{"id":"https://openalex.org/W2803626403","doi":null,"title":"Lessons From Using Genome Editing to Create a Faithful Model of a Novel Congenital Anemia","display_name":"Lessons From Using Genome Editing to Create a Faithful Model of a Novel Congenital Anemia","publication_year":2018,"publication_date":"2018-05-15","ids":{"openalex":"https://openalex.org/W2803626403","mag":"2803626403"},"language":"en","primary_location":{"id":"pmh:oai:dash.harvard.edu:1/36923351","doi":null,"is_oa":true,"landing_page_url":"http://nrs.harvard.edu/urn-3:HUL.InstRepos:36923351","pdf_url":null,"source":{"id":"https://openalex.org/S4306401540","display_name":"Digital Access to Scholarship at Harvard (DASH) (Harvard University)","issn_l":null,"issn":null,"is_oa":false,"is_in_doaj":false,"is_core":false,"listed_in":[],"host_organization":"https://openalex.org/I136199984","host_organization_name":"Harvard University","host_organization_lineage":["https://openalex.org/I136199984"],"host_organization_lineage_names":[],"type":"repository"},"license":"cc-by","license_id":"https://openalex.org/licenses/cc-by","version":"submittedVersion","is_accepted":false,"is_published":false,"raw_source_name":"","raw_type":"Thesis or Dissertation"},"volume":null,"type":"dissertation","is_traditional":true,"indexed_in":[],"open_access":{"is_oa":true,"oa_status":"green","oa_url":"http://nrs.harvard.edu/urn-3:HUL.InstRepos:36923351","any_repository_has_fulltext":true},"authorships":[{"author_position":"first","author":{"id":"https://openalex.org/A5012030921","display_name":"Xiaoli Mi","orcid":"https://orcid.org/0000-0002-0348-1001","observed_orcids":["https://orcid.org/0000-0002-0348-1001"]},"institutions":[],"countries":[],"is_corresponding":true,"raw_author_name":"Xiaoli Mi","raw_affiliation_strings":[],"raw_orcid":"https://orcid.org/0000-0002-0348-1001","affiliations":[]}],"institutions":[],"countries_distinct_count":0,"institutions_distinct_count":0,"corresponding_author_ids":["https://openalex.org/A5012030921"],"corresponding_institution_ids":[],"apc_list":null,"apc_paid":null,"fwci":null,"has_fulltext":false,"cited_by_count":0,"citation_normalized_percentile":null,"cited_by_percentile_year":null,"biblio":{"volume":null,"issue":null,"first_page":null,"last_page":null},"is_retracted":false,"is_paratext":false,"is_xpac":false,"primary_topic":{"id":"https://openalex.org/T10878","display_name":"CRISPR and Genetic Engineering","score":0.885699987411499,"subfield":{"id":"https://openalex.org/subfields/1312","display_name":"Molecular Biology"},"field":{"id":"https://openalex.org/fields/13","display_name":"Biochemistry, Genetics and Molecular Biology"},"domain":{"id":"https://openalex.org/domains/1","display_name":"Life Sciences"}},"topics":[{"id":"https://openalex.org/T10878","display_name":"CRISPR and Genetic Engineering","score":0.885699987411499,"subfield":{"id":"https://openalex.org/subfields/1312","display_name":"Molecular Biology"},"field":{"id":"https://openalex.org/fields/13","display_name":"Biochemistry, Genetics and Molecular Biology"},"domain":{"id":"https://openalex.org/domains/1","display_name":"Life Sciences"}},{"id":"https://openalex.org/T10554","display_name":"Hemoglobinopathies and Related Disorders","score":0.05999999865889549,"subfield":{"id":"https://openalex.org/subfields/2716","display_name":"Genetics (clinical)"},"field":{"id":"https://openalex.org/fields/27","display_name":"Medicine"},"domain":{"id":"https://openalex.org/domains/4","display_name":"Health Sciences"}},{"id":"https://openalex.org/T10452","display_name":"Iron Metabolism and Disorders","score":0.003100000089034438,"subfield":{"id":"https://openalex.org/subfields/2720","display_name":"Hematology"},"field":{"id":"https://openalex.org/fields/27","display_name":"Medicine"},"domain":{"id":"https://openalex.org/domains/4","display_name":"Health Sciences"}}],"keywords":[{"id":"https://openalex.org/keywords/congenital-dyserythropoietic-anemia","display_name":"congenital dyserythropoietic anemia","score":0.9380000233650208},{"id":"https://openalex.org/keywords/gata1","display_name":"GATA-1","score":0.8169999718666077},{"id":"https://openalex.org/keywords/crispr-cas9-genome-editing","display_name":"CRISPR/Cas9 genome editing","score":0.9769999980926514},{"id":"https://openalex.org/keywords/disease-modeling","display_name":"disease modeling","score":0.7900000214576721},{"id":"https://openalex.org/keywords/erythroid-cell-lines","display_name":"erythroid cell lines","score":0.6909999847412109},{"id":"https://openalex.org/keywords/homology-directed-repair","display_name":"homology-directed repair","score":0.6930000185966492},{"id":"https://openalex.org/keywords/single-guide-rna-design","display_name":"single guide RNA design","score":0.6660000085830688},{"id":"https://openalex.org/keywords/erythropoiesis","display_name":"erythropoiesis","score":0.6079999804496765},{"id":"https://openalex.org/keywords/megakaryopoiesis","display_name":"megakaryopoiesis","score":0.8849999904632568},{"id":"https://openalex.org/keywords/fetal-hemoglobin","display_name":"fetal hemoglobin","score":0.9229999780654907}],"concepts":[{"id":"https://openalex.org/C144501496","wikidata":"https://www.wikidata.org/wiki/Q5533489","display_name":"Genome editing","level":4,"score":0.5850450992584229},{"id":"https://openalex.org/C70721500","wikidata":"https://www.wikidata.org/wiki/Q177005","display_name":"Computational biology","level":1,"score":0.5198972225189209},{"id":"https://openalex.org/C41008148","wikidata":"https://www.wikidata.org/wiki/Q21198","display_name":"Computer science","level":0,"score":0.4661732017993927},{"id":"https://openalex.org/C141231307","wikidata":"https://www.wikidata.org/wiki/Q7020","display_name":"Genome","level":3,"score":0.4159987270832062},{"id":"https://openalex.org/C86803240","wikidata":"https://www.wikidata.org/wiki/Q420","display_name":"Biology","level":0,"score":0.3342050313949585},{"id":"https://openalex.org/C136764020","wikidata":"https://www.wikidata.org/wiki/Q466","display_name":"World Wide Web","level":1,"score":0.3273507356643677},{"id":"https://openalex.org/C54355233","wikidata":"https://www.wikidata.org/wiki/Q7162","display_name":"Genetics","level":1,"score":0.28575897216796875},{"id":"https://openalex.org/C104317684","wikidata":"https://www.wikidata.org/wiki/Q7187","display_name":"Gene","level":2,"score":0.14843696355819702}],"mesh":[],"locations_count":2,"locations":[{"id":"pmh:oai:dash.harvard.edu:1/36923351","doi":null,"is_oa":true,"landing_page_url":"http://nrs.harvard.edu/urn-3:HUL.InstRepos:36923351","pdf_url":null,"source":{"id":"https://openalex.org/S4306401540","display_name":"Digital Access to Scholarship at Harvard (DASH) (Harvard University)","issn_l":null,"issn":null,"is_oa":false,"is_in_doaj":false,"is_core":false,"listed_in":[],"host_organization":"https://openalex.org/I136199984","host_organization_name":"Harvard University","host_organization_lineage":["https://openalex.org/I136199984"],"host_organization_lineage_names":[],"type":"repository"},"license":"cc-by","license_id":"https://openalex.org/licenses/cc-by","version":"submittedVersion","is_accepted":false,"is_published":false,"raw_source_name":"","raw_type":"Thesis or Dissertation"},{"id":"mag:2803626403","doi":null,"is_oa":false,"landing_page_url":"https://dash.harvard.edu/handle/1/36923351","pdf_url":null,"source":null,"license":null,"license_id":null,"version":null,"is_accepted":false,"is_published":false,"raw_source_name":null,"raw_type":null}],"best_oa_location":{"id":"pmh:oai:dash.harvard.edu:1/36923351","doi":null,"is_oa":true,"landing_page_url":"http://nrs.harvard.edu/urn-3:HUL.InstRepos:36923351","pdf_url":null,"source":{"id":"https://openalex.org/S4306401540","display_name":"Digital Access to Scholarship at Harvard (DASH) (Harvard University)","issn_l":null,"issn":null,"is_oa":false,"is_in_doaj":false,"is_core":false,"listed_in":[],"host_organization":"https://openalex.org/I136199984","host_organization_name":"Harvard University","host_organization_lineage":["https://openalex.org/I136199984"],"host_organization_lineage_names":[],"type":"repository"},"license":"cc-by","license_id":"https://openalex.org/licenses/cc-by","version":"submittedVersion","is_accepted":false,"is_published":false,"raw_source_name":"","raw_type":"Thesis or Dissertation"},"sustainable_development_goals":[{"id":"https://metadata.un.org/sdg/3","display_name":"Good health and well-being","score":0.8560000061988831}],"study_designs":[],"awards":[],"funders":[],"has_content":{"grobid_xml":false,"pdf":false},"content_urls":null,"referenced_works_count":25,"referenced_works":["https://openalex.org/W798920472","https://openalex.org/W1575193685","https://openalex.org/W1981160614","https://openalex.org/W1988075836","https://openalex.org/W2029486567","https://openalex.org/W2034504333","https://openalex.org/W2040148139","https://openalex.org/W2043972484","https://openalex.org/W2064815984","https://openalex.org/W2071137315","https://openalex.org/W2075162142","https://openalex.org/W2098188264","https://openalex.org/W2112444085","https://openalex.org/W2142094474","https://openalex.org/W2144859693","https://openalex.org/W2156319424","https://openalex.org/W2163248265","https://openalex.org/W2167380395","https://openalex.org/W2173737475","https://openalex.org/W2260480416","https://openalex.org/W2275463106","https://openalex.org/W2343876552","https://openalex.org/W2604964915","https://openalex.org/W2611134270","https://openalex.org/W2611661371"],"related_works":["https://openalex.org/W2325099115","https://openalex.org/W2581247422","https://openalex.org/W2576159092","https://openalex.org/W2765760120","https://openalex.org/W2923636118","https://openalex.org/W4310120186","https://openalex.org/W4413272011","https://openalex.org/W2983316199","https://openalex.org/W4385723067","https://openalex.org/W4319984554"],"abstract_inverted_index":{"The":[0,271,493],"ease":[1],"of":[2,14,21,29,52,72,97,118,138,159,256,273,283,331,391,397,418,440,475,490,522,528,558,579],"genome":[3,41,74,208,454,523,580],"sequencing":[4],"over":[5],"the":[6,12,26,44,50,70,115,121,135,148,157,168,179,185,194,199,239,284,317,332,337,350,363,369,384,406,425,441,447,451,469,476,507],"past":[7],"decade":[8],"has":[9,89,537],"greatly":[10],"facilitated":[11],"identification":[13],"genetic":[15,84,533],"mutations":[16,33,56,410],"causing":[17],"a":[18,82,94,129,175,188,213,482,491,540,544],"large":[19],"number":[20],"human":[22,214,385],"diseases.":[23],"However,":[24],"in":[25,57,110,134,143,187,202,212,242,304,473,499,588],"vast":[27],"majority":[28],"cases,":[30],"how":[31],"these":[32,463],"lead":[34],"to":[35,61,80,173,218,260,262,279,316,525,585,591],"disease":[36,186,542,551,562,587],"remains":[37],"an":[38,77,243,252,419,589],"enigma.":[39],"Targeted":[40],"engineering":[42],"via":[43,287,399],"RNA-guided":[45],"CRISPR/Cas9":[46,211,560],"nuclease":[47],"system":[48,190],"offers":[49],"possibility":[51],"faithfully":[53],"mimicking":[54],"molecular":[55],"their":[58],"endogenous":[59],"context":[60],"study":[62,536,586],"underlying":[63,195],"mechanisms.":[64],"In":[65],"this":[66,220,247,356],"thesis,":[67],"I":[68,206,224,249,298,321,553],"explored":[69],"question":[71],"whether":[73],"editing":[75,209,267,302,338,455,524,581],"is":[76,340,435,511],"effective":[78],"approach":[79],"model":[81,184],"novel":[83,541,545],"disease.":[85,182],"Recently,":[86],"our":[87],"laboratory":[88],"identified":[90,235],"two":[91],"patients":[92,122],"with":[93,210,355,412,531,543,555],"distinct":[95,229],"form":[96],"congenital":[98],"dyserythropoietic":[99],"anemia,":[100],"characterized":[101,299],"by":[102,197,312],"erythroid":[103,215,386],"and":[104,107,161,165,181,191,226,234,269,281,309,336,365,375,424,453,481,502,547,564,568,582,594],"megakaryocytic":[105],"dysplasia":[106],"mild":[108],"elevations":[109],"fetal":[111],"hemoglobin":[112],"levels.":[113],"Curiously,":[114],"coding":[116],"sequence":[117],"DNA":[119],"from":[120,277,349,450],"was":[123,459,497],"unremarkable":[124],"but":[125],"further":[126,192,503],"analysis":[127],"revealed":[128],"common":[130,529],"hemizygous":[131],"point":[132],"mutation":[133,180,200,286,452,471,546],"last":[136],"intron":[137,364,484],"GATA1":[139,154,222,266,325,359,509],"(chrX:":[140],"48,652,176":[141],"C>T":[142,409,470],"hg19).":[144],"This":[145],"gene":[146],"encodes":[147],"hematopoietic":[149],"master":[150],"regulatory":[151],"transcription":[152],"factor":[153],"essential":[155,393],"for":[156,394,431,561,576],"differentiation":[158],"erythrocytes":[160],"megakaryocytes.":[162],"Genetic":[163],"mapping":[164],"segregation":[166],"within":[167,328,362],"families":[169],"provided":[170,548],"strong":[171],"evidence":[172],"support":[174],"causal":[176],"relationship":[177],"between":[178],"To":[183],"tractable":[189],"understand":[193],"basis":[196],"which":[198],"results":[201,472],"disordered":[203],"blood":[204],"production,":[205],"performed":[207],"cell":[216,307,387],"line":[217,388],"recreate":[219],"intronic":[221,285],"mutation.":[223],"designed":[225],"cloned":[227],"nine":[228],"single":[230],"guide":[231],"RNAs":[232],"(sgRNAs)":[233],"one":[236],"that":[237,251,323,367,383,437,468,506],"cleaved":[238],"target":[240],"locus":[241],"efficient":[244,569],"manner.":[245],"Using":[246,294],"sgRNA,":[248],"showed":[250,505],"increased":[253,276],"mass":[254],"ratio":[255],"exogenous":[257],"repair":[258,290],"template":[259],"sgRNA":[261],"Cas9":[263,318,333,432],"dramatically":[264],"improved":[265],"efficiency":[268],"diversity.":[270],"rate":[272],"genomic":[274,313],"perturbation":[275],"20%":[278],"80%":[280],"incorporation":[282],"homology":[288],"directed":[289],"occurred":[291,327,361],"at":[292,345],"3.8%.":[293],"three":[295],"computational":[296],"methods,":[297],"all":[300],"allele-specific":[301],"events":[303],"133":[305],"isogenic":[306],"lines":[308],"mapped":[310],"them":[311],"position":[314,347],"relative":[315],"cleavage":[319,334],"site.":[320],"found":[322],"most":[324,358],"changes":[326],"15":[329],"bp":[330],"site":[335,374,423,445,480],"frequency":[339],"higher":[341],"upstream":[342],"than":[343],"downstream":[344,370],"each":[346],"equidistant":[348],"predicted":[351],"double-strand":[352],"breaks.":[353],"Consistent":[354],"observation,":[357],"edits":[360],"those":[366],"altered":[368],"canonical":[371],"splice":[372,421,443,478],"acceptor":[373,422,444,479],"exon":[376],"were":[377],"exclusively":[378],"heterozygous.":[379],"These":[380,571],"findings":[381],"suggest":[382],"disfavors":[389],"alteration":[390,496],"sequences":[392],"proper":[395],"function":[396],"GATA1,":[398],"splicing":[400,448,495],"regulation":[401],"or":[402],"protein":[403,510],"coding.":[404],"Notably,":[405],"desired":[407],"homozygous":[408],"co-occurred":[411],"additional":[413],"modifications":[414],"such":[415],"as":[416],"deletion":[417,439],"alternative":[420,442,477],"protospacer":[426],"adjacent":[427],"motif":[428],"(PAM)":[429],"required":[430],"binding.":[433],"It":[434],"possible":[436,566],"concurrent":[438],"rescues":[446],"defect":[449],"recurred":[456],"until":[457],"PAM":[458],"rendered":[460],"unrecognizable.":[461],"Following":[462],"experiments,":[464],"my":[465],"colleagues":[466],"demonstrated":[467],"activation":[474],"partial":[483],"retention":[485],"event":[486],"using":[487,559],"transient":[488],"expression":[489],"minigene.":[492],"observed":[494],"confirmed":[498],"patient":[500],"samples":[501],"experiments":[504],"resultant":[508],"inactive.":[512],"While":[513],"many":[514],"recent":[515],"proof-of-principle":[516],"studies":[517],"have":[518,573],"described":[519],"successful":[520],"application":[521],"generate":[526,592],"models":[527],"diseases":[530],"well-established":[532],"alterations,":[534],"no":[535],"yet":[538],"modeled":[539],"insight":[549],"into":[550],"pathophysiology.":[552],"conclude":[554],"important":[556],"limitations":[557],"modeling":[563],"discuss":[565],"solutions":[567],"alternatives.":[570],"lessons":[572],"broad":[574],"implications":[575],"future":[577],"applications":[578],"classical":[583],"approaches":[584],"effort":[590],"functionally":[593],"clinically":[595],"relevant":[596],"knowledge.":[597]},"counts_by_year":[],"updated_date":"2026-11-04T10:54:05.112534","created_date":"2018-06-01T00:00:00"}