Rhiza Labs FluTracker Forum

Let’s separate raw experimental data and tentative explanations.

You observed two remarlable features regarding influenza genetics:

1. The nucleotide substitution rates are remarkable low on a number of avian influenza genes.

2. The average ratio synonymous/nonsynonymous (S/N) is also quite distinct:
-Avian influenza: S/N=6.22
- Mammal influenza: S/N=2.24,
for this particular sample.

The larger S/N could possibly be explained by different evolution stages on avian and mammal hosts. Only nonsynonymous mutations change the resulting RNA amino acid expression and, as a consequence, the whole biochemical expression of the resulting virions.

I understand that evolutionary pressure tends to privilege nonsynonymous mutations, those capable to modify real virus metabolism. That is the conceptual reason for synonymous mutations use as a “molecular clock”. These changes are rather “environement independent”.

If ever one of the avian genes reached the statis regime, the gene is already “optimized”, fewer nonsynonymous mutations are desirable and tend to accumulate.

Taubenberger et. al 2004 (1)


(1)

(1) Novel Origin of the 1918 Pandemic Influenza Virus Nucleoprotein Gene
Ann H. Reid, Thomas G. Fanning, Thomas A. Janczewski, Raina M. Lourens, and Jeffery K. Taubenberger*
http://jvi.asm.org/cgi/content/full/78/22/12462[/quote]

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2268457/
Phylogenetic Evidence against Evolutionary Stasis and Natural Abiotic Reservoirs of Influenza A Virus

Several additional cases with findings that seem at odds with the biology of influenza virus, including modern-looking avian influenza virus RNA sequences from an archival goose specimen collected in 1917 (T. G. Fanning, R. D. Slemons, A. H. Reid, T. A. Janczewski, J. Dean, and J. K. Taubenberger, J. Virol. 76:7860-7862, 2002), can also be explained by laboratory contamination or other experimental errors. Many putative examples of evolutionary stasis in influenza A virus appear to be due to laboratory artifacts.

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no patents on genes, publish the GISAID sequences !

Let's drop this paper for a while.

If those lab erros does not affect your previous data, let's go ahead without it.
The attempt explanation to smaller S/N for mammalian hosts still holds.
Bigger S/N <=> closer to stasis (not yet reached).

> The larger S/N could possibly be explained by different evolution stages
> on avian and mammal hosts. Only nonsynonymous mutations change the resulting RNA
> amino acid expression and, as a consequence, the whole biochemical expression of the
> resulting virions.

yes, but I think it's not about the host evolution. Fla-A evolves in birds, only accidently
it goes to mammals. It should be adapted better to birds and thus evolve with
larger diversity in birds, also on the amino-acid level.

> I understand that evolutionary pressure tends to privilege nonsynonymous mutations,

in humans we have bigger pressure from immunity. So there are more non-synonymous
changes in HA(=4) and NA(=6). But usually not in the inner segments 1,2,3,5
Although, we also have cell-based immunity (how is it in birds ?)

> those capable to modify real virus metabolism. That is the conceptual reason for
> synonymous mutations use as a “molecular clock”. These changes are rather
> “environement independent”.
> If ever one of the avian genes reached the statis regime,

where/what is it ? How can it be reached ?
I think this "stasis" word was created long ago, when they had much fewer sequencing.
The Worobey article argues that it doesn't exist

> the gene is already “optimized”,
> fewer nonsynonymous mutations are desirable and tend to accumulate.

they still occur. It's only optimized wrt. to the environment, when that changes,
(other habits, bigger swine and turkey farms,...) then the optimization must change too.

We don't see these optimal genes, which can be distinguished from others.
The process of low non-synonymous mutations seems to depend on the host,
not the sequence itself.

In birds it should also be adapted to many different species

_________________
no patents on genes, publish the GISAID sequences !

Thinking again... I'm not so happy with what I just wrote
I'm not so sure about this "stasis" in birds on the protein-level yet.
I'll have to look at statistics, rewrite programs,...

I'm looking at PB1 now, with only 6 changes between
1918 and the Dutch chickens from 2003

_________________
no patents on genes, publish the GISAID sequences !

mammalean flu also acquires more A,T nucleotides over
the decades. Is this related ?

Avian viruses are reluctant (or just slow ?)
to get new non-synonymous mutations

_________________
no patents on genes, publish the GISAID sequences !

on the amino-acid level, wrt. protein-changes only,
and considering only segments, not full viruses


does flu in birds evolve away from the great common
ancesters or does it oscillate around some
"index"-sequence ?

the amino-acid distance (#differences) does it increase
or almost stay constant ?

is there basically just one avian flu only in most segments ?
(not in segments 4,6,8)
and avian flu isn't capable to form this increasing diversity
that we see in human and swine flu ?


or is it just slower

or did essentially different segments exist before
but all except one died out


--------------------------

yes, on the nucleotide-level, we do see these bottlenecks also in birds,
points in flu evolution known from human pandemics, when one virus
in one host reassorts and becomes the ancestor of all
subsequent flu, causing other strains to die out.
Almost all avian (and thus also human,swine) come from
one or several such events 100-300 hundred years ago,
~1830,... depends on the segment. Not for 4,6,8

see threads at FT or PFS

_________________
no patents on genes, publish the GISAID sequences !

if the hypothesis of oscillating avian amino-acid evolution around
an index-sequence is correct, then what is that index-sequence ?

let me try:

>A/Index/birds/notime(H0N0)
PB2:MERIKELRDLMSQSRTREILTKTTVDHMAIIKKYTSGRQEKNPALRMKWMMAMKYPITADKRIMEMIPERNEQGQTLWSKTNDAGSDRVMVSPLAVTWWNRNGPTTSTVHYPKVYKTYFEKVERLKHGTFGPVHFRNQVKIRRRVDINPGHADLSAKEAQDVIMEVVFPNEVGARILTSESQLTITKEKKEELQDCKIAPLMVAYMLERELVRKTRFLPVAGGTSSVYIEVLHLTQGTCWEQMYTPGGEVRNDDVDQSLIIAARNIVRRATVSADPLASLLEMCHSTQIGGIRMVDILRQNPTEEQAVDICKAAMGLRISSSFSFGGFTFKRTSGSSVKREEEVLTGNLQTLKIRVHEGYEEFTMVGRRATAILRKATRRLIQLIVSGRDEQSIAEAIIVAMVFSQEDCMIKAVRGDLNFVNRANQRLNPMHQLLRHFQKDAKVLFQNWGIEPIDNVMGMIGILPDMTPSTEMSLRGVRVSKMGVDEYSSTERVVVSIDRFLRVRDQRGNVLLSPEEVSETQGTEKLTITYSSSMMWEINGPESVLVNTYQWIIRNWETVKIQWSQDPTMLYNKMEFEPFQSLVPKAARGQYSGFVRTLFQQMRDVLGTFDTVQIIKLLPFAAAPPEQSRMQFSSLTVNVRGSGMRILVRGNSPVFNYNKATKRLTVLGKDAGALTEDPDEGTAGVESAVLRGFLILGKEDKRYGPALSINELSNLAKGEKANVLIGQGDVVLVMKRKRDSSILTDSQTATKRIRMAIN}
PB1:MDVNPTLLFLKVPAQNAISTTFPYTGDPPYSHGTGTGYTMDTVNRTHQYSEKGKWTTNTETGAPQLNPIDGPLPEDNEPSGYAQTDCVLEAMAFLEESHPGIFENSCLETMEVVQQTRVDKLTQGRQTYDWTLNRNQPAATALANTIEVFRSNGLTANESGRLIDFLKDVMESMDKEEMEITTHFQRKRRVRDNMTKKMVTQRTIGKKKQRLNKRSYLIRALTLNTMTKDAERGKLKRRAIATPGMQIRGFVYFVETLARSICEKLEQSGLPVGGNEKKAKLANVVRKMMTNSQDTELSFTITGDNTKWNENQNPRMFLAMITYITRNQPEWFRNVLSIAPIMFSNKMARLGKGYMFESKSMKLRTQIPAEMLANIDLKYFNESTRKKIEKIRPLLIDGTASLSPGMMMGMFNMLSTVLGVSILNLGQKRYTKTTYWWDGLQSSDDFALIVNAPNHEGIQAGVDRFYRTCKLVGINMSKKKSYINRTGTFEFTSFFYRYGFVANFSMELPSFGVSGINESADMSIGVTVIKNNMINNDLGPATAQMALQLFIKDYRYTYRCHRGDTQIQTRRSFELKKLWEQTRSKAGLLVSDGGPNLYNIRNLHIPEVCLKWELMDEDYQGRLCNPLNPFVSHKEIESVNNAVVMPAHGPAKSMEYDAVATTHSWIPKRNRSILNTSQRGILEDEQMYQKCCNLFEKFFPSSSYRRPVGISSMVEAMVSRARIDARIDFESGRIKKEEFAEIMKICSTIEELRRQK}
PA:MEDFVRQCFNPMIVELAEKAMKEYGEDPKIETNKFAAICTHLEVCFMYSDFHFIDERGESIIVESGDPNALLKHRFEIIEGRDRTMAWTVVNSICNTTGVEKPKFLPDLYDYKENRFIEIGVTRREVHIYYLEKANKIKSEKTHIHIFSFTGEEMATKADYTLDEESRARIKTRLFTIRQEMASRGLWDSFRQSERGEETIEERFEITGTMRRLADQSLPPNFSSLENFRAYVDGFEPNGCIEGKLSQMSKEVNARIEPFLKTTPRPLRLPDGPPCSQRSKFLLMDALKLSIEDPSHEGEGIPLYDAIKCMKTFFGWKEPNIVKPHEKGINPNYLLAWKQVLAELQDIENEEKIPKTKNMKKTSQLKWALGENMAPEKVDFEDCKDVSDLKQYDSDEPESRSLASWIQSEFNKACELTDSSWIELDEIGEDVAPIEHIASMRRNYFTAEVSHCRATEYIMKGVYINTALLNASCAAMDDFQLIPMISKCRTKEGRRKTNLYGFIIKGRSHLRNDTDVVNFVSMEFSLTDPRLEPHKWEKYCVLEIGDMLLRTAIGQVSRPMFLYVRTNGTSKIKMKWGMEMRRCLLQSLQQIESMIEAESSVKEKDMTKEFFENKSETWPIGESPKGVEEGSIGKVCRTLLAKSVFNSLYASPQLEGFSAESRKLLLIVQALRDNLEPGTFDLGGLYEAIEECLINDPWVLLNASWFNSFLTHALK}
NP:MASQGTKRSYEQMETGGERQNATEIRASVGRMVGGIGRFYIQMCTELKLSDYEGRLIQNSITIERMVLSAFDERRNKYLEEHPSAGKDPKKTGGPIYRRRDGKWVRELILYDKEEIRRIWRQANNGEDATAGLTHLMIWHSNLNDATYQRTRALVRTGMDPRMCSLMQGSTLPRRSGAAGAAVKGVGTMVMELIRMIKRGINDRNFWRGENGRRTRIAYERMCNILKGKFQTAAQRAMMDQVRESRNPGNAEIEDLIFLARSALILRGSVAHKSCLPACVYGLAVASGYDFEREGYSLVGIDPFRLLQNSQVFSLIRPNENPAHKSQLVWMACHSAAFEDLRVSSFIRGTRVVPRGQLSTRGVQIASNENMETMDSSTLELRSRYWAIRTRSGGNTNQQRASAGQISVQPTFSVQRNLPFERATIMAAFTGNTEGRTSDMRTEIIRMMESARPEDVSFQGRGVFELSDEKATNPIVPSFDMSNEGSYFFGDNAEEYDN}
M1:MSLLTEVETYVLSIIPSGPLKAEIAQRLEDVFAGKNTDLEALMEWLKTRPILSPLTKGILGFVFTLTVPSERGLQRRRFVQNALNGNGDPNNMDRAVKLYKKLKREITFHGAKEVALSYSTGALASCMGLIYNRMGTVTTEVAFGLVCATCEQIADSQHRSHRQMVTTTNPLIRHENRMVLASTTAKAMEQMAGSSEQAAEAMEVASQARQMVQAMRTIGTHPSSSAGLKDDLLENLQAYQKRMGVQMQRFK}
NS1:MDSNTVSSFQVDCFLWHVRKRFADQELGDAPFLDRLRRDQKSLRGRGSTLGLDIETATRAGKQIVERILEEESDEALKMTIASVPASRYLTDMTLEEMSRDWFMLMPKQKVAGSLCIRMDQAIMDKNIILKANFSVIFDRLETLILLRAFTEEGAIVGEISPLPSLPGHTDEDVKNAIGVLIGGLEWNDNTVRVSETLQRFAWRSSDEDGRPPLPPKQKRKMARTIESEVR

_________________
no patents on genes, publish the GISAID sequences !

grr, editing these posts with long code-windows/tables
is uncomfortale. The edit and reply buttons move outside
the actual window, when you hit the window with the mouse,
the cursor jumps left,...

are there improvements planned (next version...)


how long can I edit posts ?
(in case the theory turns out to be nonsense ;-)

_________________
no patents on genes, publish the GISAID sequences !

edited 04.Nov, added sequences,segments

differences to the index/birds in PB2,PB1,PA,NP,M1,NS1

Sti:15,06,19,30,07,08
NL3:02,01,04,03,02,03
H26:19,18,29,15,06,23
Bol:12,23,13,11,03,06
Ros:13,05,14,03,06,11
779:03,04,03,06,02,68
17G:06,17,11,25,03,12
GsG:11,14,17,04,03,71
QiH:12,08,11,07,08,14
H16:03,08,08,04,07,07
Brv:08,07,10,10,04,05
546:05,04,03,04,02,71
Alt:01,01,00,03,02,68

A/red-necked stint/Australia/02/2004(H4N8)
A/Ck/Netherlands/1/2003(H7N7)
A/Ck/Henan/26/2000(H9N2)
A/cinnamon teal/Bolivia/4537/2001(H7N3)
A/fowl/Rostock/1934(H7N1)
A/pintail/Alaska/779/2005(H3N8)
A/Dk/LA/17G/1987(H3N8)
A/Gs/Guangdong/1/1996(H5N1)
A/Gs/Qinghai/62/2005(H5N1)
A/Ck/Henan/16/2004(H5N1)
A/Brevig Mission/1/1918(H1N1)
A/Dk/Memphis/546/1974(H11N9)
A/Dk/Altai/1285(1991(H5N3)

closest would be the 2005-2007 Alaska birds
(Pintails,Shovelers - most H3N8 or H4N6),
the Memphis duck, the Dutch outbreak 2003
the Altai duck,

_________________
no patents on genes, publish the GISAID sequences !