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Research Article

Human Spermatogenic Failure Purges Deleterious Mutation Load from the Autosomes and Both Sex Chromosomes, including the Gene DMRT1

  • Alexandra M. Lopes equal contributor mail,

    equal contributor Contributed equally to this work with: Alexandra M. Lopes, Kenneth I. Aston

    alopes@ipatimup.pt (AML); dconrad@genetics.wustl.edu (DFC)

    Affiliation: Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal

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  • Kenneth I. Aston equal contributor,

    equal contributor Contributed equally to this work with: Alexandra M. Lopes, Kenneth I. Aston

    Affiliation: Andrology and IVF Laboratories, Department of Surgery, University of Utah School of Medicine, Salt Lake City, Utah, United States of America

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  • Emma Thompson,

    Affiliation: Department of Human Genetics, University of Chicago, Chicago, Illinois, United States of America

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  • Filipa Carvalho,

    Affiliation: Department of Genetics, Faculty of Medicine, University of Porto, Porto, Portugal

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  • João Gonçalves,

    Affiliation: Department of Human Genetics, National Institute of Health Dr. Ricardo Jorge, Lisbon, Portugal

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  • Ni Huang,

    Affiliation: Department of Genetics, Washington University School of Medicine, St. Louis, Missouri, United States of America

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  • Rune Matthiesen,

    Affiliation: Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal

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  • Michiel J. Noordam,

    Affiliation: Department of Genetics, Washington University School of Medicine, St. Louis, Missouri, United States of America

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  • Inés Quintela,

    Affiliation: Genomics Medicine Group, National Genotyping Center, University of Santiago de Compostela, Santiago de Compostela, Spain

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  • Avinash Ramu,

    Affiliation: Department of Genetics, Washington University School of Medicine, St. Louis, Missouri, United States of America

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  • Catarina Seabra,

    Affiliation: Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal

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  • Amy B. Wilfert,

    Affiliation: Department of Genetics, Washington University School of Medicine, St. Louis, Missouri, United States of America

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  • Juncheng Dai,

    Affiliation: Department of Epidemiology and Biostatistics and Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China

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  • Jonathan M. Downie,

    Affiliation: Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah, United States of America

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  • Susana Fernandes,

    Affiliation: Department of Genetics, Faculty of Medicine, University of Porto, Porto, Portugal

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  • Xuejiang Guo,

    Affiliations: State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China, Department of Histology and Embryology, Nanjing Medical University, Nanjing, China

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  • Jiahao Sha,

    Affiliations: State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China, Department of Histology and Embryology, Nanjing Medical University, Nanjing, China

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  • António Amorim,

    Affiliations: Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal, Faculty of Sciences, University of Porto, Porto, Portugal

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  • Alberto Barros,

    Affiliations: Department of Genetics, Faculty of Medicine, University of Porto, Porto, Portugal, Centre for Reproductive Genetics Alberto Barros, Porto, Portugal

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  • Angel Carracedo,

    Affiliations: Genomics Medicine Group, National Genotyping Center, University of Santiago de Compostela, Santiago de Compostela, Spain, Galician Foundation of Genomic Medicine and University of Santiago de Compostela, CIBERER, Santiago de Compostela, Spain

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  • Zhibin Hu,

    Affiliations: Department of Epidemiology and Biostatistics and Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China, State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China

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  • Matthew E. Hurles,

    Affiliation: Genome Mutation and Genetic Disease Group, Wellcome Trust Sanger Institute, Cambridge, United Kingdom

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  • Sergey Moskovtsev,

    Affiliations: CReATe Fertility Center, University of Toronto, Toronto, Canada, Department of Obstetrics and Gynaecology, University of Toronto, Toronto, Canada

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  • Carole Ober,

    Affiliations: Department of Human Genetics, University of Chicago, Chicago, Illinois, United States of America, Department of Obstetrics and Gynecology, University of Chicago, Chicago, Illinois, United States of America

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  • Darius A. Paduch,

    Affiliation: Department of Urology, Weill Cornell Medical College, New York-Presbyterian Hospital, New York, New York, United States of America

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  • Joshua D. Schiffman,

    Affiliations: Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah, United States of America, Center for Children's Cancer Research (C3R), Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah, United States of America, Division of Pediatric Hematology/Oncology, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah, United States of America

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  • Peter N. Schlegel,

    Affiliation: Department of Urology, Weill Cornell Medical College, New York-Presbyterian Hospital, New York, New York, United States of America

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  • Mário Sousa,

    Affiliation: Laboratory of Cell Biology, UMIB, ICBAS, University of Porto, Porto, Portugal

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  • Douglas T. Carrell,

    Affiliations: Andrology and IVF Laboratories, Department of Surgery, University of Utah School of Medicine, Salt Lake City, Utah, United States of America, Department of Physiology, University of Utah School of Medicine, Salt Lake City, Utah, United States of America, Department of Obstetrics and Gynecology, University of Utah School of Medicine, Salt Lake City, Utah, United States of America

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  • Donald F. Conrad mail

    alopes@ipatimup.pt (AML); dconrad@genetics.wustl.edu (DFC)

    Affiliations: Department of Genetics, Washington University School of Medicine, St. Louis, Missouri, United States of America, Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, United States of America

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  • Published: March 21, 2013
  • DOI: 10.1371/journal.pgen.1003349

About the Authors

Alexandra M. Lopes, Rune Matthiesen, Catarina Seabra, António Amorim
Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal
Kenneth I. Aston, Douglas T. Carrell
Andrology and IVF Laboratories, Department of Surgery, University of Utah School of Medicine, Salt Lake City, Utah, United States of America
Emma Thompson, Carole Ober
Department of Human Genetics, University of Chicago, Chicago, Illinois, United States of America
Filipa Carvalho, Susana Fernandes, Alberto Barros
Department of Genetics, Faculty of Medicine, University of Porto, Porto, Portugal
João Gonçalves
Department of Human Genetics, National Institute of Health Dr. Ricardo Jorge, Lisbon, Portugal
Ni Huang, Michiel J. Noordam, Avinash Ramu, Amy B. Wilfert, Donald F. Conrad
Department of Genetics, Washington University School of Medicine, St. Louis, Missouri, United States of America
Inés Quintela, Angel Carracedo
Genomics Medicine Group, National Genotyping Center, University of Santiago de Compostela, Santiago de Compostela, Spain
Juncheng Dai, Zhibin Hu
Department of Epidemiology and Biostatistics and Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
Jonathan M. Downie, Joshua D. Schiffman
Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah, United States of America
Xuejiang Guo, Jiahao Sha, Zhibin Hu
State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China
Xuejiang Guo, Jiahao Sha
Department of Histology and Embryology, Nanjing Medical University, Nanjing, China
António Amorim
Faculty of Sciences, University of Porto, Porto, Portugal
Alberto Barros
Centre for Reproductive Genetics Alberto Barros, Porto, Portugal
Angel Carracedo
Galician Foundation of Genomic Medicine and University of Santiago de Compostela, CIBERER, Santiago de Compostela, Spain
Matthew E. Hurles
Genome Mutation and Genetic Disease Group, Wellcome Trust Sanger Institute, Cambridge, United Kingdom
Sergey Moskovtsev
CReATe Fertility Center, University of Toronto, Toronto, Canada
Sergey Moskovtsev
Department of Obstetrics and Gynaecology, University of Toronto, Toronto, Canada
Carole Ober
Department of Obstetrics and Gynecology, University of Chicago, Chicago, Illinois, United States of America
Darius A. Paduch, Peter N. Schlegel
Department of Urology, Weill Cornell Medical College, New York-Presbyterian Hospital, New York, New York, United States of America
Joshua D. Schiffman
Center for Children's Cancer Research (C3R), Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah, United States of America
Joshua D. Schiffman
Division of Pediatric Hematology/Oncology, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah, United States of America
Mário Sousa
Laboratory of Cell Biology, UMIB, ICBAS, University of Porto, Porto, Portugal
Douglas T. Carrell
Department of Physiology, University of Utah School of Medicine, Salt Lake City, Utah, United States of America
Douglas T. Carrell
Department of Obstetrics and Gynecology, University of Utah School of Medicine, Salt Lake City, Utah, United States of America
Donald F. Conrad
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, United States of America

Corresponding Authors

Competing Interests

The authors have declared that no competing interests exist.

Author Contributions

Conceived and designed the experiments: AML DTC KIA DFC. Performed the experiments: KIA AML DFC FC JG SF MS AB MJN ET CS AC. Analyzed the data: DFC AML KIA RM NH ET JMD JD AR ABW. Contributed reagents/materials/analysis tools: AML CO XG DAP PNS JS ZH SM IQ JDS DFC DTC. Wrote the paper: DFC. Participated in the interpretation of results: AA MEH. Assisted with writing the manuscript: KIA DTC AML CO JDS PNS.