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      Prevalence of sexual dimorphism in mammalian phenotypic traits

      research-article
      a , 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 7 , 9 , 10 , 11 , 11 , 12 , 13 , 14 , 14 , 8 , 5 , 15 , 16 , 17 , 18 , 19 , 20 , 5 , 21 , 6 , 8 , 22 , 23 , 10 , 24 , 3 , 25 , 7 , 3 , 21 , 8 , 4 , 26 , 15 , 16 , 17 , 18 , 19 , 21 , 21 , 27 , 7 , International Mouse Phenotyping Consortium, 23 , 28 , 8 , 8 , 5 , 7 , 21
      Nature Communications
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          Abstract

          The role of sex in biomedical studies has often been overlooked, despite evidence of sexually dimorphic effects in some biological studies. Here, we used high-throughput phenotype data from 14,250 wildtype and 40,192 mutant mice (representing 2,186 knockout lines), analysed for up to 234 traits, and found a large proportion of mammalian traits both in wildtype and mutants are influenced by sex. This result has implications for interpreting disease phenotypes in animal models and humans.

          Abstract

          Systemic dissection of sexually dimorphic phenotypes in mice is lacking. Here, Karp and the International Mouse Phenotype Consortium show that approximately 10% of qualitative traits and 56% of quantitative traits in mice as measured in laboratory setting are sexually dimorphic.

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          Most cited references35

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          Sex bias in neuroscience and biomedical research.

          Female mammals have long been neglected in biomedical research. The NIH mandated enrollment of women in human clinical trials in 1993, but no similar initiatives exist to foster research on female animals. We reviewed sex bias in research on mammals in 10 biological fields for 2009 and their historical precedents. Male bias was evident in 8 disciplines and most prominent in neuroscience, with single-sex studies of male animals outnumbering those of females 5.5 to 1. In the past half-century, male bias in non-human studies has increased while declining in human studies. Studies of both sexes frequently fail to analyze results by sex. Underrepresentation of females in animal models of disease is also commonplace, and our understanding of female biology is compromised by these deficiencies. The majority of articles in several journals are conducted on rats and mice to the exclusion of other useful animal models. The belief that non-human female mammals are intrinsically more variable than males and too troublesome for routine inclusion in research protocols is without foundation. We recommend that when only one sex is studied, this should be indicated in article titles, and that funding agencies favor proposals that investigate both sexes and analyze data by sex. Copyright © 2010 Elsevier Ltd. All rights reserved.
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            Genetics of mouse behavior: interactions with laboratory environment.

            Strains of mice that show characteristic patterns of behavior are critical for research in neurobehavioral genetics. Possible confounding influences of the laboratory environment were studied in several inbred strains and one null mutant by simultaneous testing in three laboratories on a battery of six behaviors. Apparatus, test protocols, and many environmental variables were rigorously equated. Strains differed markedly in all behaviors, and despite standardization, there were systematic differences in behavior across labs. For some tests, the magnitude of genetic differences depended upon the specific testing lab. Thus, experiments characterizing mutants may yield results that are idiosyncratic to a particular laboratory.
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              A conditional knockout resource for the genome-wide study of mouse gene function.

              Gene targeting in embryonic stem cells has become the principal technology for manipulation of the mouse genome, offering unrivalled accuracy in allele design and access to conditional mutagenesis. To bring these advantages to the wider research community, large-scale mouse knockout programmes are producing a permanent resource of targeted mutations in all protein-coding genes. Here we report the establishment of a high-throughput gene-targeting pipeline for the generation of reporter-tagged, conditional alleles. Computational allele design, 96-well modular vector construction and high-efficiency gene-targeting strategies have been combined to mutate genes on an unprecedented scale. So far, more than 12,000 vectors and 9,000 conditional targeted alleles have been produced in highly germline-competent C57BL/6N embryonic stem cells. High-throughput genome engineering highlighted by this study is broadly applicable to rat and human stem cells and provides a foundation for future genome-wide efforts aimed at deciphering the function of all genes encoded by the mammalian genome.
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                Author and article information

                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group
                2041-1723
                26 June 2017
                2017
                : 8
                : 15475
                Affiliations
                [1 ]Mouse Informatics Group, The Wellcome Trust Sanger Institute , Hinxton, Cambridge CB10 1SA, UK
                [2 ]Quantitative Biology, AstraZeneca , Unit 310, Cambridge Science Park, Cambridge CB4 0WG, UK
                [3 ]European Bioinformatics Institute (EMBL-EBI), European Molecular Biology Laboratory, Wellcome Trust Genome Campus , Hinxton, Cambridge CB10 1SD, UK
                [4 ]Human and Molecular Genetics, Baylor College of Medicine , 1 Baylor Plaza, Houston, Texas 77030, USA
                [5 ]Department of Statistics and O.R. School of Mathematical Sciences, Tel Aviv University , Tel Aviv 69978, Israel
                [6 ]Mouse Biology Program, University of California , 2795 Second Street, Suite 400, Davis, California 95618, USA
                [7 ]The Jackson Laboratory , 600 Main Street, Bar Harbor, Maine 04609, USA
                [8 ]MRC Harwell Institute, Harwell Campus , Harwell OX11 0RD, UK
                [9 ]Molecular Physiology and Biophysics, Baylor College of Medicine , 1 Baylor Plaza, Houston, Texas 77030, USA
                [10 ]The Centre for Phenogenomics , 25 Orde Street, Toronto, Ontario, Canada M5T 3H7
                [11 ]German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München , Ingolstädter Landstraße 1, Neuherberg 85764, Germany
                [12 ]School of Life Science Weihenstephan, Technische Universität München , Alte Akademie 8, Freising 85354, Germany
                [13 ]German Center for Diabetes Research (DZD) , Ingostädter Landstr. 1, Neuherberg 85764, Germany
                [14 ]Model Animal Research Center, Nanjing University , 12 Xuefu Road, Pukou, Nanjing, Jiangsu 210061, China
                [15 ]CELPHEDIA, PHENOMIN, Institut Clinique de la Souris , 1 Rue Laurent Fries, Illkirch 67404, France
                [16 ]Institut de Génétique et de Biologie Moléculaire et Cellulaire , 1 Rue Laurent Fries, Illkirch 67404, France
                [17 ]Centre National de la Recherche Scientifique , UMR7104, 1 rue Laurent Fries, Illkirch 67404, France
                [18 ]Institut National de la Santé et de la Recherche Médicale , U964, 1 rue Laurent Fries, Illkirch 67404, France
                [19 ]Université de Strasbourg , 1 rue Laurent Fries, Illkirch 67404, France
                [20 ]The Hospital for Sick Children , 555 University Avenue, Toronto, Ontario, Canada M5G 1X8
                [21 ]Mouse Genetics Project, The Wellcome Trust Sanger Institute , Hinxton, Cambridge CB10 1SA, UK
                [22 ]Department of Genetics, Evolution & Environment, University College London , Gower Street, London WC1E 6BT, UK
                [23 ]BioResource Center, RIKEN , 3-1-1 Koyadai, Tsukuba, Ibaraki 305-0074, Japan
                [24 ]The Hospital for Sick Children , 686 Bay Street, Toronto, Ontario, Canada M5G 0A4
                [25 ]Genetics Institute, University College London , Gower Street, London WC1E 6BT, UK
                [26 ]Clinical Pharmacology, Queen Mary University of London , Gower Street, London WC1E 6BT, UK
                [27 ]Wolfson Centre for Age-Related Diseases, King's College London , Wolfson Wing, Hodgkin Building, Guys Campus, London SE1 1UL, UK
                [28 ]Children’s Hospital Oakland Research Institute , 5700 Martin Luther King Jr Way, Oakland, California 94609, USA
                [29 ]BioResource Center, RIKEN , 3-1-1 Koyadai, Tsukuba, Ibaraki 305-0074, Japan
                [30 ]Mouse Biology Program, University of California , 2795 Second Street, Suite 400, Davis, California 95618, USA
                [31 ]The Centre for Phenogenomics , 25 Orde Street, Toronto, Ontario, Canada M5T 3H7
                [32 ]MRC Harwell Institute , Harwell Campus, Harwell OX11 0RD, UK
                [33 ]Mouse Genetics Project, The Wellcome Trust Sanger Institute , Hinxton, Cambridge CB10 1SA, UK
                [34 ]Institut Clinique de la Souris , 1 Rue Laurent Fries, Illkirch 67404, France
                [35 ]German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München , Ingolstädter Landstraße 1, Neuherberg 85764, Germany
                [36 ]Comprehensive Pneumology Center, Institute of Lung Biology and Disease, Helmholtz Zentrum München, German Research Center for Environmental Health , Ingolstädter Landstrasse 1, Neuherberg 85764, Germany
                [37 ]Member of the German Center for Lung Research, Helmholtz Zentrum München, German Research Center for Environmental Health , Neuherberg 85764, Germany
                [38 ]Institute of Developmental Genetics, Helmholtz Zentrum München , Ingolstädter Landstraße 1, Neuherberg 85764, Germany
                [39 ]Institute of Pathology, Helmholtz Zentrum München , Ingolstädter Landstraße 1, Neuherberg 85764, Germany
                [40 ]Technische Universität München-Weihenstephan, c/o Helmholtz Zentrum München , Ingolstädter Landstraße 1, Neuherberg 85764, Germany
                [41 ]Deutsches Institut für Neurodegenerative Erkrankungen (DZNE), Site Munich , München 80336, Germany
                [42 ]Munich Cluster for Systems Neurology (SyNergy), Adolf-Butenandt-Institut, Ludwig-Maximilians-Universität München , Schillerstr. 44, München 80336
                [43 ]Department of Cardiology, University of Heidelberg , Im Neuenheimer Feld 410, Heidelberg 69120, Germany
                [44 ]Department of Infection and Immunity, Luxembourg Institute of Health , 29, Rue Henri Koch, Esch-sur-Alzette 4354, Luxembourg
                [45 ]Department of Dermatology and Allergy Center, Odense Research Center for Anaphylaxis, Odense University Hospital, University of Southern Denmark , Odense C 5000, Denmark
                [46 ]Department of Neurology, Friedrich-Baur-Institute, University Hospital of LMU Munich , Ziemssenstrasse 1, Munich 80336, Germany
                [47 ]Medical Faculty, Institute of Molecular Psychiatry, University of Bonn , Sigmund Freud Street 25, Bonn 53127, Germany
                [48 ]Institute of Molecular Animal Breeding and Biotechnology, Gene Center, Ludwig-Maximilians-University München , Feodor-Lynen Street 25, Munich 81377, Germany
                [49 ]Institute for Medical Microbiology, Immunology and Hygiene, Technische Universität München , Trogerstrasse 30, Munich 81675, Germany
                [50 ]Technical University Munich, EKFZ—Else Kröner Fresenius Center for Nutritional Medicine , Gregor-Mendel-Street 2, Freising-Weihenstephan 85350, Germany
                [51 ]ZIEL—Institute for Food and Health, Technical University Munich , Gregor-Mendel-Street 2, Freising-Weihenstephan 85350, Germany
                [52 ]Center of Allergy & Environment (ZAUM), Technische Universität München, and Helmholtz Zentrum München, Ingolstädter Landstrasse , Neuherberg 85764, Germany
                [53 ]School of Life Science Weihenstephan, Technische Universität München , Alte Akademie 8, Freising 85354, Germany
                [54 ]German Center for Diabetes Research (DZD) , Ingolstädter Landstr. 1, Neuherberg 85764, Germany
                Author notes
                [*]

                A full list of consortium members appears at the end of the paper.

                Author information
                http://orcid.org/0000-0002-2796-5123
                http://orcid.org/0000-0002-5642-5062
                http://orcid.org/0000-0002-7898-2353
                http://orcid.org/0000-0001-7049-6900
                http://orcid.org/0000-0001-8087-4530
                http://orcid.org/0000-0002-2232-0967
                http://orcid.org/0000-0001-8532-0924
                http://orcid.org/0000-0002-2583-4170
                Article
                ncomms15475
                10.1038/ncomms15475
                5490203
                28650954
                3003dd28-3952-4387-9ba4-06140838b54b
                Copyright © 2017, The Author(s)

                This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

                History
                : 27 October 2016
                : 30 March 2017
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