title: Behavioural traits propagate across generations via segregated iterative-somatic and gametic epigenetic mechanisms.
abstract: Parental behavioural traits can be transmitted by non-genetic mechanisms to the offspring. Although trait transmission via sperm has been extensively researched, epidemiological studies indicate the exclusive/prominent maternal transmission of many non-genetic traits. Since maternal conditions impact the offspring during gametogenesis and through fetal/early-postnatal life, the resultant phenotype is likely the aggregate of consecutive germline and somatic effects; a concept that has not been previously studied. Here, we dissected a complex maternally transmitted phenotype, reminiscent of comorbid generalized anxiety/depression, to elementary behaviours/domains and their transmission mechanisms in mice. We show that four anxiety/stress-reactive traits are transmitted via independent iterative-somatic and gametic epigenetic mechanisms across multiple generations. Somatic/gametic transmission alters DNA methylation at enhancers within synaptic genes whose functions can be linked to the behavioural traits. Traits have generation-dependent penetrance and sex specificity resulting in pleiotropy. A transmission-pathway-based concept can refine current inheritance models of psychiatric diseases and facilitate the development of better animal models and new therapeutic approaches.
authors.affiliation: Department of Pharmacology, Weill Cornell Medical College, 1300 York Avenue, New York, New York 10065, USA.
authors.forename: Emma
authors.initials: E
authors.lastname: Mitchell
authors.affiliation: Department of Pharmacology, Weill Cornell Medical College, 1300 York Avenue, New York, New York 10065, USA.
authors.forename: Shifra L
authors.initials: SL
authors.lastname: Klein
authors.affiliation: Department of Immunology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, USA.
authors.forename: Kimon V
authors.initials: KV
authors.lastname: Argyropoulos
authors.affiliation: Department of Pharmacology, Weill Cornell Medical College, 1300 York Avenue, New York, New York 10065, USA.
authors.forename: Ali
authors.initials: A
authors.lastname: Sharma
authors.affiliation: Department of Pathology and Cell Biology, Columbia University Medical Center, 630 West 168th Street, New York, New York 10032, USA.|Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York, New York 10032, USA.
authors.forename: Robin B
authors.initials: RB
authors.lastname: Chan
authors.affiliation: Department of Pharmacology, Weill Cornell Medical College, 1300 York Avenue, New York, New York 10065, USA.
authors.forename: Judit Gal
authors.initials: JG
authors.lastname: Toth
authors.affiliation: Department of Pharmacology, Weill Cornell Medical College, 1300 York Avenue, New York, New York 10065, USA.
authors.forename: Luendreo
authors.initials: L
authors.lastname: Barboza
authors.affiliation: Department of Pharmacology, Weill Cornell Medical College, 1300 York Avenue, New York, New York 10065, USA.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Bavley
authors.affiliation: Department of Neurochemistry and Neuropharmacology, Institut d'Investigacions Biomèdiques de Barcelona (IIBB-CSIC), Rosselló, 161, Barcelona 08036, Spain.|Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Barcelona 08036, Spain.|Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona 08036, Spain.
authors.forename: Analia
authors.initials: A
authors.lastname: Bortolozzi
authors.affiliation: Department of Pharmacology, Weill Cornell Medical College, 1300 York Avenue, New York, New York 10065, USA.
authors.forename: Qiuying
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Department of Pharmacology, Weill Cornell Medical College, 1300 York Avenue, New York, New York 10065, USA.
authors.forename: Bingfang
authors.initials: B
authors.lastname: Liu
authors.affiliation: Mouse Genetics Core Facility, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, 417 East 68th Street, New York, New York 10065, USA.
authors.forename: Joanne
authors.initials: J
authors.lastname: Ingenito
authors.affiliation: Mouse Genetics Core Facility, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, 417 East 68th Street, New York, New York 10065, USA.
authors.forename: Willie
authors.initials: W
authors.lastname: Mark
authors.affiliation: Department of Immunology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, USA.
authors.forename: Jarrod
authors.initials: J
authors.lastname: Dudakov
authors.affiliation: Department of Pharmacology, Weill Cornell Medical College, 1300 York Avenue, New York, New York 10065, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Gross
authors.affiliation: Department of Pathology and Cell Biology, Columbia University Medical Center, 630 West 168th Street, New York, New York 10032, USA.|Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York, New York 10032, USA.
authors.forename: Gilbert
authors.initials: G
authors.lastname: Di Paolo
authors.affiliation: Department of Neurochemistry and Neuropharmacology, Institut d'Investigacions Biomèdiques de Barcelona (IIBB-CSIC), Rosselló, 161, Barcelona 08036, Spain.|Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Barcelona 08036, Spain.|Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona 08036, Spain.
authors.forename: Francesc
authors.initials: F
authors.lastname: Artigas
authors.affiliation: Department of Immunology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, USA.
authors.forename: Marcel
authors.initials: M
authors.lastname: van den Brink
authors.affiliation: Department of Pharmacology, Weill Cornell Medical College, 1300 York Avenue, New York, New York 10065, USA.
authors.forename: Miklos
authors.initials: M
authors.lastname: Toth
mesh_terms: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000818:Animals; D001007:Anxiety / Q000235:genetics / Q000523:psychology; D001522:Behavior, Animal / Q000502:physiology*; D019175:DNA Methylation / Q000235:genetics; D004195:Disease Models, Animal; D044127:Epigenesis, Genetic; D005260:Female; D005718:Gametogenesis / Q000502:physiology; D018392:Genomic Imprinting / Q000502:physiology; D005854:Germ Cells / Q000502:physiology*; D007035:Hypothermia / Q000139:chemically induced / Q000235:genetics / Q000523:psychology; D008297:Male; D000072741:Maternal Inheritance / Q000502:physiology*; D055432:Metabolomics / Q000379:methods; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D019683:Penetrance; D010641:Phenotype; D044282:Receptor, Serotonin, 5-HT1A / Q000235:genetics / Q000378:metabolism; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D013315:Stress, Psychological / Q000235:genetics / Q000523:psychology
chemical_list: D017366:Serotonin Receptor Agonists; D044282:Receptor, Serotonin, 5-HT1A; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin