reflecting continental origins of humans

Author

Kersbergen, P. (Paula), Duijn, K. (Kate) van, Kloosterman, A. (Ate), Dunnen, J.T. (Johan) den, Kayser, M.H. (Manfred), Knijff, P. (Peter) de, Kersbergen, P. (Paula), Duijn, K. (Kate) van, Kloosterman, A. (Ate), Dunnen, J.T. (Johan) den, Kayser, M.H. (Manfred), and Knijff, P. (Peter) de

Abstract

Background: The identification and use of Ancestry-Sensitive Markers (ASMs), i.e. genetic polymorphisms facilitating the genetic reconstruction of geographical origins of individuals, is far from straightforward. Results: Here we describe the ascertainment and application of five different sets of 47 single nucleotide polymorphisms (SNPs) allowing the inference of major human groups of different continental origin. For this, we first used 74 cell lines, representing human males from six different geographical areas and screened them with the Affymetrix Mapping 10K assay. In addition to using summary statistics estimating the genetic diversity among multiple groups of individuals defined by geography or language, we also used the program STRUCTURE to detect genetically distinct subgroups. Subsequently, we used a pairwise FSTranking procedure among all pairs of genetic subgroups in order to identify a single best performing set of ASMs. Our initial results were independently confirmed by genotyping this set of ASMs in 22 individuals from Somalia, Afghanistan and Sudan and in 919 samples from the CEPH Human Genome Diversity Panel (HGDP-CEPH). Conclusion: By means of our pairwise population FSTranking approach we identified a set of 47 SNPs that could serve as a panel of ASMs at a continental level.

Published
2009
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15. Identification of a region required for TSC1 stability by functional analysis of TSC1 missense mutations found in individuals with tuberous sclerosis complex

Author

Mozaffari, E. (Melika), Hoogeveen-Westerveld, M. (Marianne), Kwiatkowski, D. (David), Sampson, J. (Julian), Ekong, R. (Rosemary), Povey, S. (Sue), Dunnen, J.T. (Johan) den, Ouweland, A.M.W. (Ans) van den, Halley, D.J.J. (Dicky), Nellist, M.D. (Mark), Mozaffari, E. (Melika), Hoogeveen-Westerveld, M. (Marianne), Kwiatkowski, D. (David), Sampson, J. (Julian), Ekong, R. (Rosemary), Povey, S. (Sue), Dunnen, J.T. (Johan) den, Ouweland, A.M.W. (Ans) van den, Halley, D.J.J. (Dicky), and Nellist, M.D. (Mark)

Abstract

Background: Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterised by the development of hamartomas in a variety of organs and tissues. The disease is caused by mutations in either the TSC1 gene on chromosome 9q34, or the TSC2 gene on chromosome 16p13.3. The TSC1 and TSC2 gene products, TSC1 and TSC2, form a protein complex that inhibits signal transduction to the downstream effectors of the mammalian target of rapamycin (mTOR). Recently it has been shown that missense mutations to the TSC1 gene can cause TSC. Methods: We have used in vitro biochemical assays to investigate the effects on TSC1 function of TSC1 missense variants submitted to the Leiden Open Variation Database. Results: We identified specific substitutions between amino acids 50 and 190 in the N-terminal region of TSC1 that result in reduced steady state levels of the protein and lead to increased mTOR signalling. Conclusion: Our results suggest that amino acid residues within the N-terminal region of TSC1 are important for TSC1 function and for maintaining the activity of the TSC1-TSC2 complex.

Published
2009
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16. Novel protein-protein interactions inferred from literature context

Author

Haagen, H.H.H.B.M. (Herman) van, Hoen, P.A.C. (Peter) 't, Bovo, A.B., Morrée, A. (Antoine) de, Mulligen, E.M. (Erik) van, Chichester, C. (Christine), Kors, J.A. (Jan), Dunnen, J.T. (Johan) den, Ommen, G.J.B. van, Maarel, S.M. (Silvère) van der, Kern, V.M., Mons, B. (Barend), Schuemie, M.J. (Martijn), Haagen, H.H.H.B.M. (Herman) van, Hoen, P.A.C. (Peter) 't, Bovo, A.B., Morrée, A. (Antoine) de, Mulligen, E.M. (Erik) van, Chichester, C. (Christine), Kors, J.A. (Jan), Dunnen, J.T. (Johan) den, Ommen, G.J.B. van, Maarel, S.M. (Silvère) van der, Kern, V.M., Mons, B. (Barend), and Schuemie, M.J. (Martijn)

Abstract

We have developed a method that predicts Protein-Protein Interactions (PPIs) based on the similarity of the context in which proteins appear in literature. This method outperforms previously developed PPI prediction algorithms that rely on the conjunction of two protein names in MEDLINE abstracts. We show significant increases in coverage (76% versus 32%) and sensitivity (66% versus 41% at a specificity of 95%) for the prediction of PPIs currently archived in 6 PPI databases. A retrospective analysis shows that PPIs can efficiently be predicted before they enter PPI databases and before their interaction is explicitly described in the literature. The practical value of the method for discovery of novel PPIs is illustrated by the experimental confirmation of the inferred physical interaction between CAPN3 and PARVB, which was based on frequent co-occurrence of both proteins with concepts like Z-disc, dysferlin, and alpha-actinin. The relationships between proteins predicted by our method are broader than PPIs, and include proteins in the same complex or pathway. Dependent on the type of relationships deemed useful, the precision of our method can be as high as 90%. The full set of predicted interactions is available in a downloadable matrix and through the webtool Nermal, which lists the most likely interaction partners for a given protein. Our framework can be used for prioritizing potential interaction partners, hitherto undiscovered, for follow-up studies and to aid the generation of accurate protein interaction maps.

Published
2009
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17. Literature-aided meta-analysis of microarray data: A compendium study on muscle development and disease

Author

Jelier, R. (Rob), Hoen, P.A.C. (Peter) 't, Sterrenburg, E. (Ellen), Dunnen, J.T. (Johan) den, Ommen, G.J. (Gert) van, Kors, J.A. (Jan), Mons, B. (Barend), Jelier, R. (Rob), Hoen, P.A.C. (Peter) 't, Sterrenburg, E. (Ellen), Dunnen, J.T. (Johan) den, Ommen, G.J. (Gert) van, Kors, J.A. (Jan), and Mons, B. (Barend)

Abstract

Background: Comparative analysis of expression microarray studies is difficult due to the large influence of technical factors on experimental outcome. Still, the identified differentially expressed genes may hint at the same biological processes. However, manually curated assignment of genes to biological processes, such as pursued by the Gene Ontology (GO) consortium, is incomplete and limited. We hypothesised that automatic association of genes with biological processes through thesaurus-controlled mining of Medline abstracts would be more effective. Therefore, we developed a novel algorithm (LAMA: Literature-Aided Meta-Analysis) to quantify the similarity between transcriptomics studies. We evaluated our algorithm on a large compendium of 102 microarray studies published in the field of muscle development and disease, and compared it to similarity measures based on gene overlap and over-representation of biological processes assigned by GO. Results: While the overlap in both genes and overrepresented GO-terms was poor, LAMA retrieved many more biologically meaningful links between studies, with substantially lower influence of technical factors. LAMA correctly grouped muscular dystrophy, regeneration and myositis studies, and linked patient and corresponding mouse model studies. LAMA also retrieves the connecting biological concepts. Among other new discoveries, we associated cullin proteins, a class of ubiquitinylation proteins, with genes down-regulated during muscle regeneration, whereas ubiquitinylation was previously reported to be activated during the inverse process: muscle atrophy. Conclusion: Our literature-based association analysis is capable of finding hidden common biological denominators in microarray studies, and circumvents the need for raw data analysis or curated gene annotation databases.

Published
2008
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18. Calling on a million minds for community annotation in WikiProteins

Author

Mons, B. (Barend), Ashburner, M. (Michael), Chichester, C. (Christine), Mulligen, E.M. (Erik) van, Weeber, M. (Marc), Dunnen, J.T. (Johan) den, Ommen, G.J. (Gert) van, Musen, M. (Mark), Cockerill, M. (Matthew), Hermjakob, H. (Henning), Packer, A. (Abel), Pacheco, R. (Roberto), Lewis, S. (Suzan), Berkeley, A. (Alfred), Melton, W. (William), Barris, N. (Nickolas), Wales, J. (Jimmy), Meijssen, G. (Gerard), Moeller, E. (Erik), Roes, P.J., Borner, K. (Katy), Bairoch, A. (Amos), Mons, B. (Barend), Ashburner, M. (Michael), Chichester, C. (Christine), Mulligen, E.M. (Erik) van, Weeber, M. (Marc), Dunnen, J.T. (Johan) den, Ommen, G.J. (Gert) van, Musen, M. (Mark), Cockerill, M. (Matthew), Hermjakob, H. (Henning), Packer, A. (Abel), Pacheco, R. (Roberto), Lewis, S. (Suzan), Berkeley, A. (Alfred), Melton, W. (William), Barris, N. (Nickolas), Wales, J. (Jimmy), Meijssen, G. (Gerard), Moeller, E. (Erik), Roes, P.J., Borner, K. (Katy), and Bairoch, A. (Amos)

Abstract

WikiProteins enables community annotation in a Wiki-based system. Extracts of major data sources have been fused into an editable environment that links out to the original sources. Data from community edits create automatic copies of the original data. Semantic technology captures concepts co-occurring in one sentence and thus potential factual statements. In addition, indirect associations between concepts have been calculated. We call on a 'million minds' to annotate a 'million concepts' and to collect facts from the literature with the reward of collaborative knowledge discovery. The system is available for beta testing at http://www.wikiprofessional.org. A preview of the version highlighted by WikiProfessional is available at: http://conceptweblinker.wikiprofessional.org/default.py?url= nph-proxy.cgi/010000A/http/genomebiology.com/2008/9/5/R89

Published
2008
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19. Successful long-term growth hormone therapy in a girl with haploinsufficiency of the insulin-like growth factor-I receptor due to a terminal 15q26.2->qter deletion detected by multiplex ligation probe amplification

Author

Walenkamp, M.J.E. (Marie), Muinck Keizer-Schrama, S.M.P.F. (Sabine) de, Mos, M. (Marianne) de, Kalf, M.E. (Margot), Duyvenvoorde, H.A. (Hermine) van, Boot, A.M. (Annemieke), Kant, S.G. (Sarina), White, S.J. (Stefan), Losekoot, M. (Monique), Dunnen, J.T. (Johan) den, Karperien, M. (Marcel), Wit, J.M. (Jan), Walenkamp, M.J.E. (Marie), Muinck Keizer-Schrama, S.M.P.F. (Sabine) de, Mos, M. (Marianne) de, Kalf, M.E. (Margot), Duyvenvoorde, H.A. (Hermine) van, Boot, A.M. (Annemieke), Kant, S.G. (Sarina), White, S.J. (Stefan), Losekoot, M. (Monique), Dunnen, J.T. (Johan) den, Karperien, M. (Marcel), and Wit, J.M. (Jan)

Abstract

Context: Microscopically visible heterozygous terminal 15q deletions encompassing the IGF1R gene are rare and usually associated with intrauterine growth retardation and short stature. The incidence of submicroscopic deletions is unknown, as is the effect of GH therapy in this condition. Objective: The objective of the study was to describe the use of a novel genetic technique [multiplex ligation probe amplification (MLPA)] to detect haploinsufficiency of the IGF1R gene in a patient suspected of an IGF1R gene defect and evaluate the effect of long-term GH therapy. Patient: A 15-yr-old adolescent, born small for gestational age, showed persistent postnatal growth retardation, microcephaly, and elevated IGF-I levels. She had been treated with GH since the age of 5 yr. Methods: MLPA and array comparative genomic hybridization (aCGH) were performed to examine gene copy number changes. Dermal fibroblast cultures were used for functional analysis. Results: With MLPA, a deletion of one copy of the IGF1R gene was detected, defined by aCGH as a loss of 15q26.2->qter. IGF1R mRNA expression was decreased in fibroblasts. IGF-I binding and type 1 IGF receptor protein expression as well as activation of type 1 IGF receptor autophosphorylation and protein kinase B/Akt by IGF-I tended to be lower, but this did not reach statistical significance. GH treatment resulted in a good growth response and a normal adult height. Conclusions: MLPA and aCGH are useful tools to detect submicroscopic deletions of the IGF1R gene in patients born small for gestational age with persistent growth failure. The phenotype resembles that of a heterozygous inactivating IGF1R mutation. Long-term GH therapy causes growth acceleration in childhood and a normal adult height. Copyright

Published
2008
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20. Three Genome-wide Association Studies and a Linkage Analysis Identify HERC2 as a Human Iris Color Gene

Author

Kayser, M.H. (Manfred), Liu, F. (Fan), Janssens, A.C.J.W. (Cécile), Rivadeneira Ramirez, F. (Fernando), Lao Grueso, O. (Oscar), Duijn, K. (Kate) van, Vermeulen, M. (Mark), Arp, P.P. (Pascal), Jhamai, M. (Mila), IJcken, W.F.J. (Wilfred) van, Dunnen, J.T. (Johan) den, Heath, S.C. (Simon), Zelenika, D. (Diana), Despriet, D.D.G. (Dominique), Klaver, C.C.W. (Caroline), Vingerling, J.R. (Hans), Jong, P.T.V.M. (Paulus) de, Hofman, A. (Albert), Aulchenko, Y.S. (Yurii), Uitterlinden, A.G. (André), Oostra, B.A. (Ben), Kayser, M.H. (Manfred), Liu, F. (Fan), Janssens, A.C.J.W. (Cécile), Rivadeneira Ramirez, F. (Fernando), Lao Grueso, O. (Oscar), Duijn, K. (Kate) van, Vermeulen, M. (Mark), Arp, P.P. (Pascal), Jhamai, M. (Mila), IJcken, W.F.J. (Wilfred) van, Dunnen, J.T. (Johan) den, Heath, S.C. (Simon), Zelenika, D. (Diana), Despriet, D.D.G. (Dominique), Klaver, C.C.W. (Caroline), Vingerling, J.R. (Hans), Jong, P.T.V.M. (Paulus) de, Hofman, A. (Albert), Aulchenko, Y.S. (Yurii), Uitterlinden, A.G. (André), and Oostra, B.A. (Ben)

Abstract

Human iris color was one of the first traits for which Mendelian segregation was established. To date, the genetics of iris color is still not fully understood and is of interest, particularly in view of forensic applications. In three independent genome-wide association (GWA) studies of a total of 1406 persons and a genome-wide linkage study of 1292 relatives, all from the Netherlands, we found that the 15q13.1 region is the predominant region involved in human iris color. There were no other regions showing consistent genome-wide evidence for association and linkage to iris color. Single nucleotide polymorphisms (SNPs) in the HERC2 gene and, to a lesser extent, in the neighboring OCA2 gene were independently associated to iris color variation. OCA2 has been implicated in iris color previously. A replication study within two populations confirmed that the HERC2 gene is a new and significant determinant of human iris color variation, in addition to OCA2. Furthermore, HERC2 rs916977 showed a clinal allele distribution across 23 European populations, which was significantly correlated to iris color variation. We suggest that genetic variants regulating expression of the OCA2 gene exist in the HERC2 gene or, alternatively, within the 11.7 kb of sequence between OCA2 and HERC2, and that most iris color variation in Europeans is explained by those two genes. Testing markers in the HERC2-OCA2 region may be useful in forensic applications to predict eye color phenotypes of unknown persons of European genetic origin.

Published
2008
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21. Rapid detection of BRCA1 mutations by the protein truncation test

Author

Hogervorst, F.B.L. (Frans), Cornelis, R.S. (Renée), Bout, M. (Mattie), Vliet, M. (Margreethe) van, Oosterwijk, J.C. (Jan), Olmer, R. (Renske), Bakker, B. (Boudewijn), Klijn, J.G.M. (Jan), Vasen, H. (Hans), Meijers-Heijboer, H. (Hanne), Menko, F. (Fred), Cornelisse, G.J. (Gees), Dunnen, J.T. (Johan) den, Devilee, P. (Peter), Ommen, G.J. (Gert) van, Hogervorst, F.B.L. (Frans), Cornelis, R.S. (Renée), Bout, M. (Mattie), Vliet, M. (Margreethe) van, Oosterwijk, J.C. (Jan), Olmer, R. (Renske), Bakker, B. (Boudewijn), Klijn, J.G.M. (Jan), Vasen, H. (Hans), Meijers-Heijboer, H. (Hanne), Menko, F. (Fred), Cornelisse, G.J. (Gees), Dunnen, J.T. (Johan) den, Devilee, P. (Peter), and Ommen, G.J. (Gert) van

Abstract

More than 75% of the reported mutations in the hereditary breast and ovarian cancer gene, BRCA1, result in truncated proteins. We have used the protein truncation test (PIT) to screen for mutations in exon 11, which encodes 61 % of BRCA1. In 45 patients from breast and/or ovarian cancer families we found six novel mutations: two single nucleotide insertions, three small deletions (1−5 bp) and a nonsense mutation identified two unrelated families. Furthermore, we were able to amplify the remaining coding region by RT−PCR using lymphocyte RNA. Combined with PTT, we detected aberrantly spliced products affecting exons 5 and 6 in one of two BRCA1−linked families examined. The protein truncation test promises to become a valuable technique in detecting BRCA1 mutations.

Published
1995
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