LOCUS NC_012532 10794 bp RNA linear VRL 08-FEB-2016 DEFINITION Zika virus, complete genome. ACCESSION NC_012532 VERSION NC_012532.1 GI:226377833 DBLINK BioProject: PRJNA36615 KEYWORDS RefSeq. SOURCE Zika virus ORGANISM Zika virus Viruses; ssRNA viruses; ssRNA positive-strand viruses, no DNA stage; Flaviviridae; Flavivirus. REFERENCE 1 (bases 1 to 10794) AUTHORS Kuno,G. and Chang,G.-J.J. TITLE Full-length sequencing and genomic characterization of Bagaza, Kedougou, and Zika viruses JOURNAL Arch Virol. 152 (4), 687-696 (2007) PUBMED 17195954 REFERENCE 2 (bases 1 to 10794) AUTHORS Kuno,G. and Chang,G.J. TITLE Biological transmission of arboviruses: reexamination of and new insights into components, mechanisms, and unique traits as well as their evolutionary trends JOURNAL Clin. Microbiol. Rev. 18 (4), 608-637 (2005) PUBMED 16223950 REFERENCE 3 (bases 1 to 10794) CONSRTM NCBI Genome Project TITLE Direct Submission JOURNAL Submitted (06-APR-2009) National Center for Biotechnology Information, NIH, Bethesda, MD 20894, USA REFERENCE 4 (bases 1 to 10794) AUTHORS Kuno,G. and Chang,G.-J.J. TITLE Direct Submission JOURNAL Submitted (01-AUG-2006) Division of Vector-Borne Infect. Dis., CDC, P.O. Box 2087, Fort Collins, CO 80522-2087, USA REMARK Sequence update by submitter REFERENCE 5 (bases 1 to 10794) AUTHORS Kuno,G., Chang,G.-J.J. and Tsuchiya,K.R. TITLE Direct Submission JOURNAL Submitted (21-MAY-2004) Arbovirus Diseases Branch, Division of Vector-Borne Infectious Diseases, Centers for Disease Control and Prevention, P.O. Box 2087, Fort Collins, CO 80522, USA COMMENT REVIEWED REFSEQ: This record has been curated by NCBI staff. The reference sequence was derived from AY632535. Mature peptides were annotated by RefSeq staff using the cleavage sites reported in Kuno and Chang, 2007 (PMID 17195954). Questions about the annotation of this sequence should be directed to info@ncbi.nlm.nih.gov. COMPLETENESS: full length. FEATURES Location/Qualifiers source 1..10794 /organism="Zika virus" /mol_type="genomic RNA" /strain="MR 766" /host="sentinel monkey" /db_xref="taxon:64320" /country="Uganda" /note="mosquito-borne flavivirus" 5'UTR 1..106 gene 107..10366 /gene="flavivirus polyprotein gene" /locus_tag="ZIKV_gp1" /db_xref="GeneID:7751225" CDS 107..10366 /gene="flavivirus polyprotein gene" /locus_tag="ZIKV_gp1" /codon_start=1 /product="flavivirus polyprotein" /protein_id="YP_002790881.1" /db_xref="GI:226377834" /db_xref="GeneID:7751225" /translation="MKNPKEEIRRIRIVNMLKRGVARVNPLGGLKRLPAGLLLGHGPI RMVLAILAFLRFTAIKPSLGLINRWGSVGKKEAMEIIKKFKKDLAAMLRIINARKERK RRGADTSIGIIGLLLTTAMAAEITRRGSAYYMYLDRSDAGKAISFATTLGVNKCHVQI MDLGHMCDATMSYECPMLDEGVEPDDVDCWCNTTSTWVVYGTCHHKKGEARRSRRAVT LPSHSTRKLQTRSQTWLESREYTKHLIKVENWIFRNPGFALVAVAIAWLLGSSTSQKV IYLVMILLIAPAYSIRCIGVSNRDFVEGMSGGTWVDVVLEHGGCVTVMAQDKPTVDIE LVTTTVSNMAEVRSYCYEASISDMASDSRCPTQGEAYLDKQSDTQYVCKRTLVDRGWG NGCGLFGKGSLVTCAKFTCSKKMTGKSIQPENLEYRIMLSVHGSQHSGMIGYETDEDR AKVEVTPNSPRAEATLGGFGSLGLDCEPRTGLDFSDLYYLTMNNKHWLVHKEWFHDIP LPWHAGADTGTPHWNNKEALVEFKDAHAKRQTVVVLGSQEGAVHTALAGALEAEMDGA KGRLFSGHLKCRLKMDKLRLKGVSYSLCTAAFTFTKVPAETLHGTVTVEVQYAGTDGP CKIPVQMAVDMQTLTPVGRLITANPVITESTENSKMMLELDPPFGDSYIVIGVGDKKI THHWHRSGSTIGKAFEATVRGAKRMAVLGDTAWDFGSVGGVFNSLGKGIHQIFGAAFK SLFGGMSWFSQILIGTLLVWLGLNTKNGSISLTCLALGGVMIFLSTAVSADVGCSVDF SKKETRCGTGVFIYNDVEAWRDRYKYHPDSPRRLAAAVKQAWEEGICGISSVSRMENI MWKSVEGELNAILEENGVQLTVVVGSVKNPMWRGPQRLPVPVNELPHGWKAWGKSYFV RAAKTNNSFVVDGDTLKECPLEHRAWNSFLVEDHGFGVFHTSVWLKVREDYSLECDPA VIGTAVKGREAAHSDLGYWIESEKNDTWRLKRAHLIEMKTCEWPKSHTLWTDGVEESD LIIPKSLAGPLSHHNTREGYRTQVKGPWHSEELEIRFEECPGTKVYVEETCGTRGPSL RSTTASGRVIEEWCCRECTMPPLSFRAKDGCWYGMEIRPRKEPESNLVRSMVTAGSTD HMDHFSLGVLVILLMVQEGLKKRMTTKIIMSTSMAVLVVMILGGFSMSDLAKLVILMG ATFAEMNTGGDVAHLALVAAFKVRPALLVSFIFRANWTPRESMLLALASCLLQTAISA LEGDLMVLINGFALAWLAIRAMAVPRTDNIALPILAALTPLARGTLLVAWRAGLATCG GIMLLSLKGKGSVKKNLPFVMALGLTAVRVVDPINVVGLLLLTRSGKRSWPPSEVLTA VGLICALAGGFAKADIEMAGPMAAVGLLIVSYVVSGKSVDMYIERAGDITWEKDAEVT GNSPRLDVALDESGDFSLVEEDGPPMREIILKVVLMAICGMNPIAIPFAAGAWYVYVK TGKRSGALWDVPAPKEVKKGETTDGVYRVMTRRLLGSTQVGVGVMQEGVFHTMWHVTK GAALRSGEGRLDPYWGDVKQDLVSYCGPWKLDAAWDGLSEVQLLAVPPGERARNIQTL PGIFKTKDGDIGAVALDYPAGTSGSPILDKCGRVIGLYGNGVVIKNGSYVSAITQGKR EEETPVECFEPSMLKKKQLTVLDLHPGAGKTRRVLPEIVREAIKKRLRTVILAPTRVV AAEMEEALRGLPVRYMTTAVNVTHSGTEIVDLMCHATFTSRLLQPIRVPNYNLNIMDE AHFTDPSSIAARGYISTRVEMGEAAAIFMTATPPGTRDAFPDSNSPIMDTEVEVPERA WSSGFDWVTDHSGKTVWFVPSVRNGNEIAACLTKAGKRVIQLSRKTFETEFQKTKNQE WDFVITTDISEMGANFKADRVIDSRRCLKPVILDGERVILAGPMPVTHASAAQRRGRI GRNPNKPGDEYMYGGGCAETDEGHAHWLEARMLLDNIYLQDGLIASLYRPEADKVAAI EGEFKLRTEQRKTFVELMKRGDLPVWLAYQVASAGITYTDRRWCFDGTTNNTIMEDSV PAEVWTKYGEKRVLKPRWMDARVCSDHAALKSFKEFAAGKRGAALGVMEALGTLPGHM TERFQEAIDNLAVLMRAETGSRPYKAAAAQLPETLETIMLLGLLGTVSLGIFFVLMRN KGIGKMGFGMVTLGASAWLMWLSEIEPARIACVLIVVFLLLVVLIPEPEKQRSPQDNQ MAIIIMVAVGLLGLITANELGWLERTKNDIAHLMGRREEGATMGFSMDIDLRPASAWA IYAALTTLITPAVQHAVTTSYNNYSLMAMATQAGVLFGMGKGMPFMHGDLGVPLLMMG CYSQLTPLTLIVAIILLVAHYMYLIPGLQAAAARAAQKRTAAGIMKNPVVDGIVVTDI DTMTIDPQVEKKMGQVLLIAVAISSAVLLRTAWGWGEAGALITAATSTLWEGSPNKYW NSSTATSLCNIFRGSYLAGASLIYTVTRNAGLVKRRGGGTGETLGEKWKARLNQMSAL EFYSYKKSGITEVCREEARRALKDGVATGGHAVSRGSAKIRWLEERGYLQPYGKVVDL GCGRGGWSYYAATIRKVQEVRGYTKGGPGHEEPMLVQSYGWNIVRLKSGVDVFHMAAE PCDTLLCDIGESSSSPEVEETRTLRVLSMVGDWLEKRPGAFCIKVLCPYTSTMMETME RLQRRHGGGLVRVPLCRNSTHEMYWVSGAKSNIIKSVSTTSQLLLGRMDGPRRPVKYE EDVNLGSGTRAVASCAEAPNMKIIGRRIERIRNEHAETWFLDENHPYRTWAYHGSYEA PTQGSASSLVNGVVRLLSKPWDVVTGVTGIAMTDTTPYGQQRVFKEKVDTRVPDPQEG TRQVMNIVSSWLWKELGKRKRPRVCTKEEFINKVRSNAALGAIFEEEKEWKTAVEAVN DPRFWALVDREREHHLRGECHSCVYNMMGKREKKQGEFGKAKGSRAIWYMWLGARFLE FEALGFLNEDHWMGRENSGGGVEGLGLQRLGYILEEMNRAPGGKMYADDTAGWDTRIS KFDLENEALITNQMEEGHRTLALAVIKYTYQNKVVKVLRPAEGGKTVMDIISRQDQRG SGQVVTYALNTFTNLVVQLIRNMEAEEVLEMQDLWLLRKPEKVTRWLQSNGWDRLKRM AVSGDDCVVKPIDDRFAHALRFLNDMGKVRKDTQEWKPSTGWSNWEEVPFCSHHFNKL YLKDGRSIVVPCRHQDELIGRARVSPGAGWSIRETACLAKSYAQMWQLLYFHRRDLRL MANAICSAVPVDWVPTGRTTWSIHGKGEWMTTEDMLMVWNRVWIEENDHMEDKTPVTK WTDIPYLGKREDLWCGSLIGHRPRTTWAENIKDTVNMVRRIIGDEEKYMDYLSTQVRY LGEEGSTPGVL" mat_peptide 107..472 /gene="flavivirus polyprotein gene" /locus_tag="ZIKV_gp1" /product="anchored capsid protein C" /protein_id="YP_009227206.1" /db_xref="GI:985757037" mat_peptide 107..418 /gene="flavivirus polyprotein gene" /locus_tag="ZIKV_gp1" /product="capsid protein C" /protein_id="YP_009227196.1" /db_xref="GI:985757027" mat_peptide 473..976 /gene="flavivirus polyprotein gene" /locus_tag="ZIKV_gp1" /product="membrane glycoprotein precursor M" /protein_id="YP_009227197.1" /db_xref="GI:985757028" mat_peptide 473..751 /gene="flavivirus polyprotein gene" /locus_tag="ZIKV_gp1" /product="protein pr" /protein_id="YP_009227207.1" /db_xref="GI:985757038" mat_peptide 752..976 /gene="flavivirus polyprotein gene" /locus_tag="ZIKV_gp1" /product="membrane glycoprotein M" /protein_id="YP_009227208.1" /db_xref="GI:985757039" mat_peptide 977..2476 /gene="flavivirus polyprotein gene" /locus_tag="ZIKV_gp1" /product="envelope protein E" /protein_id="YP_009227198.1" /db_xref="GI:985757029" mat_peptide 2477..3532 /gene="flavivirus polyprotein gene" /locus_tag="ZIKV_gp1" /product="nonstructural protein NS1" /protein_id="YP_009227199.1" /db_xref="GI:985757030" mat_peptide 3533..4210 /gene="flavivirus polyprotein gene" /locus_tag="ZIKV_gp1" /product="nonstructural protein NS2A" /protein_id="YP_009227200.1" /db_xref="GI:985757031" mat_peptide 4211..4600 /gene="flavivirus polyprotein gene" /locus_tag="ZIKV_gp1" /product="nonstructural protein NS2B" /protein_id="YP_009227201.1" /db_xref="GI:985757032" mat_peptide 4601..6451 /gene="flavivirus polyprotein gene" /locus_tag="ZIKV_gp1" /product="nonstructural protein NS3" /protein_id="YP_009227202.1" /db_xref="GI:985757033" mat_peptide 6452..6832 /gene="flavivirus polyprotein gene" /locus_tag="ZIKV_gp1" /product="nonstructural protein NS4A" /protein_id="YP_009227203.1" /db_xref="GI:985757034" mat_peptide 6833..6901 /gene="flavivirus polyprotein gene" /locus_tag="ZIKV_gp1" /product="protein 2K" /protein_id="YP_009227209.1" /db_xref="GI:985757040" mat_peptide 6902..7654 /gene="flavivirus polyprotein gene" /locus_tag="ZIKV_gp1" /product="nonstructural protein NS4B" /protein_id="YP_009227204.1" /db_xref="GI:985757035" mat_peptide 7655..10363 /gene="flavivirus polyprotein gene" /locus_tag="ZIKV_gp1" /product="RNA-dependent RNA polymerase NS5" /protein_id="YP_009227205.1" /db_xref="GI:985757036" 3'UTR 10367..10794 ORIGIN 1 agttgttgat ctgtgtgagt cagactgcga cagttcgagt ctgaagcgag agctaacaac 61 agtatcaaca ggtttaattt ggatttggaa acgagagttt ctggtcatga aaaaccccaa 121 agaagaaatc cggaggatcc ggattgtcaa tatgctaaaa cgcggagtag cccgtgtaaa 181 ccccttggga ggtttgaaga ggttgccagc cggacttctg ctgggtcatg gacccatcag 241 aatggttttg gcgatactag cctttttgag atttacagca atcaagccat cactgggcct 301 tatcaacaga tggggttccg tggggaaaaa agaggctatg gaaataataa agaagttcaa 361 gaaagatctt gctgccatgt tgagaataat caatgctagg aaagagagga agagacgtgg 421 cgcagacacc agcatcggaa tcattggcct cctgctgact acagccatgg cagcagagat 481 cactagacgc gggagtgcat actacatgta cttggatagg agcgatgccg ggaaggccat 541 ttcgtttgct accacattgg gagtgaacaa gtgccacgta cagatcatgg acctcgggca 601 catgtgtgac gccaccatga gttatgagtg ccctatgctg gatgagggag tggaaccaga 661 tgatgtcgat tgctggtgca acacgacatc aacttgggtt gtgtacggaa cctgtcatca 721 caaaaaaggt gaggcacggc gatctagaag agccgtgacg ctcccttctc actctacaag 781 gaagttgcaa acgcggtcgc agacctggtt agaatcaaga gaatacacga agcacttgat 841 caaggttgaa aactggatat tcaggaaccc cgggtttgcg ctagtggccg ttgccattgc 901 ctggcttttg ggaagctcga cgagccaaaa agtcatatac ttggtcatga tactgctgat 961 tgccccggca tacagtatca ggtgcattgg agtcagcaat agagacttcg tggagggcat 1021 gtcaggtggg acctgggttg atgttgtctt ggaacatgga ggctgcgtta ccgtgatggc 1081 acaggacaag ccaacagtcg acatagagtt ggtcacgacg acggttagta acatggccga 1141 ggtaagatcc tattgctacg aggcatcgat atcggacatg gcttcggaca gtcgttgccc 1201 aacacaaggt gaagcctacc ttgacaagca atcagacact caatatgtct gcaaaagaac 1261 attagtggac agaggttggg gaaacggttg tggacttttt ggcaaaggga gcttggtgac 1321 atgtgccaag tttacgtgtt ctaagaagat gaccgggaag agcattcaac cggaaaatct 1381 ggagtatcgg ataatgctat cagtgcatgg ctcccagcat agcgggatga ttggatatga 1441 aactgacgaa gatagagcga aagtcgaggt tacgcctaat tcaccaagag cggaagcaac 1501 cttgggaggc tttggaagct taggacttga ctgtgaacca aggacaggcc ttgacttttc 1561 agatctgtat tacctgacca tgaacaataa gcattggttg gtgcacaaag agtggtttca 1621 tgacatccca ttgccttggc atgctggggc agacaccgga actccacact ggaacaacaa 1681 agaggcattg gtagaattca aggatgccca cgccaagagg caaaccgtcg tcgttctggg 1741 gagccaggaa ggagccgttc acacggctct cgctggagct ctagaggctg agatggatgg 1801 tgcaaaggga aggctgttct ctggccattt gaaatgccgc ctaaaaatgg acaagcttag 1861 attgaagggc gtgtcatatt ccttgtgcac tgcggcattc acattcacca aggtcccagc 1921 tgaaacactg catggaacag tcacagtgga ggtgcagtat gcagggacag atggaccctg 1981 caagatccca gtccagatgg cggtggacat gcagaccctg accccagttg gaaggctgat 2041 aaccgccaac cccgtgatta ctgaaagcac tgagaactca aagatgatgt tggagcttga 2101 cccaccattt ggggattctt acattgtcat aggagttggg gacaagaaaa tcacccacca 2161 ctggcatagg agtggtagca ccatcggaaa ggcatttgag gccactgtga gaggcgccaa 2221 gagaatggca gtcctggggg atacagcctg ggacttcgga tcagtcgggg gtgtgttcaa 2281 ctcactgggt aagggcattc accagatttt tggagcagcc ttcaaatcac tgtttggagg 2341 aatgtcctgg ttctcacaga tcctcatagg cacgctgcta gtgtggttag gtttgaacac 2401 aaagaatgga tctatctccc tcacatgctt ggccctgggg ggagtgatga tcttcctctc 2461 cacggctgtt tctgctgacg tggggtgctc agtggacttc tcaaaaaagg aaacgagatg 2521 tggcacgggg gtattcatct ataatgatgt tgaagcctgg agggaccggt acaagtacca 2581 tcctgactcc ccccgcagat tggcagcagc agtcaagcag gcctgggaag aggggatctg 2641 tgggatctca tccgtttcaa gaatggaaaa catcatgtgg aaatcagtag aaggggagct 2701 caatgctatc ctagaggaga atggagttca actgacagtt gttgtgggat ctgtaaaaaa 2761 ccccatgtgg agaggtccac aaagattgcc agtgcctgtg aatgagctgc cccatggctg 2821 gaaagcctgg gggaaatcgt attttgttag ggcggcaaag accaacaaca gttttgttgt 2881 cgacggtgac acactgaagg aatgtccgct tgagcacaga gcatggaata gttttcttgt 2941 ggaggatcac gggtttggag tcttccacac cagtgtctgg cttaaggtca gagaagatta 3001 ctcattagaa tgtgacccag ccgtcatagg aacagctgtt aagggaaggg aggccgcgca 3061 cagtgatctg ggctattgga ttgaaagtga aaagaatgac acatggaggc tgaagagggc 3121 ccacctgatt gagatgaaaa catgtgaatg gccaaagtct cacacattgt ggacagatgg 3181 agtagaagaa agtgatctta tcatacccaa gtctttagct ggtccactca gccaccacaa 3241 caccagagag ggttacagaa cccaagtgaa agggccatgg cacagtgaag agcttgaaat 3301 ccggtttgag gaatgtccag gcaccaaggt ttacgtggag gagacatgcg gaactagagg 3361 accatctctg agatcaacta ctgcaagtgg aagggtcatt gaggaatggt gctgtaggga 3421 atgcacaatg cccccactat cgtttcgagc aaaagacggc tgctggtatg gaatggagat 3481 aaggcccagg aaagaaccag agagcaactt agtgaggtca atggtgacag cggggtcaac 3541 cgatcatatg gaccacttct ctcttggagt gcttgtgatt ctactcatgg tgcaggaggg 3601 gttgaagaag agaatgacca caaagatcat catgagcaca tcaatggcag tgctggtagt 3661 catgatcttg ggaggatttt caatgagtga cctggccaag cttgtgatcc tgatgggtgc 3721 tactttcgca gaaatgaaca ctggaggaga tgtagctcac ttggcattgg tagcggcatt 3781 taaagtcaga ccagccttgc tggtctcctt cattttcaga gccaattgga caccccgtga 3841 gagcatgctg ctagccctgg cttcgtgtct tctgcaaact gcgatctctg ctcttgaagg 3901 tgacttgatg gtcctcatta atggatttgc tttggcctgg ttggcaattc gagcaatggc 3961 cgtgccacgc actgacaaca tcgctctacc aatcttggct gctctaacac cactagctcg 4021 aggcacactg ctcgtggcat ggagagcggg cctggctact tgtggaggga tcatgctcct 4081 ctccctgaaa gggaaaggta gtgtgaagaa gaacctgcca tttgtcatgg ccctgggatt 4141 gacagctgtg agggtagtag accctattaa tgtggtagga ctactgttac tcacaaggag 4201 tgggaagcgg agctggcccc ctagtgaagt tctcacagcc gttggcctga tatgtgcact 4261 ggccggaggg tttgccaagg cagacattga gatggctgga cccatggctg cagtaggctt 4321 gctaattgtc agctatgtgg tctcgggaaa gagtgtggac atgtacattg aaagagcagg 4381 tgacatcaca tgggaaaagg acgcggaagt cactggaaac agtcctcggc ttgacgtggc 4441 actggatgag agtggtgact tctccttggt agaggaagat ggtccaccca tgagagagat 4501 catactcaag gtggtcctga tggccatctg tggcatgaac ccaatagcta taccttttgc 4561 tgcaggagcg tggtatgtgt atgtgaagac tgggaaaagg agtggcgccc tctgggacgt 4621 gcctgctccc aaagaagtga agaaaggaga gaccacagat ggagtgtaca gagtgatgac 4681 tcgcagactg ctaggttcaa cacaggttgg agtgggagtc atgcaagagg gagtcttcca 4741 caccatgtgg cacgttacaa aaggagccgc actgaggagc ggtgagggaa gacttgatcc 4801 atactggggg gatgtcaagc aggacttggt gtcatactgt gggccttgga agttggatgc 4861 agcttgggat ggactcagcg aggtacagct tttggccgta cctcccggag agagggccag 4921 aaacattcag accctgcctg gaatattcaa gacaaaggac ggggacatcg gagcagttgc 4981 tctggactac cctgcaggga cctcaggatc tccgatccta gacaaatgtg gaagagtgat 5041 aggactctat ggcaatgggg ttgtgatcaa gaatggaagc tatgttagtg ctataaccca 5101 gggaaagagg gaggaggaga ctccggttga atgtttcgaa ccctcgatgc tgaagaagaa 5161 gcagctaact gtcttggatc tgcatccagg agccggaaaa accaggagag ttcttcctga 5221 aatagtccgt gaagccataa aaaagagact ccggacagtg atcttggcac caactagggt 5281 tgtcgctgct gagatggagg aggccttgag aggacttccg gtgcgttaca tgacaacagc 5341 agtcaacgtc acccattctg ggacagaaat cgttgatttg atgtgccatg ccactttcac 5401 ttcacgctta ctacaaccca tcagagtccc taattacaat ctcaacatca tggatgaagc 5461 ccacttcaca gacccctcaa gtatagctgc aagaggatac atatcaacaa gggttgaaat 5521 gggcgaggcg gctgccattt ttatgactgc cacaccacca ggaacccgtg atgcgtttcc 5581 tgactctaac tcaccaatca tggacacaga agtggaagtc ccagagagag cctggagctc 5641 aggctttgat tgggtgacag accattctgg gaaaacagtt tggttcgttc caagcgtgag 5701 aaacggaaat gaaatcgcag cctgtctgac aaaggctgga aagcgggtca tacagctcag 5761 caggaagact tttgagacag aatttcagaa aacaaaaaat caagagtggg actttgtcat 5821 aacaactgac atctcagaga tgggcgccaa cttcaaggct gaccgggtca tagactctag 5881 gagatgccta aaaccagtca tacttgatgg tgagagagtc atcttggctg ggcccatgcc 5941 tgtcacgcat gctagtgctg ctcagaggag aggacgtata ggcaggaacc ctaacaaacc 6001 tggagatgag tacatgtatg gaggtgggtg tgcagagact gatgaaggcc atgcacactg 6061 gcttgaagca agaatgcttc ttgacaacat ctacctccag gatggcctca tagcctcgct 6121 ctatcggcct gaggccgata aggtagccgc cattgaggga gagtttaagc tgaggacaga 6181 gcaaaggaag accttcgtgg aactcatgaa gagaggagac cttcccgtct ggctagccta 6241 tcaggttgca tctgccggaa taacttacac agacagaaga tggtgctttg atggcacaac 6301 caacaacacc ataatggaag acagtgtacc agcagaggtt tggacaaagt atggagagaa 6361 gagagtgctc aaaccgagat ggatggatgc tagggtctgt tcagaccatg cggccctgaa 6421 gtcgttcaaa gaattcgccg ctggaaaaag aggagcggct ttgggagtaa tggaggccct 6481 gggaacactg ccaggacaca tgacagagag gtttcaggaa gccattgaca acctcgccgt 6541 gctcatgcga gcagagactg gaagcaggcc ttataaggca gcggcagccc aactgccgga 6601 gaccctagag accattatgc tcttaggttt gctgggaaca gtttcactgg ggatcttctt 6661 cgtcttgatg cggaataagg gcatcgggaa gatgggcttt ggaatggtaa cccttggggc 6721 cagtgcatgg ctcatgtggc tttcggaaat tgaaccagcc agaattgcat gtgtcctcat 6781 tgttgtgttt ttattactgg tggtgctcat acccgagcca gagaagcaaa gatctcccca 6841 agataaccag atggcaatta tcatcatggt ggcagtgggc cttctaggtt tgataactgc 6901 aaacgaactt ggatggctgg aaagaacaaa aaatgacata gctcatctaa tgggaaggag 6961 agaagaagga gcaaccatgg gattctcaat ggacattgat ctgcggccag cctccgcctg 7021 ggctatctat gccgcattga caactctcat caccccagct gtccaacatg cggtaaccac 7081 ttcatacaac aactactcct taatggcgat ggccacacaa gctggagtgc tgtttggcat 7141 gggcaaaggg atgccattta tgcatgggga ccttggagtc ccgctgctaa tgatgggttg 7201 ctattcacaa ttaacacccc tgactctgat agtagctatc attctgcttg tggcgcacta 7261 catgtacttg atcccaggcc tacaagcggc agcagcgcgt gctgcccaga aaaggacagc 7321 agctggcatc atgaagaatc ccgttgtgga tggaatagtg gtaactgaca ttgacacaat 7381 gacaatagac ccccaggtgg agaagaagat gggacaagtg ttactcatag cagtagccat 7441 ctccagtgct gtgctgctgc ggaccgcctg gggatggggg gaggctggag ctctgatcac 7501 agcagcgacc tccaccttgt gggaaggctc tccaaacaaa tactggaact cctctacagc 7561 cacctcactg tgcaacatct tcagaggaag ctatctggca ggagcttccc ttatctatac 7621 agtgacgaga aacgctggcc tggttaagag acgtggaggt gggacgggag agactctggg 7681 agagaagtgg aaagctcgtc tgaatcagat gtcggccctg gagttctact cttataaaaa 7741 gtcaggtatc actgaagtgt gtagagagga ggctcgccgt gccctcaagg atggagtggc 7801 cacaggagga catgccgtat cccggggaag tgcaaagatc agatggttgg aggagagagg 7861 atatctgcag ccctatggga aggttgttga cctcggatgt ggcagagggg gctggagcta 7921 ttatgccgcc accatccgca aagtgcagga ggtgagagga tacacaaagg gaggtcccgg 7981 tcatgaagaa cccatgctgg tgcaaagcta tgggtggaac atagttcgtc tcaagagtgg 8041 agtggacgtc ttccacatgg cggctgagcc gtgtgacact ctgctgtgtg acataggtga 8101 gtcatcatct agtcctgaag tggaagagac acgaacactc agagtgctct ctatggtggg 8161 ggactggctt gaaaaaagac caggggcctt ctgtataaag gtgctgtgcc catacaccag 8221 cactatgatg gaaaccatgg agcgactgca acgtaggcat gggggaggat tagtcagagt 8281 gccattgtgt cgcaactcca cacatgagat gtactgggtc tctggggcaa agagcaacat 8341 cataaaaagt gtgtccacca caagtcagct cctcctggga cgcatggatg gccccaggag 8401 gccagtgaaa tatgaggagg atgtgaacct cggctcgggt acacgagctg tggcaagctg 8461 tgctgaggct cctaacatga aaatcatcgg caggcgcatt gagagaatcc gcaatgaaca 8521 tgcagaaaca tggtttcttg atgaaaacca cccatacagg acatgggcct accatgggag 8581 ctacgaagcc cccacgcaag gatcagcgtc ttccctcgtg aacggggttg ttagactcct 8641 gtcaaagcct tgggacgtgg tgactggagt tacaggaata gccatgactg acaccacacc 8701 atacggccaa caaagagtct tcaaagaaaa agtggacacc agggtgccag atccccaaga 8761 aggcactcgc caggtaatga acatagtctc ttcctggctg tggaaggagc tggggaaacg 8821 caagcggcca cgcgtctgca ccaaagaaga gtttatcaac aaggtgcgca gcaatgcagc 8881 actgggagca atatttgaag aggaaaaaga atggaagacg gctgtggaag ctgtgaatga 8941 tccaaggttt tgggccctag tggataggga gagagaacac cacctgagag gagagtgtca 9001 cagctgtgtg tacaacatga tgggaaaaag agaaaagaag caaggagagt tcgggaaagc 9061 aaaaggtagc cgcgccatct ggtacatgtg gttgggagcc agattcttgg agtttgaagc 9121 ccttggattc ttgaacgagg accattggat gggaagagaa aactcaggag gtggagtcga 9181 agggttagga ttgcaaagac ttggatacat tctagaagaa atgaatcggg caccaggagg 9241 aaagatgtac gcagatgaca ctgctggctg ggacacccgc attagtaagt ttgatctgga 9301 gaatgaagct ctgattacca accaaatgga ggaagggcac agaactctgg cgttggccgt 9361 gattaaatac acataccaaa acaaagtggt gaaggttctc agaccagctg aaggaggaaa 9421 aacagttatg gacatcattt caagacaaga ccagagaggg agtggacaag ttgtcactta 9481 tgctctcaac acattcacca acttggtggt gcagcttatc cggaacatgg aagctgagga 9541 agtgttagag atgcaagact tatggttgtt gaggaagcca gagaaagtga ccagatggtt 9601 gcagagcaat ggatgggata gactcaaacg aatggcggtc agtggagatg actgcgttgt 9661 gaagccaatc gatgataggt ttgcacatgc cctcaggttc ttgaatgaca tgggaaaagt 9721 taggaaagac acacaggagt ggaaaccctc gactggatgg agcaattggg aagaagtccc 9781 gttctgctcc caccacttca acaagctgta cctcaaggat gggagatcca ttgtggtccc 9841 ttgccgccac caagatgaac tgattggccg agctcgcgtc tcaccagggg caggatggag 9901 catccgggag actgcctgtc ttgcaaaatc atatgcgcag atgtggcagc tcctttattt 9961 ccacagaaga gaccttcgac tgatggctaa tgccatttgc tcggctgtgc cagttgactg 10021 ggtaccaact gggagaacca cctggtcaat ccatggaaag ggagaatgga tgaccactga 10081 ggacatgctc atggtgtgga atagagtgtg gattgaggag aacgaccata tggaggacaa 10141 gactcctgta acaaaatgga cagacattcc ctatctagga aaaagggagg acttatggtg 10201 tggatccctt atagggcaca gaccccgcac cacttgggct gaaaacatca aagacacagt 10261 caacatggtg cgcaggatca taggtgatga agaaaagtac atggactatc tatccaccca 10321 agtccgctac ttgggtgagg aagggtccac acccggagtg ttgtaagcac caattttagt 10381 gttgtcaggc ctgctagtca gccacagttt ggggaaagct gtgcagcctg taaccccccc 10441 aggagaagct gggaaaccaa gctcatagtc aggccgagaa cgccatggca cggaagaagc 10501 catgctgcct gtgagcccct cagaggacac tgagtcaaaa aaccccacgc gcttggaagc 10561 gcaggatggg aaaagaaggt ggcgaccttc cccacccttc aatctggggc ctgaactgga 10621 gactagctgt gaatctccag cagagggact agtggttaga ggagaccccc cggaaaacgc 10681 aaaacagcat attgacgtgg gaaagaccag agactccatg agtttccacc acgctggccg 10741 ccaggcacag atcgccgaac ttcggcggcc ggtgtgggga aatccatggt ttct
Rarely
have scientists engaged with a new research agenda with such a sense of
urgency and from such a small knowledge base as in the current epidemic
of microcephaly (6000 notified suspected cases in Brazil1 and the first case detected in Colombia in March, 20162)
associated with the Zika virus outbreak across the Americas. Indeed, in
2015, in a review of infections that have neurological consequences,
Zika virus was not even mentioned.3 In only 5 months since the detection of the first excess cases of microcephaly in Brazil,4
WHO has declared the clusters of microcephaly and other neurological
disorders to be a Public Health Emergency of International Concern.5
WHO had also stated that the causal relation of these disorders with
Zika virus infection had not yet been scientifically proven.5
The reluctance to accept the causal link stems from the rarity of
isolation of Zika virus or detection of RNA in neonates with
microcephaly.1
Before
the outbreak of Zika virus in the Americas, the largest documented
outbreak was in French Polynesia in 2013–14. An elegant piece of
evidence supporting the theory that Zika is the cause of microcephaly
comes from that outbreak. In the first investigation, no peak in the
number of fetuses or neonates with microcephaly was detected.6
The theory that mother-to-child Zika virus infection was a cause of the
microcephaly epidemic in Brazil, however, required that there had been
an increase in microcephaly associated with the Zika outbreak in French
Polynesia. Further investigation identified 17 cases of severe
neurological malformations, including microcephaly, and showed that a
peak had been missed because most women had terminations.7
In The Lancet, Simon Cauchemez and colleagues8
present a reanalysis of the data on Zika and microcephaly from the
French Polynesian outbreak to estimate the magnitude of risk in women
infected with Zika virus during pregnancy. They used serological data to
estimate the total number of infections during the outbreak and data
from surveillance on consultations for suspected Zika virus disease to
attribute these infections to the weeks of the outbreak. They did an
exhaustive search of medical records to identify all cases of
microcephaly during the period Sept 1, 2013, to July 31, 2015. Eight
cases of microcephaly were identified, seven of which occurred in a
4-month period around the end of the Zika virus outbreak. The baseline
prevalence of microcephaly was two (95% CI 0–8) per 10 000 neonates. The
researchers developed a mathematical model with six periods of assumed
increased risk of microcephaly given Zika infection to investigate when
the risk of infection and the magnitude of the risk were greatest. The
period of risk with the best fit was infection in the first trimester of
pregnancy. The risk of microcephaly associated with Zika virus
infection was 95 (34–191) per 10 000 women infected in the first
trimester: essentially a risk of microcephaly for infection in the first
trimester of around 1% (0·3–1·9)
The finding that the
highest risk of microcephaly was associated with infection in the first
trimester of pregnancy is biologically plausible, given the timing of
brain development and the type and severity of the neurological
abnormalities.9
However, the absolute risk of 1% estimated by Cauchemez and colleagues
is perhaps lower than expected. In the state of Pernambuco, Brazil,
where the risk was highest, during the 4 months of the epidemic 2% of
all neonates were notified as suspected cases of microcephaly, not only
those born to women known to have been infected.4 Half of the suspected cases were confirmed by the presence of calcifications, other brain abnormalities, or both.4 How to interpret the data has been the subject of some debate.10
After the paper by Cauchemez and colleagues8 was written, Brasil and colleagues11
reported preliminary results for 72 pregnant women with symptomatic,
laboratory-confirmed Zika virus infections, recruited in Rio de Janeiro
before fetal outcomes were known. Ultrasound images were available for
42 women, of which 12 (29%) showed abnormalities over the range of
gestational ages at infection.11
Nine women had rash and viraemia in the first trimester, and
microcephaly was detected by ultrasonography in two of these, which
corresponds to 22% risk of microcephaly after symptomatic Zika infection
in the first trimester.11
These three different approaches addressed different questions: the risk in all neonates during the epidemic in Pernambuco4
and the risk in neonates from women infected with Zika virus in the
first trimester of pregnancy in the other two studies (with clinical
symptoms in Rio de Janeiro11 and independently of clinical symptoms in French Polynesia8).
As expected the estimates are different, but are they consistent with a
single underlying risk or, alternatively, will risk be dependent on
other factors, such as the presence of clinical symptoms or previous
dengue infection? Further data will soon be available from Pernambuco,
Colombia, Rio de Janeiro, and maybe other sites that will gradually
answer these questions. The fast production of knowledge during this
epidemic is an opportunity to observe science in the making: from
formulation of new hypotheses and production of new results that will
provide confirmations and contradictions to the refinement of methods
and the gradual building of consensus. I expect we will teach our
students about the production of science using examples from this Public
Health Emergency of International Concern for many years to come.
I declare no competing interests.
References
- Teixeira, MG, Costa, MCN, de Oliveira, WK, Nunes, ML, and Rodrigues, LC. The epidemic of Zika virus-related microcephaly in Brazil: detection, control, etiology, and future scenarios. Am J Public Health. 2016; 106: 601–605
- Butler, D. First Zika-linked birth defects detected in Colombia. Nature. 2016; 531: 153
- John, CC, Carabin, H, Montano, SM et al. Global research priorities for infections that affect the nervous system. Nature. 2015; 527: S178–S186
- Centro de Operações de Emergências em Saúde Pública Sobre Microcefalias. Informe epidemiológico no 15–semana epidemiológica(SE)08/2016(21A 27/02/2016). http://combateaedes.saude.gov.br/images/pdf/informe_microcefalia_epidemiologico15.pdf; Aug 8, 2016. ((accessed March 3, 2016).)
- WHO. WHO Director-General summarizes the outcome of the Emergency Committee regarding clusters of microcephaly and Guillain-Barré syndrome. http://www.who.int/mediacentre/news/statements/2016/emergency-committee-zika-microcephaly/en/#; Feb 1, 2016. ((accessed March 3, 2016).)
- Mallet, HP, Vial, AL, and Nusso, D. Bilan de l'epidemie a virus Zika en Polynesie Francaise, 2013–2014. Bull Inf Sanit Epidemiol Stat. 2015; 13: 1–5
- Centre D'Hygiene et de Salubrite Publique. Note sur les investigations autour des malformations cérébrales congénitales ayant suivi l'épidémie de zika de 2013–2014. http://www.hygiene-publique.gov.pf/IMG/pdf/note_malformations_congenitales_cerebrales; December, 2015. ((accessed Dec 1, 2015).)
- Cauchemez, S, Besnard, M, Bompard, P et al. Association between Zika virus and microcephaly in French Polynesia, 2013–15: a retrospective study. Lancet. 2016; (published online March 15.)http://dx.doi.org/10.1016/S0140-6736(16)00651-6.
- Schuler-Faccini, L, Ribeiro, EM, Feitosa, IM et al. Possible association between Zika vírus infection and microcephaly—Brazil, 2015. MMWR Morb Mortal Wkly Rep. 2016; 65: 59–62
- Victora, CG, Schuler-Faccini, L, Matijasevich, A, Ribeiro, E, Pessoa, A, and Barros, FC. Microcephaly in Brazil: how to interpret reported numbers?. Lancet. 2016; 387: 621–624
- Brasil, P, Pereira, JP Jr, Gabaglia, CR et al. Zika virus infection in pregnant women in Rio de Janeiro—preliminary report. N Engl J Med. 2016; DOI: http://dx.doi.org/10.1056/NEJMoa1602412 (published online March 4.)