H3N2 Homologous Recombination Confirmed

Published by: jack 2010-03-19

HA sequences from the recent Science paper on the global spread of seasonal flu have been made public. Included in these sequences were isolates from South Korea in 2002. The sequences had been deposited at Genbank by a South Korean lab, but not published. Those sequences had obvious recombination with H3N2 sequences in circulation a decade earlier.

The sequences in the Science paper were generated independently by a lab in Japan or Atlanta (CDC). The sequences generated in Japan and Atlanta exactly matched the sequences from South Korea, confirming the homologous recombination.

What factors lead to recombination occurring?
Recombination happens when the same host is co-infected with two or more related influenza viruses. After recombnation, the recombinant has to offer some sort of advantage to at least remain viable with other recombinanats or the parental sequences. It has the same requirement as reassortment, but recombinants in the form of single nucleotide polymorphisms are MUCH more common than reassortment.

Science paper abstract

http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=Retrieve&db=pubmed&list_uids=18420927

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Comment in:: Science. 2008 Apr 18;320(5874):311. (http://www.ncbi.nlm.nih.gov/pubmed/18420912?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus)

The global circulation of seasonal influenza A (H3N2) viruses.

Russell CA (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Russell%20CA%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Jones TC (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Jones%20TC%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Barr IG (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Barr%20IG%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Cox NJ (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Cox%20NJ%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Garten RJ (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Garten%20RJ%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Gregory V (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Gregory%20V%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Gust ID (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Gust%20ID%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Hampson AW (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Hampson%20AW%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Hay AJ (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Hay%20AJ%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Hurt AC 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anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Komadina N (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Komadina%20N%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Lapedes AS (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Lapedes%20AS%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Lin YP (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Lin%20YP%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Mosterin A (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Mosterin%20A%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Obuchi M (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Obuchi%20M%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Odagiri T (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Odagiri%20T%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Osterhaus AD (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Osterhaus%20AD%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Rimmelzwaan GF (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Rimmelzwaan%20GF%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Shaw MW (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Shaw%20MW%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Skepner E (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Skepner%20E%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Stohr K (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Stohr%20K%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Tashiro M (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Tashiro%20M%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Fouchier RA (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Fouchier%20RA%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Smith DJ (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Smith%20DJ%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus).
Department of Zoology, University of Cambridge, Cambridge, UK.
Antigenic and genetic analysis of the hemagglutinin of approximately 13,000 human influenza A (H3N2) viruses from six continents during 2002-2007 revealed that there was continuous circulation in east and Southeast Asia (E-SE Asia) via a region-wide network of temporally overlapping epidemics and that epidemics in the temperate regions were seeded from this network each year. Seed strains generally first reached Oceania, North America, and Europe, and later South America. This evidence suggests that once A (H3N2) viruses leave E-SE Asia, they are unlikely to contribute to long-term viral evolution. If the trends observed during this period are an accurate representation of overall patterns of spread, then the antigenic characteristics of A (H3N2) viruses outside E-SE Asia may be forecast each year based on surveillance within E-SE Asia, with consequent improvements to vaccine strain selection.
PMID: 18420927 [PubMed - indexed for MEDLINE]

LOCUS EU501155 987 bp cRNA linear VRL 30-MAY-2008
DEFINITION Influenza A virus (A/Incheon/260/2002(H3N2)) hemagglutinin (HA)
gene, partial cds.
ACCESSION EU501155
VERSION EU501155.1 GI:184107461
KEYWORDS .
SOURCE Influenza A virus (A/Incheon/260/2002(H3N2))
ORGANISM Influenza A virus (A/Incheon/260/2002(H3N2)) (http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?id=271616)
Viruses; ssRNA negative-strand viruses; Orthomyxoviridae;
Influenzavirus A.
REFERENCE 1 (bases 1 to 987)
AUTHORS Russell,C.A., Jones,T.C., Barr,I.G., Cox,N.J., Garten,R.J.,
Gregory,V., Gust,I.D., Hampson,A.W., Hay,A.J., Hurt,A.C., de
Jong,J.C., Kelso,A., Klimov,A.I., Kageyama,T., Komadina,N.,
Lapedes,A.S., Lin,Y.P., Mosterin,A., Obuchi,M., Odagiri,T.,
Osterhaus,A.D., Rimmelzwaan,G.F., Shaw,M.W., Skepner,E., Stohr,K.,
Tashiro,M., Fouchier,R.A. and Smith,D.J.
TITLE The global circulation of seasonal influenza A (H3N2) viruses
JOURNAL Science 320 (5874), 340-346 (2008)
PUBMED 18420927 (http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=Retrieve&db=pubmed&list_uids=18420927)
REFERENCE 2 (bases 1 to 987)
AUTHORS Russell,C.A., Jones,T.C., Barr,I.G., Cox,N.J., Gregory,V.,
Gust,I.D., Hampson,A.W., Hay,A.J., Hurt,A.C., de Jong,J.C.,
Kelso,A., Klimov,A.I., Kageyama,T., Komadina,N., Lapedes,A.S.,
Lin,Y.P., Mosterin,A., Obuchi,M., Odagiri,T., Osterhaus,A.D.M.E.,
Rimmelzwaan,G.F., Shaw,M.W., Skepner,E., Stohr,K., Tashiro,M.,
Fouchier,R.A.M. and Smith,D.J.
TITLE Direct Submission
JOURNAL Submitted (15-FEB-2008) Centers for Disease Control and Prevention,
1600 Clifton Rd, Atlanta, GA 30333, USA
FEATURES Location/Qualifiers
source 1..987
/organism="Influenza A virus (A/Incheon/260/2002(H3N2))"
/mol_type="viral cRNA"
/strain="A/Incheon/260/2002"
/serotype="H3N2"
/specific_host="Homo sapiens"
/db_xref="taxon:271616 (http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?id=271616)"
/segment="4"
/country="South Korea: Incheon"
/collection_date="14-Nov-2002"
/collected_by="Dr Chun Kang, National Institute of Health,
Seoul, Republic of Korea"
gene (http://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?val=184107461&from=1&to=987&view=gbwithparts) <1..>987
/gene="HA"
CDS (http://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?val=184107461&from=1&to=987&view=gbwithparts) <1..>987
/gene="HA"
/codon_start=1
/product="hemagglutinin"
/protein_id="ACC66354.1 (http://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?val=ACC66354.1)"
/db_xref="GI:184107462"
/translation="QKLPGNDNSTATLCLGHHAVPNGTIVKTITNDQIEVTNATELVQ
SSSTGGICDSPHQILDGENCTLIDALLGDPQCDGFQNKKWDLFVERSKAY SNCYPYDV
PDYASLRSLVASSGTLEFNNESFNWTGVTQNGTSSACKRRSNKSFFSRLN WLTHLKYK
YPALNVTMPNNEKFDKLYIWGVHHPGTDSDQTSLYVRASGRVTVSTKRSQ QTVIPNIG
SRPWVRGLSSRISIYWTIVKPGDILLINSTGNLIAPRGYFKIRSGKSSIM RSDAPIGT
CSSECITPNGSIPNDKPFQNVNRITYGACPRYVKQNTLKLATGMRNVPEK QTR"
ORIGIN
1 caaaaacttc ccggaaatga caacagcacg gcaacgctgt gccttgggca ccatgcagta
61 ccaaacggaa cgatagtgaa aacaatcacg aatgaccaaa ttgaagttac taatgctact
121 gagctggttc agagttcctc aacaggtgga atatgcgaca gtcctcatca gatccttgat
181 ggagaaaact gcacactaat agatgctcta ttgggagacc ctcagtgtga tggcttccaa
241 aataagaaat gggacctttt tgttgaacgc agcaaagcct acagcaactg ttacccttat
301 gatgtgccgg attatgcctc ccttaggtca ctagttgcct catccggcac actggagttt
361 aacaatgaaa gcttcaattg gactggagtc actcagaatg gaacaagctc tgcttgcaaa
421 aggagatcta ataaaagttt ctttagtaga ttgaattggt tgacccactt aaaatacaaa
481 tacccagcat tgaacgtgac tatgccaaac aatgaaaaat ttgacaaatt gtacatttgg

M3GA V 7.1 - Killer Flu - The Plague III::
H5N1 Receptor Binding Domain Recombination The number of suspected and confirmed bird flu outbreaks in southwestern South
http://chem11.proboards.com/index.cgi?board=gaiasphere&action=display&thread=2192HOME

Swine Influenza A Evolution via Recombination – Genetic Drift Reservoir ::
Similarly, the examples of recombination in human H3N2 HA sequences from South This type of acquisition is most easily explained by homologous recombination.
http://precedings.nature.com/documents/385/version/1HOME

541 ggggttcacc acccgggtac ggacagtgac caaaccagcc tatatgttcg agcatcaggg
601 agagtcacag tctctaccaa aagaagccaa caaactgtaa tcccgaatat cgggtctaga
661 ccctgggtaa ggggtctgtc cagtagaata agcatctatt ggacaatagt aaaaccggga
721 gacatactgt tgattaatag caccgggaac ctaattgctc ctcggggtta cttcaaaata
781 cgcagtggga aaagctcaat aatgaggtca gatgcaccca ttggcacctg cagttctgaa
841 tgcatcactc caaatggaag cattcccaat gacaaaccct ttcaaaatgt aaacaggatc
901 acatatgggg cctgtcccag gtatgttaag caaaacactc tgaaattggc aacagggatg
961 cggaatgtac cagagaaaca aactaga
The above sequences, generated by the CDC in Atlanta confirms the portion of sequence generated by the Korean CDC in 2004, which had obvious recombination

http://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?db=nuccore&id=46410052

It is fitting that the CDC in Atlanta confirm the data, which removes all doubt concerning to homologous recombination in H3N2 human influenza.

they don't say this "a billion to one". It depends on the method how much
value you put on this data for small recombination in NA.
Just the result of some calculation, without the details this doesn't
mean a lot. They didn't seem to put much value on it.

I did a complete statistics, some single events about lab-errors won't change much.
Why should single-nucleotide recombination be frequent but double...-nucleotide not ?

There could be some predisposition(3d-structure,ability to mutate non-syn. in some sorts of cells)
for some mutations like G743A so they occur more likely than others.
You should do a complete statistics over the whole database to detect and evaluate these
Most of the recombination is between sequences that are closely related. The closer the relationship, the further apart the polymorphisms are.

The recent travel log I posted for H7N2 had a series of three polymorphisms from North America.

Earlier dicussion of J Virol paper

http://www.flutrackers.com/forum/showthread.php?t=61120&highlight=taubenberger

I sincerely hope this confirmation of homologous recombination by CDC will be admitted by them.:surrender:

I also hope it does not take years---for the world's sake.

I believe the "lab contamination" excuse for recombination has finally been beaten, and point mutation can now RIP.

I also believe Dr. Niman deserves many handwritten apologies.:tiphat:
Here is slide 17

http://www.recombinomics.com/phylo/H3N2_HA_Recombinants.html

presented at "Targeted Immunotherapeutics & Vaccine Summit" on August 21, 2006 in Cambridge

http://www.recombinomics.com/presentations.html

If the CDC didn't get it then, they should get it now, since they have CONFIRMED the data on the slide.

The pillars are about to come crashing down.

2006

Targeted Immunotherapeutics & Vaccine Summit (http://www.targetedimvacs.com/) -
Novel Vaccines: Bridging Research Development, and Production
Cambridge, Massachusets

August 21 - Overcoming Challenges

9:35 - 10:05 AM

Pandemic and Seasonal Influenza Evolution Via Recombination - Selection of Vaccine Targets

Henry L. Niman, Ph.D., President & Founder, Recombinomics, Inc.

Pandemic H5N1 and seasonal H3N2 influenza rapidly evolve via recombination.Identification of parental strains allows for prediction of sequences of emerging virus prior to emergence. Data mining of sequence databases also allows for prediction of time and location of significant genetic changes, including altered affinity in the receptor binding domain. Recombination rules can be used to identify novel vaccine targets and increase lead time over emerging viruses.

H5N1 Hong Kong PB2 Recombinant (slide 11 (http://www.recombinomics.com/phylo/H5N1_HK_PB2.html))
H5N1 Hong Kong PB1 Recombinant (slide 12 (http://www.recombinomics.com/phylo/H5N1_HK_PB1.html))
H5N1 Hong Kong PA Recombinants (slide 13 (http://www.recombinomics.com/phylo/H5N1_HK_PA.html))
H5N1 Hong Kong NP Recombinant (slide 14 (http://www.recombinomics.com/phylo/H5N1_HK_NP.html))
H9N2 Korea NA Recombinants (slide 15 (http://www.recombinomics.com/phylo/H9N2_NA.html))
H3N2 Korea HA Recombinants (slide 17 (http://www.recombinomics.com/phylo/H3N2_HA_Recombinants.html))
Canadian Swine PB2 Recombination (slide 23 (http://www.recombinomics.com/phylo/Canadian_Swine_PB2.html))
Canadian Swine PA Recombination (slide 24 (http://www.recombinomics.com/phylo/Canadian_Swine_PA.html))
Canadian Swine PB1 Haplotypes (slide 26 (http://www.recombinomics.com/phylo/Canadian_Swine_PB1.html))

Earlier comments

http://precedings.nature.com/documents/385/version/1

Henry Niman (http://precedings.nature.com/users/290) on 26 March 2008 15:12 UTC
The Journal of Virology ahead of print (J. Virol. doi:10.1128/JVI.02683-07) paper, �Homologous Recombination is Very Rare or Absent in Human Influenza A Virus� cites this pre-print as bioinformatics evidence for influenza recombination.
However, the paper fails to find strong homologous recombination evidence in the dataset analyzed. There are several reasons for this failure. The study was limited to complete human gene sequences, which eliminated several clear examples in human HA sequences from South Korea in 2002. The requirement for human sequences eliminated additional examples, such as the swine recombinants described in this pre-print, and other examples in swine or birds. The full sequence requirement also eliminated many sequences from China, South Korea, and southeast Asia where many donor sequences originate.
The above requirements created a database that was largely composed of sequences generated under an NIAID Influenza Sequencing Project, which largely consisted of isolates from the United States or Australia. Therefore, most co-infections would involve closely related sequences. Recombination between closely related sequences would generate limited number of differences in the recombinants relative to the parental sequences. Moreover, the study was directed toward the identification of recombinants plus the two parental sequences. Although there were hundreds of examples of short regions supporting recombination, only two isolates were identified as recombinants which had recombined regions greater than 100 BP, which was the minimum requirement for confirmation by phylogenetic analysis. However, the paper also suggested that isolates with clear cut evidence for recombination involving large regions could have been generated during amplification because of contaminating sequences.
The recombinants described in this paper involved large regions of identity between the recombinants and the parental sequences. For the most striking examples, in PB2 and PA, generation of these recombinants during amplification would require the presence of two 1977 Tennessee isolates, a 1998 North Carolina isolates, a 2002 Korea isolate, and a 1931 Iowa isolate. Moreover, several sequences would have required the simultaneous presence of many of these isolates during the amplification, and the above isolates would have had to selectively contaminate the PB2 and PA sequences. Additional contamination would have been required during amplification of additional genes and be absent from the application of the human genes to artificially create the other gene sequences.
Such a scenario is highly unlikely.

For those who need help interpreting the slide, it has the sequence of A/Wyoming/3/2003 in the top row, which was one of the vaccine targets for A/Fujian/411/2002, the dominant H3N2 strain in circulation. The next six rows are from H3N2 isolates in South Korea in 2002, which fall into two similar groupings. The first has A/Cheonnman/323/2002, A/Cheonnman/338/2002, A/Cheonnman/340/2002. The second has A/Kyongbuk/320/2002, A/Daejin/258/2002, and A/Incheon/260/2002. The bottom row is the other parental sequence, A/Seoul/45/91 collected more than a decade earlier.

The recombinants match the contemporary sequence for the first 574 positions, then switch to the 1991 isolate for positions 575-963. However, the first set switches back to contemporary sequences over short stretches. The examples are clear cut recombinants.

The sequences published in Science include a representative of each group. A/Cheonnam/323/2002 from the first group was confirmed by Japan, while A/Incheon/260/2002 from the second group was confirmed by the CDC in Atlanta. Both labs resequenced the first 900+ positions, which matched the sequences deposited in 2004, providing independent confirmation of the obvious homologous recombination.

Commentary

http://www.recombinomics.com/News/06010801/H3N2_Recombination_Confirmed.htmlCommentary

Homologous Recombination in H3N2 Seasonal Flu Confirmed
Recombinomics Commentary 06:55
June 1, 2008

HA sequences from approximately 13,000 H3N2 isolates were released today at Genbank. These sequences were generated under a broad consortium as listed for the Science paper (http://www.flutrackers.com/forum/showthread.php?t=65400), �The global circulation of seasonal influenza A (H3N2) viruses.�

Included in these sequences were examples of obvious recombination from patients in South Korea in 2002. These sequences had been generated by the Korean CDC and deposited at Genbank in 2004. Although the six sequences with recombination fell into two related groups, all sequences had been generated by the same lab, raising concerns of lab error.

The data had been presented (http://www.recombinomics.com/presentations.html)on August 21, 2006 at the vaccine meeting, �Targeted Immunotherapeutics & Vaccine Summit� demonstrating (see slide 17 (http://www.recombinomics.com/phylo/H3N2_HA_Recombinants.html)) the recombination and showing the two groupings with A/Cheonnman/323 (http://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?db=nuccore&id=46410038)/2002, A/Cheonnman/338 (http://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?db=nuccore&id=46410040)/2002, A/Cheonnman/340 (http://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?db=nuccore&id=46410042)/2002 in one group and A/Kyongbuk/320 (http://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?db=nuccore&id=46410058)/2002, A/Daejin/258 (http://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?db=nuccore&id=46410048)/2002, and A/Incheon/260 (http://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?db=nuccore&id=46410052)/2002 in a second group. Although the two groups were easily distinguished, all six isolates had clear cut homologous recombination. The recombinants matched the contemporary sequence, A/Wyoming/03/2003 for the first 574 positions, and then switched to the 1991 isolate, A/Seoul/45/91, for positions 575-963. However, the first set switches back to contemporary sequences over short stretches.

A recent Journal of Virology paper (http://www.flutrackers.com/forum/showthread.php?t=61120&highlight=taubenberger), �Homologous recombination is very rare or absent in human influenza A viru,� found short stretches of recombination, but only found two examples of longer regions of recombination, which it attributed to lab error. The study severely limited the sequences analyzed, and excluded the six examples from Korea through a number of restrictions. The study only looked at sequences generated under an NIAID influenza sequencing program, which was limited to a small number of contributing institutions over a relatively short time frame for the vast majority of sequences. The study also required identification of the parental sequences, which had to come from the limited dataset.

The recombination in Korea was limited by a number of criteria. Only 2 of the 8 gene segments from the Korean patients had been sequenced, so in addition to not being sequenced under the NIAID program, the sequences were excluded because they where not generated by whole genome analysis. Moreover, the parental sequences were from human sequences circulating a decade earlier, and these sequences were also not in the NIAID program. Moreover, the public sequences were only of HA and were partial sequences. However, although the recombinant and parental sequences did not meet the criteria of the study, they did represent sequences that were either generated via homologous recombination or lab error.

The sequences in the Science paper confirmed that the data was not due to lab error. One isolate, A/Cheonnman/323 (http://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?db=nuccore&id=184107443)/2002, representing the first group, was re-sequenced in Japan and the sequence matched the original sequence. Another isolate, A/Incheon/260 (http://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?db=nuccore&id=184107461)/2002, was re-sequenced by the CDC in Atlanta and also matched the original sequence.

Thus, the original examples of homologous recombination in the six sequences generated by the Korean CDC, were independently confirmed by labs in Japan and the United States.

These confirmations demonstrate the need for broader analysis in the search for homologous recombination in human influenza. The first set of isolates also demonstrates multiple template switches, which decreases the size of the acquired sequences. These shorter sequences were found in the J Virology study, where the likelihood that the NA data was due to chance instead of homologous recombination was one billion to one. However, the most common exchanges happen between closely related sequences, resulting in acquisitions of single nucleotide polymorphisms, such as the example of G743A (http://precedings.nature.com/documents/459/version/3) in NA of H5N1.

These acquisitions from previously described sequences allow for predictions of changes, leading to vaccine targets more representative of future emerging genomes.

.

What factors lead to recombination occurring?

they don't say this "a billion to one". It depends on the method how much
value you put on this data for small recombination in NA.
Just the result of some calculation, without the details this doesn't
mean a lot. They didn't seem to put much value on it.

I did a complete statistics, some single events about lab-errors won't change much.
Why should single-nucleotide recombination be frequent but double...-nucleotide not ?

There could be some predisposition(3d-structure,ability to mutate non-syn. in some sorts of cells)
for some mutations like G743A so they occur more likely than others.
You should do a complete statistics over the whole database to detect and evaluate these
G743A was dramtic because there were plenty of donor sequences flying around. It was NOT present in the clade 2.2 sequences in 2006 other than the clade found in southern Germany / Switzerland / France (and one isolate in Nigeria). It wasn't in any of the 2006 clade 2.2 precursor sequences.

Like the sudden acquisition of Tamiflu resistance H274Y in H1N1 seasonal flu, you continue to ignore the timing of the acquisitions, which are concurrent and on multiple genetic backgrounds and have NOTHING to do with 3d-structure or changes in certain cells.

You are posting utter nonsense again that has NOTHING to do with the DATA.

Commentary

http://www.recombinomics.com/News/06010801/H3N2_Recombination_Confirmed.html

J Virol abstract

http://www.ncbi.nlm.nih.gov/pubmed/18353939?ordinalpos=3&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVDocSum

1: J Virol. (javascript:AL_get(this, 'jour', 'J Virol.');) 2008 May;82(10):4807-11. Epub 2008 Mar 19.http://www.ncbi.nlm.nih.gov/corehtml/query/egifs/http:--highwire.stanford.edu-icons-externalservices-pubmed-standard-jvi_final.gif (http://www.ncbi.nlm.nih.gov/entrez/utils/fref.fcgi?PrId=3051&itool=AbstractPlus-def&uid=18353939&db=pubmed&url=http://jvi.asm.org/cgi/pmidlookup?view=long&pmid=18353939) Links (javascript:PopUpMenu2_Set(Menu18353939);)

Homologous recombination is very rare or absent in human influenza A virus.

Boni MF (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Boni%20MF%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Zhou Y (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Zhou%20Y%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Taubenberger JK (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Taubenberger%20JK%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Holmes EC (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Holmes%20EC%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus).
Resources for the Future, 1616 P St. NW, Washington, DC 20036, USA. boni@rff.org
To determine the extent of homologous recombination in human influenza A virus, we assembled a data set of 13,852 sequences representing all eight segments and both major circulating subtypes, H3N2 and H1N1. Using an exhaustive search and a nonparametric test for mosaic structure, we identified 315 sequences (approximately 2%) in five different RNA segments that, after a multiple-comparison correction, had statistically significant mosaic signals compatible with homologous recombination. Of these, only two contained recombinant regions of sufficient length (>100 nucleotides [nt]) that the occurrence of homologous recombination could be verified using phylogenetic methods, with the rest involving very short sequence regions (15 to 30 nt). Although this secondary analysis revealed patterns of phylogenetic incongruence compatible with the action of recombination, neither candidate recombinant was strongly supported. Given our inability to exclude the occurrence of mixed infection and template switching during amplification, laboratory artifacts provide an alternative and likely explanation for the occurrence of phylogenetic incongruence in these two cases. We therefore conclude that, if it occurs at all, homologous recombination plays only a very minor role in the evolution of human influenza A virus.
PMID: 18353939 [PubMed - indexed for MEDLINE]

strange that CDC, Holmes et.al, Boni et.al, ... won't comment on this.
Something must be wrong with the system, when officials or public employees
or paper authors or researchers are not allowed to speak what they think. When they
avoid email and internet discussion.

strange that niman won't comment/mention/acknowledge on the much lower frequency
of recombination and preservation in humans vs. birds/swine .

strange that while both recombination and preservation are so rare in human flu,
we have an example here where both happen simultaneously.

The used dataset in the Boni et.al paper was not soo small, they had 14000 complete human
sequences, while meanwhile 40000 are available at genbank, 30000 complete ones.
I did a more exhaustive analysis with statistics of p-value distribution
and comparison with avian and random sequences (see the old thread), which confirmed
the result for human-flu-recombination.

I don't know, how this sample-sharing,sequencing is done - couldn't it be that
CDC got the contaminated samples ?
Your understanding of recombination is fundamentally flawed. Recombination resulting in SMALLER stretches is EXPECTED because it is much easier for recombinatioin to happen between closely related sequences than distantly related sequences. The J Virol paper found the small regions and acknowledged that the odds were a billion to one against the recombination being due to chance instead of recombination, but still published under a title indicating the homologous recombination wasn't found. They then used some hand waving about lab error, just as you are doing.

The G743A did included PLAQUE PURIFIED isolates, i.e. NO MIXTURES, and showed that the G743A simultaneously appeared on two different genetic backgroiunds, which was quickly expanded to at least EIGHT different genetic backgrounds. Trying to explain this by RANDOM MUTATIONS is NONSENSE.

One of the basic tenets of infleunza genetics is founded on this NONSENSE, which leads to the absurdities appearing in peer reviewed journal articles again and again.

Influenza studies are POLITICAL and have limited scientific basis, but H5N1 doesn't read the press releases or hocus pocus passing for scientific research.

The CDC clearly published the H7N2 sequences without much analysis, which is why the data was pulled within 30 days of publication. I would sincerely doubt that the CDC has picked up the recombination it just published in Science.

They actively ignore recombination.

However, those days are quickly coming to an end.

Korean CDC sequence confirmed by CDC in Atlanta

LOCUS AY589657 1653 bp RNA linear VRL 25-APR-2004

Clay and Iron Ministries::
in the swine H1N1 is readily explain by homologous recombination with locally The Health Ministry confirmed there has been no fatal case of influenza A (H1N1)
http://www.clayandiron.com/news.jhtml?method=view&news.id=2014HOME

Subtyping of Avian Influenza Viruses H1 to H15 on the Basis of ::
TABLE 3. Detection of homologous subtypes HA genes of previously Cumulative number of confirmed human cases of avian influenza A/(H5N1) reported to WHO.
http://jcm.asm.org/cgi/content/full/46/9/3048HOME

DEFINITION Influenza A virus (A/Incheon/260/2002(H3N2)) hemagglutinin (HA)
gene, partial cds.
ACCESSION AY589657
VERSION AY589657.1 GI:46410052
KEYWORDS .
SOURCE Influenza A virus (A/Incheon/260/2002(H3N2))
ORGANISM Influenza A virus (A/Incheon/260/2002(H3N2)) (http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?id=271616)
Viruses; ssRNA negative-strand viruses; Orthomyxoviridae;
Influenzavirus A.
REFERENCE 1 (bases 1 to 1653)
AUTHORS Kim,K.A., Lee,J.Y., Hwang,J.H., Kim,Y.Y., Jang,S.W., Park,M.S.,
Park,Y.K. and Kang,C.
TITLE Molecular analysis of the hemagglutinin (HA) gene of influenza
A/H3N2 viruses isolated in Korea during the 2002-03 epidemic season
JOURNAL Unpublished
REFERENCE 2 (bases 1 to 1653)
AUTHORS Kim,K.A., Lee,J.Y., Hwang,J.H., Kim,Y.Y., Jang,S.W., Park,M.S.,
Park,Y.K. and Kang,C.
TITLE Direct Submission
JOURNAL Submitted (04-APR-2004) Div. of Res. Virus, Korea Center for
Disease Control and Prevention, 5, Nokbun-Dong, Eunpyung-Gu, Seoul
122-701, South Korea
FEATURES Location/Qualifiers
source 1..1653
/organism="Influenza A virus (A/Incheon/260/2002(H3N2))"
/mol_type="genomic RNA"
/strain="A/Incheon/260/2002(H3N2)"
/db_xref="taxon:271616 (http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?id=271616)"
/country="South Korea"
gene (http://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?val=46410052&from=1&to=1653&view=gbwithparts) <1..1653
/gene="HA"
CDS (http://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?val=46410052&from=1&to=1653&view=gbwithparts) <1..1653
/gene="HA"
/codon_start=1
/product="hemagglutinin"
/protein_id="AAS93880.1 (http://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?val=AAS93880.1)"
/db_xref="GI:46410053"
/translation="QKLPGNDNSTATLCLGHHAVPNGTIVKTITNDQIEVTNATELVQ
SSSTGGICDSPHQILDGENCTLIDALLGDPQCDGFQNKKWDLFVERSKAY SNCYPYDV
PDYASLRSLVASSGTLEFNNESFNWTGVTQNGTSSACKRRSNKSFFSRLN WLTHLKYK
YPALNVTMPNNEKFDKLYIWGVHHPGTDSDQTSLYVRASGRVTVSTKRSQ QTVIPNIG
SRPWVRGLSSRISIYWTIVKPGDILLINSTGNLIAPRGYFKIRSGKSSIM RSDAPIGT
CSSECITPNGSIPNDKPFQNVNRITYGACPRYVKQNTLKLATGMRNVPEK QTRGIFGA
IAGFIENGWEGMVDGWYGFRHQNSEGTGQAADLKSTQAAINQINGKLNRL IGKTNEKF
HQIEKEFSEVEGRIQDLEKYVEDTKIDLWSYNAELLVALENQHTIDLTDS EMNKLFER
TKKQLRENAEDMGNGCFKIYHKCDNACIESIRNGTYDHDVYRDEALNNRF QIKGVELK
SGYKDWILWISFAISCFLLCVALLGFIMWACQKGNIRCNICI"
ORIGIN
1 caaaaacttc ccggaaatga caacagcacg gcaacgctgt gccttgggca ccatgcagta
61 ccaaacggaa cgatagtgaa aacaatcacg aatgaccaaa ttgaagttac taatgctact
121 gagctggttc agagttcctc aacaggtgga atatgcgaca gtcctcatca gatccttgat
181 ggagaaaact gcacactaat agatgctcta ttgggagacc ctcagtgtga tggcttccaa
241 aataagaaat gggacctttt tgttgaacgc agcaaagcct acagcaactg ttacccttat
301 gatgtgccgg attatgcctc ccttaggtca ctagttgcct catccggcac actggagttt
361 aacaatgaaa gcttcaattg gactggagtc actcagaatg gaacaagctc tgcttgcaaa
421 aggagatcta ataaaagttt ctttagtaga ttgaattggt tgacccactt aaaatacaaa
481 tacccagcat tgaacgtgac tatgccaaac aatgaaaaat ttgacaaatt gtacatttgg
541 ggggttcacc acccgggtac ggacagtgac caaaccagcc tatatgttcg agcatcaggg
601 agagtcacag tctctaccaa aagaagccaa caaactgtaa tcccgaatat cgggtctaga
661 ccctgggtaa ggggtctgtc cagtagaata agcatctatt ggacaatagt aaaaccggga
721 gacatactgt tgattaatag caccgggaac ctaattgctc ctcggggtta cttcaaaata
781 cgcagtggga aaagctcaat aatgaggtca gatgcaccca ttggcacctg cagttctgaa
841 tgcatcactc caaatggaag cattcccaat gacaaaccct ttcaaaatgt aaacaggatc
901 acatatgggg cctgtcccag gtatgttaag caaaacactc tgaaattggc aacagggatg
961 cggaatgtac cagagaaaca aactagaggc atattcggcg caatcgcagg tttcatagaa
1021 aatggttggg agggaatggt ggacggttgg tacggtttca ggcatcaaaa ttctgagggc
1081 acaggacaag cagcagatct caaaagcact caagcagcaa tcaaccaaat caatgggaaa
1141 ctgaataggt taatcgggaa aacaaacgag aaattccatc agattgaaaa agaattctca
1201 gaagtagaag ggagaattca ggacctcgag aaatatgttg aggacactaa aatagatctc
1261 tggtcataca acgcggagct tcttgttgcc ctggagaacc aacatacaat tgatctaact
1321 gactcagaaa tgaacaaact gtttgaaaga acaaagaagc aactgaggga aaatgctgag
1381 gatatgggca atggttgttt caaaatatac cacaaatgtg acaatgcctg catagagtca
1441 atcagaaatg gaacttatga ccatgatgta tacagagatg aagcattaaa caaccggttc
1501 cagatcaaag gtgttgagct gaagtcagga tacaaagatt ggatcctatg gatttccttt
1561 gccatatcat gttttttgct ttgtgttgct ttgttggggt tcatcatgtg ggcctgccaa
1621 aaaggcaaca ttaggtgcaa catttgcatt tga

they don't say this "a billion to one". It depends on the method how much
value you put on this data for small recombination in NA.
Just the result of some calculation, without the details this doesn't
mean a lot. They didn't seem to put much value on it.

I did a complete statistics, some single events about lab-errors won't change much.
Why should single-nucleotide recombination be frequent but double...-nucleotide not ?

There could be some predisposition(3d-structure,ability to mutate non-syn. in some sorts of cells)
for some mutations like G743A so they occur more likely than others.
You should do a complete statistics over the whole database to detect and evaluate these
Please, I also posted on the three consecutive polymorphisms in PB2 from vaccine resistant H5N1 in Israel, which match the H1N1 1918 pandemic sequence

http://www.recombinomics.com/News/04150801/H5N1_Israel_PB2.html

You are selectively IGNORING the PUBLIC data.

Discussion on Science paper

http://www.flutrackers.com/forum/showthread.php?t=65400

they don't say this "a billion to one". It depends on the method how much
value you put on this data for small recombination in NA.
Just the result of some calculation, without the details this doesn't
mean a lot. They didn't seem to put much value on it.

I did a complete statistics, some single events about lab-errors won't change much.
Why should single-nucleotide recombination be frequent but double...-nucleotide not ?

There could be some predisposition(3d-structure,ability to mutate non-syn. in some sorts of cells)
for some mutations like G743A so they occur more likely than others.
You should do a complete statistics over the whole database to detect and evaluate these
I am not sure why anyone would believe your "statistics". The J Virol paper indicated the chance that the short NA sequences were not due to recombination were a billion to one, and you say such a p value isn't significant.

The examples of recombination are well beyond statistics, and your definition of "significant" appears to be quite unique (and has no scientific support).

President of the United States of America, Abraham Lincoln, born 1801-assassinated 1865, had many wise quotations and great wisdom:

I am a firm believer in the people. If given the truth, they can be depended upon to meet any national crises.
The great point is to bring them the real facts.

Abraham Lincoln

You may deceive all the people part of the time, and part of the people all the time, but not all the people all the time.

Abraham Lincoln

Better to remain silent and be thought a fool than to speak out and remove all doubt.

Abraham Lincoln

http://www.quotationspage.com/quotes/Abraham_Lincoln/

http://home.att.net/~rjnorton/Lincoln77.html

http://www.ourdocuments.gov/doc.php?doc=36

LOCUS EU501146 987 bp cRNA linear VRL 30-MAY-2008
DEFINITION Influenza A virus (A/Cheonnam/323/2002(H3N2)) hemagglutinin (HA)
gene, partial cds.
ACCESSION EU501146
VERSION EU501146.1 GI:184107443
KEYWORDS .
SOURCE Influenza A virus (A/Cheonnam/323/2002(H3N2))
ORGANISM Influenza A virus (A/Cheonnam/323/2002(H3N2)) (http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?id=271609)
Viruses; ssRNA negative-strand viruses; Orthomyxoviridae;
Influenzavirus A.
REFERENCE 1 (bases 1 to 987)
AUTHORS Russell,C.A., Jones,T.C., Barr,I.G., Cox,N.J., Garten,R.J.,
Gregory,V., Gust,I.D., Hampson,A.W., Hay,A.J., Hurt,A.C., de
Jong,J.C., Kelso,A., Klimov,A.I., Kageyama,T., Komadina,N.,
Lapedes,A.S., Lin,Y.P., Mosterin,A., Obuchi,M., Odagiri,T.,
Osterhaus,A.D., Rimmelzwaan,G.F., Shaw,M.W., Skepner,E., Stohr,K.,
Tashiro,M., Fouchier,R.A. and Smith,D.J.
TITLE The global circulation of seasonal influenza A (H3N2) viruses
JOURNAL Science 320 (5874), 340-346 (2008)
PUBMED 18420927 (http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=Retrieve&db=pubmed&list_uids=18420927)
REFERENCE 2 (bases 1 to 987)
AUTHORS Russell,C.A., Jones,T.C., Barr,I.G., Cox,N.J., Gregory,V.,
Gust,I.D., Hampson,A.W., Hay,A.J., Hurt,A.C., de Jong,J.C.,
Kelso,A., Klimov,A.I., Kageyama,T., Komadina,N., Lapedes,A.S.,
Lin,Y.P., Mosterin,A., Obuchi,M., Odagiri,T., Osterhaus,A.D.M.E.,
Rimmelzwaan,G.F., Shaw,M.W., Skepner,E., Stohr,K., Tashiro,M.,
Fouchier,R.A.M. and Smith,D.J.
TITLE Direct Submission
JOURNAL Submitted (15-FEB-2008) National Institute of Infectious Disease,
Toyama 1-23-1, Tokyo, Shinjuku-ku 162 8640, Japan
FEATURES Location/Qualifiers
source 1..987
/organism="Influenza A virus (A/Cheonnam/323/2002(H3N2))"
/mol_type="viral cRNA"
/strain="A/Cheonnam/323/2002"
/serotype="H3N2"
/specific_host="Homo sapiens"
/db_xref="taxon:271609 (http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?id=271609)"
/segment="4"
/country="South Korea: Cheonnam"
/collection_date="20-Nov-2002"
/collected_by="Dr Chun Kang, National Institute of Health,
Seoul, Republic of Korea"
gene (http://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?val=184107443&from=1&to=987&view=gbwithparts) <1..>987
/gene="HA"
CDS (http://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?val=184107443&from=1&to=987&view=gbwithparts) <1..>987
/gene="HA"
/codon_start=1
/product="hemagglutinin"
/protein_id="ACC66345.1 (http://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?val=ACC66345.1)"
/db_xref="GI:184107444"
/translation="QKLPGNDNSTATLCLGHHAVPNGTIVKTITNDQIEVTNATELVQ
SSSTGGICDSPHQILDGENCTLIDALLGDPQCDGFQNKKWDLFVERRKAY SNCYPYDV
PDYASLRSLVASSGTLEFNNESFNWTGVTQNGTSSACKRRSNKSFFSRLN WLTHLKYK
YPALNVTMPNNEKFDKLYIWGVHHPGTDSDQTSLYVQASGRVTVSTKRSQ QTVIPNIG
SRPWVRGVSSRISIYWTIVKPGDILLINSTGNLIAPRGYFKIRSGKSSIM RSDAPIGT
CNSECITPNGSIPNDKPFQNVNRITYGACPRYVKQNTLKLATGMRNVPEK QTR"
ORIGIN
1 caaaaacttc ccggaaatga caacagcacg gcaacgctgt gccttgggca ccatgcagta
61 ccaaacggaa cgatagtgaa aacaatcacg aatgaccaaa ttgaagttac taatgctact
121 gagctggttc agagttcctc aacaggtgga atatgcgaca gtcctcatca gatccttgat
181 ggagaaaact gcacactaat agatgctcta ttgggagacc ctcagtgtga tggcttccaa
241 aataagaaat gggacctttt tgttgaacgc agaaaagcct acagcaactg ttacccttat
301 gatgtgccgg attatgcctc ccttaggtca ctagttgcct catccggcac actggagttt
361 aacaatgaaa gcttcaattg gactggagtc actcagaatg gaacaagctc tgcttgcaaa
421 aggagatcta ataaaagttt ctttagtaga ttgaattggt tgacccactt aaaatacaaa
481 tacccagcat tgaacgtgac tatgccaaac aatgaaaaat ttgacaaatt gtacatttgg
541 ggggttcacc acccgggtac ggacagtgac caaaccagcc tatatgttca agcatcaggg
601 agagtcacag tctctaccaa aagaagccaa caaactgtaa tcccgaatat cgggtctaga
661 ccctgggtaa ggggtgtgtc cagtagaata agcatctatt ggacaatagt aaaaccggga
721 gacatacttt tgattaacag cacagggaat ctaattgctc ctcggggtta cttcaaaata
781 cgaagtggga aaagctcaat aatgaggtca gatgcaccca ttggcacctg caattctgaa
841 tgcatcactc caaatggaag cattcccaat gacaaaccct ttcaaaatgt aaacaggatc
901 acatatgggg cctgtcccag atatgttaag caaaacactc tgaaattggc aacagggatg
961 cggaatgtac cagagaaaca aactaga