African Americans and European Americans exhibit distinct gene expression patterns across tissues and tumors that are associated with immunologic and infectious functions and environmental exposures

African Americans and European Americans exhibit distinct gene expression patterns across tissues and tumors that are associated with immunologic and infectious functions and environmental exposures | 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 Research Article African Americans and European Americans exhibit distinct gene expression patterns across tissues and tumors that are associated with immunologic and infectious functions and environmental exposures Urminder Singh, Kyle Hernandez, Bruce Aronow, Eve Wurtele This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-88890/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 21 May, 2021 Read the published version in Scientific Reports → Version 1 posted You are reading this latest preprint version Abstract The COVID-19 pandemic has affected African American populations disproportionately with respect to prevalence, morbidity, and mortality. Because gene expression profiles represent combined genetic, socioenvironmental, and physiological effects, and could provide therapeutic biomarkers and environmental mitigation strategies, we undertook a large-scale assessment of differential gene expression between African Americans and European Americans. To do this, we mined RNA-Seq datasets from normal and diseased (tumor) conditions whose metadata could be used to evaluate differential patterns. We observed widespread differential expression of genes implicated in COVID-19 and integral to epithelial boundary function, inflammation, infection, and reactive oxygen stress. Notably, expression of the little-studied F8A2 gene is up to 40-fold greater in African Americans. F8A2, like F8A1, encodes HAP40 protein, which mediates early endosome movement. African American gene expression signatures reveal increased number or activity of esophageal glandular cells and lung ACE2-positive basal keratinocytes. These findings have potential to establish prognostic signatures, refine approaches to minimizing risk of severe infection, and improve precision treatment of COVID-19. Epigenetics & Genomics Cancer Biology Medical Genetics COVID-19 African American populations gene expression profiles European Americans Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Full Text Additional Declarations There is NO Competing Interest. Supplementary Files SIFigsSinghetal2020NM.pdf Supplementary Figures SupplementaryFile1S128mwDEResults.xlsx SupplementaryFile2S2955limmaDE.xlsx SupplementaryFile3S5659overrepresentationofGO.xlsx SupplementaryFile4S60F8Acorrelations.xlsx Cite Share Download PDF Status: Published Journal Publication published 21 May, 2021 Read the published version in Scientific Reports → 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-88890","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":3243129,"identity":"dcf0be38-907e-4f06-9628-1871326e2265","order_by":0,"name":"Urminder Singh","email":"","orcid":"","institution":"Iowa State University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Urminder","middleName":"","lastName":"Singh","suffix":""},{"id":3243130,"identity":"9c699a5d-d873-4fbd-bdb3-868d80220a83","order_by":1,"name":"Kyle Hernandez","email":"","orcid":"","institution":"University of Chicago","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Kyle","middleName":"","lastName":"Hernandez","suffix":""},{"id":3243131,"identity":"cb176c2b-cc3e-4338-9ea8-d49edd8d1e5e","order_by":2,"name":"Bruce Aronow","email":"","orcid":"https://orcid.org/0000-0001-5109-6514","institution":"Cincinnati Children's Hospital Medical Center","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Bruce","middleName":"","lastName":"Aronow","suffix":""},{"id":3243128,"identity":"ef2f292a-50c5-40d1-89b6-cf7070202294","order_by":3,"name":"Eve Wurtele","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAvElEQVRIiWNgGAWjYHACNoYPBnAOM3FaGGcAtfBAVBOphZmHgRQtuu3Hnz22KbCzt2c/f/ABQ4V1YgMhLWZncsyNcwySE3t4kpkNGM6kE6HlQA6bdI4BcwIPQzKbBGPbYSK0nH/+TNrCoN6eh/8x+w/Gf8RouZFgJs1gcJixRyKZjYGxgSgtb8wkewyOJ/bceGwskXAs3ZgIh6U/k/jxp9qevT/x4YcPNdayBLWgggTSlI+CUTAKRsEowAUAEv44uFbm7csAAAAASUVORK5CYII=","orcid":"","institution":"Iowa State University","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Eve","middleName":"","lastName":"Wurtele","suffix":""}],"badges":[],"createdAt":"2020-10-06 21:50:31","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-88890/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-88890/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41598-021-89224-1","type":"published","date":"2021-05-21T12:00:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":2868620,"identity":"5c2c54b0-1558-4593-be77-733be7c27121","added_by":"auto","created_at":"2020-10-08 19:49:59","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":346973,"visible":true,"origin":"","legend":"Gene Set Enrichment Analysis (GSEA) enrichment of KEGG pathways in African Americans compared to\nEuropean Americans in pooled GTEx data. GSEA comprehensively analyses data for expression of all genes, rather than only\nthe DE genes. A. The most common pathways enriched among upregulated genes in African Americans for tissue-types in\nGTEx. Complete list of enriched pathways and sample-types is in Additional File 2. CK-CK, cytokine-cytokine receptor\ninteraction; glutathione-oxidative metabolism includes (oxidative) metabolism of xenobiotics. The full enrichment analysis for\neach sample-type is shown in Supplementary Table S57-S59. B. The five most highly enriched pathways among upregulated\ngenes of pooled samples from all sample-types in GTEx are: Tol-like receptor signaling; chemokine signaling; primary\nimmunodeficiency; viral protein interaction with cytokine and cytokine receptor; metabolism of xenobiotics by cytochrome\nP450.","description":"","filename":"F1.png","url":"https://assets-eu.researchsquare.com/files/rs-88890/v1/ce24e635ae05f4a7a68a5730.png"},{"id":2868623,"identity":"ddd82340-926f-4f27-aeba-dc3853d1ac8b","added_by":"auto","created_at":"2020-10-08 19:50:01","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":296041,"visible":true,"origin":"","legend":"Upregulated expression of CCL3L3 chemokine and mitochondrial glutathione-S-transferase GSTM1 in African\nAmericans compared to European Americans across multiple conditions. A. CCL3L3 is more highly expressed in African\nAmericans over a wide range of sample-types. CL3L3 binds to chemokine receptor proteins including CCR1, CCR3, and\nCCR5. B. GSTM1 is more highly expressed in African Americans over a wide range of sample-types. GSTM1 is a key player\nin metabolism of ROS and xenobiotics. (See Supplementary Tables S2-S28 for complete DE analysis). Violin plots summarize\nexpression over each sample across the two populations. AA, African American; EA, European American. Horizontal lines\nrepresent mean log expression. Teal *, MW test for DE significant (BH corrected p-value \u003c 0:05). Blue *, Hartigans’ dip test, which\nassesses bimodal distribution potentially corresponding to hidden covariates. For a given gene and sample-type, a bimodal\nstructure could imply presence of underlying hidden variables that affect expression of that gene, such as unreported\nsub-population structure or other environmental/genetic factors affecting gene expression in that multi-cellular organism.\nExpression distribution is also influenced by differences in population sizes (significant p-value \u003c 0:05). FC, fold change\nAA/EA. GTEx and TCGA violin plots represent the pooled samples from each project. DE were computed within\nMetaOmGraph (MOG)18, in MOG’s statistical analysis module; R scripts were executed interactively via MOG to generate the\nviolin plots.","description":"","filename":"F2.png","url":"https://assets-eu.researchsquare.com/files/rs-88890/v1/41bc793662bb8ff8fde6b794.png"},{"id":2868625,"identity":"d45a7cd8-c3c0-4e3b-92ff-2207f120291e","added_by":"auto","created_at":"2020-10-08 19:50:03","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":273624,"visible":true,"origin":"","legend":"Differential expression of the HAP40 genes F8A1 and F8A2 in African Americans and European Americans across\nmultiple sample-types. HAP40 is a key molecular component of Huntington’s Disease, and shifts endosomal trafficking from\nthe microtubules to actin fibers23. A. F8A1 expression is upregulated in European Americans. B. F8A2 expression is\nupregulated in African Americans. Violin plots summarize expression over each sample across the two populations. AA,\nAfrican American; EA, European American. Horizontal lines represent mean log expression. Teal *, MW test for DE significant\n(BH corrected p-value \u003c 0:05). Blue *, Hartigans’ dip test, which assesses bimodal distribution potentially corresponding to hidden\ncovariates. For a given gene and sample-type, a bimodal structure could imply presence of underlying hidden variables that\naffect expression of that gene, such as unreported sub-population structure or other environmental/genetic factors affecting\ngene expression in that multi-cellular organism. Expression distribution is also influenced by differences in population sizes\n(significant p-value \u003c 0:05). FC, fold change AA/EA. GTEx and TCGA violin plots represent the pooled samples from each\nproject. DE were computed within MetaOmGraph (MOG)18, in MOG’s statistical analysis module; R scripts were executed\ninteractively via MOG to generate the violin plots. (See Supplementary Figure 2 for line plot comparison across individuals) reads to one or the other gene.","description":"","filename":"F3.png","url":"https://assets-eu.researchsquare.com/files/rs-88890/v1/0ea071a26cc3c97f9918dc9e.png"},{"id":2868627,"identity":"a5eb0bdf-62d2-47de-8fd8-0b02bbc31803","added_by":"auto","created_at":"2020-10-08 19:50:03","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":120051,"visible":true,"origin":"","legend":"Esophageal gene signatures vary in African Americans and European Americans in a cell-specific manner. Gene\nsignature upregulated in African American versus European American esophagus maps to two cell lineages with prominent\npresence in the human cell atlas (https://data.humancellatlas.org/) esophageal dataset. One significant fraction of the African\nAmerican-upregulated gene signature maps to glandular mucous epithelial cells of esophogeal glands (genes marked by red, far\nright bar). Expression of several of the genes upregulated in African Americans is highly restricted to the mucous epithelial\ncells (TSAPN8, PRR4, ELAPOR1), whereas FOLR1, for example, is more highly expressed in the ductal epithelial cells of the\ngland. A second, smaller, signature corresponds to hematolymphoid/myeloid lineage dendritic cells, as shown by CDC1C,\nPLD4, HERPUD1, and LPXN (genes marked by green, far right bar). In addition to a number of genes that are most strongly\nexpressed by those cell types, there are several genes that are essentially exclusively expressed by those cells.\nToppCell-constructed gene modules (http://toppcell.cchmc.org) for each of the cell types reported to be present in the large\nscRNA-Seq dataset from esophagus29.","description":"","filename":"F4.png","url":"https://assets-eu.researchsquare.com/files/rs-88890/v1/87eae9025ef36059d78a1a19.png"},{"id":2868629,"identity":"5a9cdedc-ac38-4b8c-bc7f-726f7151fdd9","added_by":"auto","created_at":"2020-10-08 19:50:03","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":185678,"visible":true,"origin":"","legend":"Lung gene signatures upregulated in African Americans versus European Americans map to proximal airway\nkeratinocytic epithelial lineage, and to mesenchymal mesothelial and neuroendocrine cells. Marker genes for kerotinocytes\n(genes marked by yellow, far right bar); ciliated epithelial cells (genes marked by turquoise, far right bar); mesothelial\nmesenchymal cells (genes marked by red, far right bar); and neuroendocrine mesenchymal cells (mesenchymal). Note that the\nkeratinocytic proximal basal epithelial cell is the cell subtype with the highest expression of ACE2 receptor, a major target of\nCOVID-19 (ACE2 marked by black on bar at right). ToppCell-constructed gene modules (http://toppcell.cchmc.org) for each of\nthe cell types reported to be present in the large scRNA-Seq dataset from lung28.","description":"","filename":"F5.png","url":"https://assets-eu.researchsquare.com/files/rs-88890/v1/4a965a5f6297c118210ffab5.png"},{"id":13539966,"identity":"a7ae6d80-93fc-4151-abac-39a4ef7acc34","added_by":"auto","created_at":"2021-09-17 01:45:32","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3947167,"visible":true,"origin":"","legend":"","description":"","filename":"MainSinghetal2020NM.pdf.pdf","url":"https://assets-eu.researchsquare.com/files/rs-88890/v1_covered.pdf"},{"id":2868643,"identity":"b055283d-d8d4-4399-985b-afccda9fab90","added_by":"auto","created_at":"2020-10-08 19:50:20","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2740156,"visible":true,"origin":"","legend":"","description":"","filename":"MainSinghetal2020NM.pdf.pdf","url":"https://assets-eu.researchsquare.com/files/rs-88890/v1_stamped.pdf"},{"id":2868621,"identity":"a49b9e7f-63c7-4518-bac7-24b825c18e66","added_by":"auto","created_at":"2020-10-08 19:49:59","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":446365,"visible":true,"origin":"","legend":"Supplementary Figures","description":"","filename":"SIFigsSinghetal2020NM.pdf","url":"https://assets-eu.researchsquare.com/files/rs-88890/v1/27456f6908f863f1fea0f995.pdf"},{"id":2868622,"identity":"c59b300e-0220-4409-b5b3-173a55db90e6","added_by":"auto","created_at":"2020-10-08 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19:50:03","extension":"xlsx","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":70977,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryFile3S5659overrepresentationofGO.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-88890/v1/e2e65ab42c4e9024925d61ce.xlsx"},{"id":2868628,"identity":"a912b43e-6f52-4065-af6b-66a51cc5aac0","added_by":"auto","created_at":"2020-10-08 19:50:03","extension":"xlsx","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":4450995,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryFile4S60F8Acorrelations.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-88890/v1/8b161a931a24a811c4865465.xlsx"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e Competing Interest.","formattedTitle":"African Americans and European Americans exhibit distinct gene expression patterns across tissues and tumors that are associated with immunologic and infectious functions and environmental exposures","fulltext":[{"header":"Full Text","content":"\u003cp\u003eThis preprint is available for \u003ca href='/article/rs-88890/latest.pdf' target='_blank'\u003edownload as a PDF\u003c/a\u003e.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"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":"COVID-19, African American populations, gene expression profiles, European Americans","lastPublishedDoi":"10.21203/rs.3.rs-88890/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-88890/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"The COVID-19 pandemic has affected African American populations disproportionately with respect to prevalence, morbidity, and mortality. Because gene expression profiles represent combined genetic, socioenvironmental, and physiological effects, and could provide therapeutic biomarkers and environmental mitigation strategies, we undertook a large-scale assessment of differential gene expression between African Americans and European Americans. To do this, we mined RNA-Seq datasets from normal and diseased (tumor) conditions whose metadata could be used to evaluate differential patterns. We observed widespread differential expression of genes implicated in COVID-19 and integral to epithelial boundary function, inflammation, infection, and reactive oxygen stress. Notably, expression of the little-studied F8A2 gene is up to 40-fold greater in African\r\nAmericans. F8A2, like F8A1, encodes HAP40 protein, which mediates early endosome movement. African American gene expression signatures reveal increased number or activity of esophageal glandular cells and lung ACE2-positive basal keratinocytes. These findings have potential to establish prognostic signatures, refine approaches to minimizing risk of severe infection, and improve precision treatment of COVID-19.","manuscriptTitle":"African Americans and European Americans exhibit distinct gene expression patterns across tissues and tumors that are associated with immunologic and infectious functions and environmental exposures","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2020-10-08 19:48:27","doi":"10.21203/rs.3.rs-88890/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":"6c996121-8591-418e-bce3-d9ba67083ba9","owner":[],"postedDate":"October 8th, 2020","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":729707,"name":"Epigenetics \u0026 Genomics"},{"id":729708,"name":"Cancer Biology"},{"id":729709,"name":"Medical Genetics"}],"tags":[],"updatedAt":"2020-10-08T19:48:27+00:00","versionOfRecord":{"articleIdentity":"rs-88890","link":"https://doi.org/10.1038/s41598-021-89224-1","journal":{"identity":"scientific-reports","isVorOnly":false,"title":"Scientific Reports"},"publishedOn":"2021-05-21 12:00:00","publishedOnDateReadable":"May 21st, 2021"},"versionCreatedAt":"2020-10-08 19:48:27","video":"","vorDoi":"10.1038/s41598-021-89224-1","vorDoiUrl":"https://doi.org/10.1038/s41598-021-89224-1","workflowStages":[]},"version":"v1","identity":"rs-88890","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-88890","identity":"rs-88890","version":["v1"]},"buildId":"7rjqhiLT3MXkJMwkYKINL","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}