xbb.1.16 SubLineage with Orf9b:A22T /N:G25D mostly in East Asia& Southeast Asia (113 seqs in 2023-05-23)

[krosa1910]

Sublineage of xbb.1.16
Mutations on top of xbb.1.16: G28347A/ Orf9b:A22T or N:G25D
This is the first time I propose some lineage with change in Orf9b/N protein section, and I don't really understand why seemingly one mutation gets to be explained as two mutations.
gisaid inquiry: xbb.1.16+G28347A
51 seqs, earliest EPI_ISL_17360665 Malaysia 2023-03-14 latest EPI_ISL_17602957 Thailand 2023-04-25

EPI_ISL_17360665, EPI_ISL_17360667, EPI_ISL_17467386,
EPI_ISL_17472300, EPI_ISL_17474263, EPI_ISL_17482110,
EPI_ISL_17516244, EPI_ISL_17517247, EPI_ISL_17525612,
EPI_ISL_17538435, EPI_ISL_17539019, EPI_ISL_17539135,
EPI_ISL_17539417, EPI_ISL_17539699, EPI_ISL_17547952,
EPI_ISL_17554623, EPI_ISL_17554632, EPI_ISL_17556188,
EPI_ISL_17556348, EPI_ISL_17561369, EPI_ISL_17561457,
EPI_ISL_17563100, EPI_ISL_17563150, EPI_ISL_17563232,
EPI_ISL_17563267, EPI_ISL_17563316, EPI_ISL_17563775,
EPI_ISL_17563818, EPI_ISL_17563835, EPI_ISL_17563990,
EPI_ISL_17564111, EPI_ISL_17564116, EPI_ISL_17564132,
EPI_ISL_17564179, EPI_ISL_17594921, EPI_ISL_17595402,
EPI_ISL_17596437, EPI_ISL_17602957, EPI_ISL_17604215,
EPI_ISL_17604291, EPI_ISL_17604338, EPI_ISL_17604487,
EPI_ISL_17604725, EPI_ISL_17605080, EPI_ISL_17605084-17605085,
EPI_ISL_17605105, EPI_ISL_17605129, EPI_ISL_17605358,
EPI_ISL_17605997, EPI_ISL_17606060

3Australia, 3 Austria, 1 Canada, 1 HK, 1 India, 3 Japan, 2 Malaysia, 1 Shanghai, 2 Singapore, 32 SK, 1 Thailand, 2 US in different states (NY,VA)

tree ：https://nextstrain.org/fetch/genome.ucsc.edu/trash/ct/singleSubtreeAuspice_genome_21211_518c70.json?f_userOrOld=uploaded%20sample&label=id:node_4739318

I was analyzing the probability of S:444N with others and they have notified me of some XBB.1.16 that recently gained S:444N. Yet that branch was too small so I propose a larger clade containing the branch.

It seemed that the whole clade was spreading globally although East Asia/ Southeast Asia was a hotspot because of their proximity to the origin: Malaysia. However, spread in Canada and Austria showed that it is capable of spreading afar. Furthermore, it seemed a local superspread in South Korea happened and created more than 30 seqs there.

[aviczhl2]

We also have #1820 for orf9b:T24S.
XBB.1.16 is good at getting new orf9b mutations.

[FedeGueli]

orf9b is a shorter(97AA) alternate reading of N starting 3AA after N but it is encoded by the same nucleotides so it could happen that a nuc mutation changes AA in both N and Orf9b or be silent in one and non sinonymous in the other or silent in both.

I am a rookie so dont take my single words as gold, maybe @ryhisner could explain it far better than me

[krosa1910]

orf9b is a shorter(97AA) alternate reading of N starting 3AA after N but it is encoded by the same nucleotides so it could happen that a nuc mutation changes AA in both N and Orf9b or be silent in one and non sinonymous in the other or silent in both.

I am a rookie so dont take my single words as gold, maybe @ryhisner could explain it far better than me

Is that the case in Orf9b:I5T (which I think is silent in N)?

[ryhisner]

The second nucleotide in each ORF9b residue corresponds to the third nucleotide in an N residue, so most ORF9b mutations involving the second nucleotide are usually synonymous in N. Important examples include ORF9b:I5T (XBB.1.9, XBB.1.16), ORF9b:N55S (XBB.1.16), and ORF9b:D89E (BA.2.3.20).

I've been reading the Krogan Lab preprint from October, and they talk about how ORF9b antagonizes with interferon-stimulated genes (ISGs) and innate immune activation by binding to something called MAVS-Tom70, but only when it's not phosphorylated at ORF9b:S53. Another protein called TBK1 that is apparently activated by MAVS-Tom70 is able to phosphorylate ORF9b:S53, destroying its ability to downregulate ISGs. Somehow this forms a negative feedback loop, though it's unclear to me exactly how. Anyway, I wonder whether ORF9b:N55S might somehow reduce the ability of TBK1 to phosphorylate ORF9b:S53, which would enhance ORF9b's ability to antagonize the innate immune response.

[FedeGueli]

Good catch @ryhisner !

[krosa1910]

@corneliusroemer can this be assiged if reaching 100? I am pretty sure it would reach that number soon next week.

[krosa1910]

@InfrPopGen @corneliusroemer Could this be assigned? It has already reached 100 seq with today's update.

[InfrPopGen]

@InfrPopGen @corneliusroemer Could this be assigned? It has already reached 100 seq with today's update.

Thanks for proposing this, and for the question @krosa1910

There's not a threshold number of known sequences/cases for designation, there needs to be some epidemiological importance (e.g. the unique mutations the lineage has acquired relative to its parent lineage appear to be giving it a significant growth advantage, or the lineage has attracted a lot of research interest because it is associated with some epidemiological event or is an important part of some major investigation, so it needs a label to distinguish it). This arises from the Pango rules which are here.

This lineage appears to have some growth advantage relative to its parent worldwide or across Asia (about 25%), but it is showing potential disadvantages at the country level (e.g. in South Korea and Japan), which could mean that the regional advantages are caused by uneven sampling among countries. Consequently, this lineage needs further monitoring in order to distinguish real advantages from chance/founder events and sampling bias.

[krosa1910]

@InfrPopGen @corneliusroemer Could this be assigned? It has already reached 100 seq with today's update.

Thanks for proposing this, and for the question @krosa1910

There's not a threshold number of known sequences/cases for designation, there needs to be some epidemiological importance (e.g. the unique mutations the lineage has acquired relative to its parent lineage appear to be giving it a significant growth advantage, or the lineage has attracted a lot of research interest because it is associated with some epidemiological event or is an important part of some major investigation, so it needs a label to distinguish it). This arises from the Pango rules which are here.

This lineage appears to have some growth advantage relative to its parent worldwide or across Asia (about 25%), but it is showing potential disadvantages at the country level (e.g. in South Korea and Japan), which could mean that the regional advantages are caused by uneven sampling among countries. Consequently, this lineage needs further monitoring in order to distinguish real advantages from chance/founder events and sampling bias.

Thanks for the explanation here, I understand the logic but I dare to disagree with some of the details here.
Your claim that this lineage is showing potential disadvantage at South Korea is simply by chance. South Korea have just updated 13 seqs of this today and covspectrum did not count for that. I don't have convincing evidence to tell that the variant would now have a positive growth profile, but given that the variant's submission today is located within 04-25 to 05-02, it could make the graph much more convex-looking.
If the next update demonstrate what I say, then this variant should have a larger infered growth and I think that you do have good reason to assign for it then.

[krosa1910]

@InfrPopGen @corneliusroemer Could this be assigned? It has already reached 100 seq with today's update.

Thanks for proposing this, and for the question @krosa1910

There's not a threshold number of known sequences/cases for designation, there needs to be some epidemiological importance (e.g. the unique mutations the lineage has acquired relative to its parent lineage appear to be giving it a significant growth advantage, or the lineage has attracted a lot of research interest because it is associated with some epidemiological event or is an important part of some major investigation, so it needs a label to distinguish it). This arises from the Pango rules which are here.

This lineage appears to have some growth advantage relative to its parent worldwide or across Asia (about 25%), but it is showing potential disadvantages at the country level (e.g. in South Korea and Japan), which could mean that the regional advantages are caused by uneven sampling among countries. Consequently, this lineage needs further monitoring in order to distinguish real advantages from chance/founder events and sampling bias.

And I want to add a point here, that is this variant seem to be spreading locally effectively in South Korea. Most (49/53)of the South Korean seqs have the mutation A27669G, while only one seq outside South Korea has that mutation. I believe that the ability to locally transmit abroad is also be a trait that we look for in variants, and that raised importance of this issue.

[InfrPopGen]

Your claim that this lineage is showing potential disadvantage at South Korea is simply by chance...
Actually, it was the advantages elsewhere that might be by chance, but I get what you mean.

If the next update demonstrate what I say, then this variant should have a larger infered growth and I think that you do have good reason to assign for it then.

Yes, exactly, that's what the wait is for, to see if that disadvantage disappears with more data (which as you say, is coming through the pipeline).

[krosa1910]

Your claim that this lineage is showing potential disadvantage at South Korea is simply by chance...
Actually, it was the advantages elsewhere that might be by chance, but I get what you mean.

If the next update demonstrate what I say, then this variant should have a larger infered growth and I think that you do have good reason to assign for it then.

Yes, exactly, that's what the wait is for, to see if that disadvantage disappears with more data (which as you say, is coming through the pipeline).

I know this may sound naive or silly, but I still think that simply for "fairness" this variant should be assigned. XBB.1.16.5 has no non-silent mutations, a lower conferred growth advantage, and similar number/geological spread. Furthermore it is submitted as an issue at the same time as my issue (1983 and 1984), yet it get assigned three weeks before and not long after submitted. The growth after XBB.1.16.5 was assigned is minimal, while my variant have more than doubled, which is capable of keeping up with the general XBB.1.16* on gisaid.

I understand that a lot of our issues resulted from a local burst of spread and assignment should be cautious to avoid those ones. Yet this variant's performance overseas outshine South Korea and appeared in many new countries/ state/provinces of large countries, so I think that it is not driven by local burst.

Please seriously consider this variant. @corneliusroemer @InfrPopGen

[FedeGueli]

@corneliusroemer milestone is wrong , sorry for bothering, it XBB.1.16.10