Offspring genetic diversity regulates rearing experiences that predict differential susceptibility to Chd8 haploinsufficiency

Offspring genetic diversity regulates rearing experiences that predict differential susceptibility to Chd8 haploinsufficiency | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Offspring genetic diversity regulates rearing experiences that predict differential susceptibility to Chd8 haploinsufficiency Manal Tabbaa, Alexis Gamez, A'di Dust, Maja Matarić, Pat Levitt This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6058389/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Mouse models of human disease focus on determining the direct impact of genetic mutations on phenotypes related to clinical presentations. For example, loss of function mutations in the autism-associated CHD8 gene is highly penetrant for trait and behavioral abnormalities in children, but there is substantial clinical heterogeneity in the occurrence and extent of disruptions between individuals. Using a large genetic reference panel of mice, we recently showed that genetic background strongly regulates variability in trait disruptions caused by Chd8 haploinsufficiency. Here, we hypothesized that genetics could also impact the variability in response to early life experiences, thus contributing to differential susceptibility to neurodevelopmental disorders. To examine how genetic diversity impacts rearing experience, we systematically observed the behavior of genetically diverse offspring raised by genetically identical mothers. The results reveal strain differences in pup and maternal behaviors. Machine learning analysis reveals that early life litter experiences are strong predictors of sex-dependent postweaning social, anxiety-like, and cognitive trait disruptions due to Chd8 haploinsufficiency. The study suggests that offspring phenotypes in mutant models of disease are due to a combination of heritable and early experience factors, demonstrating the utility of incorporating genetic diversity in studies to model the mechanisms that underlie the heterogeneity of disrupted phenotypes in neurodevelopmental disorders. Biological sciences/Developmental biology/Disease model Biological sciences/Genetics/Behavioural genetics Biological sciences/Neuroscience/Genetics of the nervous system CHD8 haploinsufficiency maternal care offspring behavior genetic diversity genetic reference panel Collaborative Cross trait heterogeneity early life experience rearing autism neurodevelopment neurodevelopmental disorders Full Text Additional Declarations There is NO Competing Interest. Supplementary Files SupplementaryTable1.xlsx Dataset 1 SupplementaryTable2.xlsx Dataset 2 Supplementarytable3.xlsx Dataset 3 SupplementaryTable4.xlsx Dataset 4 Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6058389","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":421922561,"identity":"1b78fa37-eef8-4cb8-95cb-004328bd51d0","order_by":0,"name":"Manal Tabbaa","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA20lEQVRIiWNgGAWjYHACNmYgIccgwdwAEzEgoAGixZhBgpFELYkNRGvRnd/87HFBjV16/+zGxg+MbXXyDOzN2yTwaTE7xmZuPONYcu6MOwebJRjbDhs28BwrI6CFwUyah405d4MEyG1tBxIYJHLMCGhh/ybN868+3UAisfkH0GEJDPJvCGnhMZPmbTucANTSBrSFGWgLDyEtOeXGM/uOG864kdhmkXDusGEbT1qxBV4th49ve1zwrVqef0by4Rsfyurk+dkPb7yBTwsqSGAARdQoGAWjYBSMAooBAHlsQ6zmovtNAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0002-6803-8764","institution":"Children's Hospital Los Angeles and University of Southern California","correspondingAuthor":true,"prefix":"","firstName":"Manal","middleName":"","lastName":"Tabbaa","suffix":""},{"id":421922562,"identity":"249a2754-7165-4a9a-ba26-2cd0a522034e","order_by":1,"name":"Alexis Gamez","email":"","orcid":"","institution":"Children's Hospital Los Angeles","correspondingAuthor":false,"prefix":"","firstName":"Alexis","middleName":"","lastName":"Gamez","suffix":""},{"id":421922563,"identity":"79b5c82c-a4dc-448b-bd9c-40bdf6e08f2a","order_by":2,"name":"A'di Dust","email":"","orcid":"","institution":"University of Southern California","correspondingAuthor":false,"prefix":"","firstName":"A'di","middleName":"","lastName":"Dust","suffix":""},{"id":421922564,"identity":"0f438f08-14f9-427c-b30e-6113e725ee7a","order_by":3,"name":"Maja Matarić","email":"","orcid":"","institution":"University of Southern California","correspondingAuthor":false,"prefix":"","firstName":"Maja","middleName":"","lastName":"Matarić","suffix":""},{"id":421922565,"identity":"a73e8f64-6bb5-4591-8327-334736d98f8a","order_by":4,"name":"Pat Levitt","email":"","orcid":"","institution":"Children's Hospital Los Angeles and University of Southern California","correspondingAuthor":false,"prefix":"","firstName":"Pat","middleName":"","lastName":"Levitt","suffix":""}],"badges":[],"createdAt":"2025-02-18 18:00:18","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6058389/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6058389/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":81139445,"identity":"c5d3d778-eab5-4a46-b050-33f5ef698c9a","added_by":"auto","created_at":"2025-04-22 16:23:33","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":4506455,"visible":true,"origin":"","legend":"Article File","description":"","filename":"Tabbaaetal.2025.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6058389/v1_covered_6ed1d95d-f060-4438-a47f-0d834704025e.pdf"},{"id":77558621,"identity":"e5475dab-7d81-43a2-b1bc-d3d624c16734","added_by":"auto","created_at":"2025-03-03 06:14:27","extension":"xlsx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":16422,"visible":true,"origin":"","legend":"\u003cp\u003eDataset 1\u003c/p\u003e","description":"","filename":"SupplementaryTable1.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-6058389/v1/a2af30d9cfe0a0e24f3d1914.xlsx"},{"id":77557463,"identity":"5787a467-9e46-4e59-9b39-b93ccaff51e4","added_by":"auto","created_at":"2025-03-03 06:06:25","extension":"xlsx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":20421,"visible":true,"origin":"","legend":"\u003cp\u003eDataset 2\u003c/p\u003e","description":"","filename":"SupplementaryTable2.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-6058389/v1/1e297276ce6e7846c0e917fb.xlsx"},{"id":77557462,"identity":"fa86c87e-12b4-4f17-8786-581df567579b","added_by":"auto","created_at":"2025-03-03 06:06:25","extension":"xlsx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":10517,"visible":true,"origin":"","legend":"\u003cp\u003eDataset 3\u003c/p\u003e","description":"","filename":"Supplementarytable3.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-6058389/v1/c3aef7a29c5bfbd13aaa8d59.xlsx"},{"id":77557466,"identity":"d6258c7b-20f9-4235-ab2c-911acfc2c5cd","added_by":"auto","created_at":"2025-03-03 06:06:29","extension":"xlsx","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":15048,"visible":true,"origin":"","legend":"Dataset 4","description":"","filename":"SupplementaryTable4.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-6058389/v1/bfb2eb0e0638f51df905eaa0.xlsx"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e Competing Interest.","formattedTitle":"Offspring genetic diversity regulates rearing experiences that predict differential susceptibility to Chd8 haploinsufficiency","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"CHD8 haploinsufficiency, maternal care, offspring behavior, genetic diversity, genetic reference panel, Collaborative Cross, trait heterogeneity, early life experience, rearing, autism, neurodevelopment, neurodevelopmental disorders","lastPublishedDoi":"10.21203/rs.3.rs-6058389/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6058389/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Mouse models of human disease focus on determining the direct impact of genetic mutations on phenotypes related to clinical presentations. For example, loss of function mutations in the autism-associated CHD8 gene is highly penetrant for trait and behavioral abnormalities in children, but there is substantial clinical heterogeneity in the occurrence and extent of disruptions between individuals. Using a large genetic reference panel of mice, we recently showed that genetic background strongly regulates variability in trait disruptions caused by Chd8 haploinsufficiency. Here, we hypothesized that genetics could also impact the variability in response to early life experiences, thus contributing to differential susceptibility to neurodevelopmental disorders. To examine how genetic diversity impacts rearing experience, we systematically observed the behavior of genetically diverse offspring raised by genetically identical mothers. The results reveal strain differences in pup and maternal behaviors. Machine learning analysis reveals that early life litter experiences are strong predictors of sex-dependent postweaning social, anxiety-like, and cognitive trait disruptions due to Chd8 haploinsufficiency. The study suggests that offspring phenotypes in mutant models of disease are due to a combination of heritable and early experience factors, demonstrating the utility of incorporating genetic diversity in studies to model the mechanisms that underlie the heterogeneity of disrupted phenotypes in neurodevelopmental disorders.","manuscriptTitle":"Offspring genetic diversity regulates rearing experiences that predict differential susceptibility to Chd8 haploinsufficiency","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-03-03 06:06:21","doi":"10.21203/rs.3.rs-6058389/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"e6b5e886-a451-4389-9502-295d5f4f3bca","owner":[],"postedDate":"March 3rd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":44975253,"name":"Biological sciences/Developmental biology/Disease model"},{"id":44975254,"name":"Biological sciences/Genetics/Behavioural genetics"},{"id":44975255,"name":"Biological sciences/Neuroscience/Genetics of the nervous system"}],"tags":[],"updatedAt":"2025-04-22T16:15:21+00:00","versionOfRecord":[],"versionCreatedAt":"2025-03-03 06:06:21","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6058389","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6058389","identity":"rs-6058389","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}