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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. 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

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. Computational pan-genomics: Status, promises and challenges

Author

Marschall, T. (Tanja), Marz, M. (Manja), Abeel, T. (Thomas), Dijkstra, L. (Louis), Dutilh, B.E. (Bas), Ghaffaari, A. (Ali), Kersey, P. (Paul), Kloosterman, W.P. (Wigard), Mäkinen, V. (Veli), Novak, A.M. (Adam M.), Paten, B. (Benedict), Porubsky, D. (David), Rivals, E. (Eric), Alkan, C. (Can), Baaijens, J.A. (Jasmijn A.), Bakker, P.I.W. (Paul) de, Boeva, V. (Valentina), Bonnal, R.J.P. (Raoul J.P.), Chiaromonte, F. (Francesca), Chikhi, R. (Rayan), Ciccarelli, F.D. (Francesca D.), Cijvat, R. (Robin), Datema, E. (Erwin), Duijn, C.M. (Cornelia) van, Eichler, E.E. (Evan), Ernst, C. (Corinna), Eskin, E. (E.), Garrison, E. (Erik), El-Kebir, M. (Mohammed), Klau, G.W. (Gunnar W.), Korbel, J.O. (Jan), Lameijer, E.-W. (Eric-Wubbo), Langmead, B. (Benjamin), Martin, M. (Marcel), Medvedev, P. (Paul), Mu, J.C. (John C.), Neerincx, P.B.T. (Pieter B T), Ouwens, K. (Klaasjan), Peterlongo, P. (Pierre), Pisanti, N. (Nadia), Rahmann, S. (S.), Raphael, B.J. (Benjamin J.), Reinert, K. (Knut), Ridder, D. (Dick) de, de Ridder, J. (Jeroen), Schlesner, M. (Matthias), Schulz-Trieglaff, O. (Ole), Sanders, A.D. (Ashley D.), Sheikhizadeh, S. (Siavash), Shneider, C. (Carl), Smit, S. (Sandra), Valenzuela, D. (Daniel), Wang, J. (Jiayin), Wessels, L. (Lodewyk), Zhang, Y. (Ying), Guryev, V. (Victor), Vandin, F. (Fabio), Ye, K. (Kai), Schönhuth, A. (Alexander), Marschall, T. (Tanja), Marz, M. (Manja), Abeel, T. (Thomas), Dijkstra, L. (Louis), Dutilh, B.E. (Bas), Ghaffaari, A. (Ali), Kersey, P. (Paul), Kloosterman, W.P. (Wigard), Mäkinen, V. (Veli), Novak, A.M. (Adam M.), Paten, B. (Benedict), Porubsky, D. (David), Rivals, E. (Eric), Alkan, C. (Can), Baaijens, J.A. (Jasmijn A.), Bakker, P.I.W. (Paul) de, Boeva, V. (Valentina), Bonnal, R.J.P. (Raoul J.P.), Chiaromonte, F. (Francesca), Chikhi, R. (Rayan), Ciccarelli, F.D. (Francesca D.), Cijvat, R. (Robin), Datema, E. (Erwin), Duijn, C.M. (Cornelia) van, Eichler, E.E. (Evan), Ernst, C. (Corinna), Eskin, E. (E.), Garrison, E. (Erik), El-Kebir, M. (Mohammed), Klau, G.W. (Gunnar W.), Korbel, J.O. (Jan), Lameijer, E.-W. (Eric-Wubbo), Langmead, B. (Benjamin), Martin, M. (Marcel), Medvedev, P. (Paul), Mu, J.C. (John C.), Neerincx, P.B.T. (Pieter B T), Ouwens, K. (Klaasjan), Peterlongo, P. (Pierre), Pisanti, N. (Nadia), Rahmann, S. (S.), Raphael, B.J. (Benjamin J.), Reinert, K. (Knut), Ridder, D. (Dick) de, de Ridder, J. (Jeroen), Schlesner, M. (Matthias), Schulz-Trieglaff, O. (Ole), Sanders, A.D. (Ashley D.), Sheikhizadeh, S. (Siavash), Shneider, C. (Carl), Smit, S. (Sandra), Valenzuela, D. (Daniel), Wang, J. (Jiayin), Wessels, L. (Lodewyk), Zhang, Y. (Ying), Guryev, V. (Victor), Vandin, F. (Fabio), Ye, K. (Kai), and Schönhuth, A. (Alexander)

Abstract

Many disciplines, from human genetics and oncology to plant breeding, microbiology and virology, commonly face the challenge of analyzing rapidly increasing numbers of genomes. In case of Homo sapiens, the number of sequenced genomes will approach hundreds of thousands in the next few years. Simply scaling up established bioinformatics pipelines will not be sufficient for leveraging the full potential of such rich genomic data sets. Instead, novel, qualitatively different Computational methods and paradigms are needed.We will witness the rapid extension of Computational pan-genomics, a new sub-area of research in Computational biology. In this article, we generalize existing definitions and understand a pangenome as any collection of genomic sequences to be analyzed jointly or to be used as a reference. We examine already available approaches to construct and use pan-genomes, discuss the potential benefits of future technologies and methodologies and review open challenges from the vantage point of the above-mentioned biological disciplines. As a prominent example for a Computational paradigm shift, we particularly highlight the transition from the representation of reference genomes as strings to representations a

Published
2018
Full Text
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5. Computational pan-genomics: status, promises and challenges

Author

The Computational Pan-Genomics Consortium, Marschall, T. (Tobias), Marz, M. (Manja), Abeel, T. (Thomas), Dijkstra, L.J. (Louis), Dutilh, B.E. (Bas), Ghaffaari, A. (Ali), Kersey, P. (Paul), Kloosterman, W.P. (Wigard), Mäkinen, V. (Veli), Novak, A.M. (Adam), Paten, B. (Benedict), Porubsky, D. (David), Rivals, E. (Eric), Alkan, C. (Can), Baaijens, J.A. (Jasmijn), Bakker, P.I.W. (Paul) de, Boeva, V. (Valentina), Bonnal, R.J.P. (Raoul), Chiaromonte, F. (Francesca), Chikhi, R. (Rayan), Ciccarelli, F.D. (Francesca), Cijvat, C.P. (Robin), Datema, E. (Erwin), Duijn, C.M. (Cornelia) van, Eichler, E.E. (Evan), Ernst, C. (Corinna), Eskin, E. (Eleazar), Garrison, E. (Erik), El-Kebir, M. (Mohammed), Klau, G.W. (Gunnar), Korbel, J.O. (Jan), Lameijer, E.-W. (Eric-Wubbo), Langmead, B. (Benjamin), Martin, M. (Marcel), Medvedev, P. (Paul), Mu, J.C. (John), Neerincx, P.B.T. (Pieter), Ouwens, K. (Klaasjan), Peterlongo, P. (Pierre), Pisanti, N. (Nadia), Rahmann, S. (Sven), Raphael, B.J. (Benjamin), Reinert, K. (Knut), Ridder, D. (Dick) de, Ridder, J. (Jeroen) de, Schlesner, M. (Matthias), Schulz-Trieglaff, O. (Ole), Sanders, A.D. (Ashley), Sheikhizadeh, S. (Siavash), Shneider, C. (Carl), Smit, S. (Sandra), Valenzuela, D. (Daniel), Wang, J. (Jiayin), Wessels, L.F.A. (Lodewyk), Zhang, Y. (Ying), Guryev, V. (Victor), Vandin, F. (Fabio), Ye, K. (Kai), Schönhuth, A. (Alexander), The Computational Pan-Genomics Consortium, Marschall, T. (Tobias), Marz, M. (Manja), Abeel, T. (Thomas), Dijkstra, L.J. (Louis), Dutilh, B.E. (Bas), Ghaffaari, A. (Ali), Kersey, P. (Paul), Kloosterman, W.P. (Wigard), Mäkinen, V. (Veli), Novak, A.M. (Adam), Paten, B. (Benedict), Porubsky, D. (David), Rivals, E. (Eric), Alkan, C. (Can), Baaijens, J.A. (Jasmijn), Bakker, P.I.W. (Paul) de, Boeva, V. (Valentina), Bonnal, R.J.P. (Raoul), Chiaromonte, F. (Francesca), Chikhi, R. (Rayan), Ciccarelli, F.D. (Francesca), Cijvat, C.P. (Robin), Datema, E. (Erwin), Duijn, C.M. (Cornelia) van, Eichler, E.E. (Evan), Ernst, C. (Corinna), Eskin, E. (Eleazar), Garrison, E. (Erik), El-Kebir, M. (Mohammed), Klau, G.W. (Gunnar), Korbel, J.O. (Jan), Lameijer, E.-W. (Eric-Wubbo), Langmead, B. (Benjamin), Martin, M. (Marcel), Medvedev, P. (Paul), Mu, J.C. (John), Neerincx, P.B.T. (Pieter), Ouwens, K. (Klaasjan), Peterlongo, P. (Pierre), Pisanti, N. (Nadia), Rahmann, S. (Sven), Raphael, B.J. (Benjamin), Reinert, K. (Knut), Ridder, D. (Dick) de, Ridder, J. (Jeroen) de, Schlesner, M. (Matthias), Schulz-Trieglaff, O. (Ole), Sanders, A.D. (Ashley), Sheikhizadeh, S. (Siavash), Shneider, C. (Carl), Smit, S. (Sandra), Valenzuela, D. (Daniel), Wang, J. (Jiayin), Wessels, L.F.A. (Lodewyk), Zhang, Y. (Ying), Guryev, V. (Victor), Vandin, F. (Fabio), Ye, K. (Kai), and Schönhuth, A. (Alexander)

Abstract

Many disciplines, from human genetics and oncology to plant breeding, microbiology and virology, commonly face the challenge of analyzing rapidly increasing numbers of genomes. In case of Homo sapiens, the number of sequenced genomes will approach hundreds of thousands in the next few years. Simply scaling up established bioinformatics pipelines will not be sufficient for leveraging the full potential of such rich genomic data sets. Instead, novel, qualitatively different computational methods and paradigms are needed. We will witness the rapid extension of computational pan-genomics, a new sub-area of research in computational biology. In this article, we generalize existing definitions and understand a pan-genome as any collection of genomic sequences to be analyzed jointly or to be used as a reference. We examine already available approaches to construct and use pan-genomes, discuss the potential benefits of future technologies and methodologies and review open challenges from the vantage point of the above-mentioned biological disciplines. As a prominent example for a computational paradigm shift, we particularly highlight the transition from the representation of reference genomes as strings to representations as graphs. We outline how this and other challenges from different application domains translate into common computational problems, point out relevant bioinformatics techniques and identify open problems in computer science. With this review, we aim to increase awareness that a joint approach to computational pan-genomics can help address many of the problems currently faced in various domains.

Published
2018
Full Text
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6. Computational pan-genomics: status, promises and challenges

Author

The Computational Pan-Genomics Consortium, Marschall, T. (Tobias), Marz, M. (Manja), Abeel, T. (Thomas), Dijkstra, L.J. (Louis), Dutilh, B.E. (Bas), Ghaffaari, A. (Ali), Kersey, P. (Paul), Kloosterman, W.P. (Wigard), Mäkinen, V. (Veli), Novak, A.M. (Adam), Paten, B. (Benedict), Porubsky, D. (David), Rivals, E. (Eric), Alkan, C. (Can), Baaijens, J.A. (Jasmijn), Bakker, P.I.W. (Paul) de, Boeva, V. (Valentina), Bonnal, R.J.P. (Raoul), Chiaromonte, F. (Francesca), Chikhi, R. (Rayan), Ciccarelli, F.D. (Francesca), Cijvat, C.P. (Robin), Datema, E. (Erwin), Duijn, C.M. (Cornelia) van, Eichler, E.E. (Evan), Ernst, C. (Corinna), Eskin, E. (Eleazar), Garrison, E. (Erik), El-Kebir, M. (Mohammed), Klau, G.W. (Gunnar), Korbel, J.O. (Jan), Lameijer, E.-W. (Eric-Wubbo), Langmead, B. (Benjamin), Martin, M. (Marcel), Medvedev, P. (Paul), Mu, J.C. (John), Neerincx, P.B.T. (Pieter), Ouwens, K. (Klaasjan), Peterlongo, P. (Pierre), Pisanti, N. (Nadia), Rahmann, S. (Sven), Raphael, B.J. (Benjamin), Reinert, K. (Knut), Ridder, D. (Dick) de, Ridder, J. (Jeroen) de, Schlesner, M. (Matthias), Schulz-Trieglaff, O. (Ole), Sanders, A.D. (Ashley), Sheikhizadeh, S. (Siavash), Shneider, C. (Carl), Smit, S. (Sandra), Valenzuela, D. (Daniel), Wang, J. (Jiayin), Wessels, L.F.A. (Lodewyk), Zhang, Y. (Ying), Guryev, V. (Victor), Vandin, F. (Fabio), Ye, K. (Kai), Schönhuth, A. (Alexander), The Computational Pan-Genomics Consortium, Marschall, T. (Tobias), Marz, M. (Manja), Abeel, T. (Thomas), Dijkstra, L.J. (Louis), Dutilh, B.E. (Bas), Ghaffaari, A. (Ali), Kersey, P. (Paul), Kloosterman, W.P. (Wigard), Mäkinen, V. (Veli), Novak, A.M. (Adam), Paten, B. (Benedict), Porubsky, D. (David), Rivals, E. (Eric), Alkan, C. (Can), Baaijens, J.A. (Jasmijn), Bakker, P.I.W. (Paul) de, Boeva, V. (Valentina), Bonnal, R.J.P. (Raoul), Chiaromonte, F. (Francesca), Chikhi, R. (Rayan), Ciccarelli, F.D. (Francesca), Cijvat, C.P. (Robin), Datema, E. (Erwin), Duijn, C.M. (Cornelia) van, Eichler, E.E. (Evan), Ernst, C. (Corinna), Eskin, E. (Eleazar), Garrison, E. (Erik), El-Kebir, M. (Mohammed), Klau, G.W. (Gunnar), Korbel, J.O. (Jan), Lameijer, E.-W. (Eric-Wubbo), Langmead, B. (Benjamin), Martin, M. (Marcel), Medvedev, P. (Paul), Mu, J.C. (John), Neerincx, P.B.T. (Pieter), Ouwens, K. (Klaasjan), Peterlongo, P. (Pierre), Pisanti, N. (Nadia), Rahmann, S. (Sven), Raphael, B.J. (Benjamin), Reinert, K. (Knut), Ridder, D. (Dick) de, Ridder, J. (Jeroen) de, Schlesner, M. (Matthias), Schulz-Trieglaff, O. (Ole), Sanders, A.D. (Ashley), Sheikhizadeh, S. (Siavash), Shneider, C. (Carl), Smit, S. (Sandra), Valenzuela, D. (Daniel), Wang, J. (Jiayin), Wessels, L.F.A. (Lodewyk), Zhang, Y. (Ying), Guryev, V. (Victor), Vandin, F. (Fabio), Ye, K. (Kai), and Schönhuth, A. (Alexander)

Abstract

Many disciplines, from human genetics and oncology to plant breeding, microbiology and virology, commonly face the challenge of analyzing rapidly increasing numbers of genomes. In case of Homo sapiens, the number of sequenced genomes will approach hundreds of thousands in the next few years. Simply scaling up established bioinformatics pipelines will not be sufficient for leveraging the full potential of such rich genomic data sets. Instead, novel, qualitatively different computational methods and paradigms are needed. We will witness the rapid extension of computational pan-genomics, a new sub-area of research in computational biology. In this article, we generalize existing definitions and understand a pan-genome as any collection of genomic sequences to be analyzed jointly or to be used as a reference. We examine already available approaches to construct and use pan-genomes, discuss the potential benefits of future technologies and methodologies and review open challenges from the vantage point of the above-mentioned biological disciplines. As a prominent example for a computational paradigm shift, we particularly highlight the transition from the representation of reference genomes as strings to representations as graphs. We outline how this and other challenges from different application domains translate into common computational problems, point out relevant bioinformatics techniques and identify open problems in computer science. With this review, we aim to increase awareness that a joint approach to computational pan-genomics can help address many of the problems currently faced in various domains.

Published
2018
Full Text
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7. 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
Full Text
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8. 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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9. Characteristics of de novo structural changes in the human genome

Author

Kloosterman, W.P. (Wigard), Francioli, L.C. (Laurent), Hormozdiari, F. (Fereydoun), Marschall, T. (Tanja), Hehir-Kwa, J. (Jayne), Lameijer, E.-W. (Eric-Wubbo), Moed, H. (Heleen), Renkens, I. (Ivo), Van Roosmalen, M.J. (Markus J.), Arp, P.P. (Pascal), Coe, B.P. (Bradley P.), Handsaker, R.E. (Robert), Suchiman, E.D. (Eka D.), Cuppen, E. (Edwin), Thung, D.T. (Djie Tjwan), McVey, M. (Mitch), Wendl, M.C. (Michael C.), Uitterlinden, A.G. (André), Schönhuth, A. (Alexander), Eichler, E.E. (Evan), Bakker, P.I.W. (Paul) de, Ye, K. (Kai), Guryev, V. (Victor), Van Ommen, G.-J.B. (Gert-Jan B.), Kloosterman, W.P. (Wigard), Francioli, L.C. (Laurent), Hormozdiari, F. (Fereydoun), Marschall, T. (Tanja), Hehir-Kwa, J. (Jayne), Lameijer, E.-W. (Eric-Wubbo), Moed, H. (Heleen), Renkens, I. (Ivo), Van Roosmalen, M.J. (Markus J.), Arp, P.P. (Pascal), Coe, B.P. (Bradley P.), Handsaker, R.E. (Robert), Suchiman, E.D. (Eka D.), Cuppen, E. (Edwin), Thung, D.T. (Djie Tjwan), McVey, M. (Mitch), Wendl, M.C. (Michael C.), Uitterlinden, A.G. (André), Schönhuth, A. (Alexander), Eichler, E.E. (Evan), Bakker, P.I.W. (Paul) de, Ye, K. (Kai), Guryev, V. (Victor), and Van Ommen, G.-J.B. (Gert-Jan B.)

Abstract

Small insertions and deletions (indels) and large structural variations (SVs) are major contributors to human genetic diversity and disease. However, mutation rates and characteristics of de novo indels and SVs in the general population have remained largely unexplored. We report 332 validated de novo structural changes identified in whole genomes of 250 families, including complex indels, retrotransposon insertions, and interchromosomal events. These data indicate a mutation rate of 2.94 indels (120 bp) and 0.16 SVs (>20 bp) per generation. De novo structural changes affect on average 4.1 kbp of genomic sequence and 29 coding bases per generation, which is 91 and 52 times more nucleotides than de novo substitutions, respectively. This contrasts with the equal genomic footprint of inherited SVs and substitutions. An excess of structural changes originated on paternal haplotypes. Additionally, we observed a nonuniform distribution of de novo SVs across offspring. These results reveal the importance of different mutational mechanisms to changes in human genome structure across generations.

Published
2015
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