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Further non-UTF 8 fixes

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trvrb committed Oct 2, 2019
1 parent 59553ea commit eab3c2e2097ba4c5ae9cd39c5d8ee2c3cf3f8028
Showing with 5 additions and 5 deletions.
  1. +5 −5 manuscript/main.tex
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While most research is devoted to the study of antigenic drift via specific amino acid substitutions, separate genomic segments coding for HA and NA can reassort, allowing novel genomic constellations to arise, a process that occurs frequently in nature \citep{nelson_multiple_2008, marshall_influenza_2013}.
Reassortment can sometimes create novel adaptive genotypes \citep{neverov_intrasubtype_2014, dudas_reassortment_2015}, but generally results in deleterious, incompatible genotypes \citep{rabadan_non-random_2008, villa_fitness_2017}.
In one notable example, the spread of the Fujian/2002 antigenic variant was attributable in part to reassortment between HA and other genomic segments, including NA \citep{holmes_whole_2005}.
The rapid development of sequencing technology and specific strategies for influenza virus genomics in the past decade enables sequencing of thousands of full viral genomes annually, where each genome consists of the coding sequences on each of the 8 influenza genome segments minus segment termini.
The rapid development of sequencing technology and specific strategies for influenza virus genomics in the past decade enables sequencing of thousands of "full" viral genomes annually, where each genome consists of the coding sequences on each of the 8 influenza genome segments minus segment termini.
Now, nearly all influenza-positive surveillance specimens received by the United States Centers for Disease Control and Prevention (CDC) are sequenced directly using a next generation sequencing (NGS) strategy and submitted to the Global Initiative on Sharing All Influenza Data (GISAID) Epiflu database \citep{elbe2017data}.
Sequencing direct clinical samples avoids issues of virus evolution during in vitro propagation.
From this abundance of genomic data, the dynamics of reassortment can be analyzed at high temporal and genotypic resolution.

Here, we use tools from the Nextstrain project \citep{hadfield_nextstrain_2018} to show that a reassortant A(H3N2) genome constellation dominated the 20172018 North American influenza season.
Here, we use tools from the Nextstrain project \citep{hadfield_nextstrain_2018} to show that a reassortant A(H3N2) genome constellation dominated the 2017--2018 North American influenza season.
We go on to show that viruses with this genome constellation had the HA and PB1 segments of one parental virus with the other six segments of another virus, and that the progenitor virus likely emerged in late 2016 or early 2017.

\begin{figure}[t]
@@ -55,7 +55,7 @@ \subsection*{Phylogenetic analysis}
Ancestral locations are estimated as the marginal distribution on ancestral node states following this CTMC model.

\subsection*{Reassortment analysis}
To detect reassortment, we constructed tangle treessets of two trees representing different segments, with tips from matching viruses connected by lines.
To detect reassortment, we constructed tangle trees -- sets of two trees representing different segments, with tips from matching viruses connected by lines.
We then compared topologies of tangle trees that matched the phylogeny of HA segment with that of other segments.
When incongruent tree topologies were found, we compared whether the viruses labelled as A2 and A2/re in the HA phylogeny were adjacent in the other segment's phylogeny, and if it appeared that A2/re was a subclade of A2.
If not, we inferred that a reassortment had taken place that combined the HA segment of an A2-like background with the other segment from a separate background.
@@ -97,7 +97,7 @@ \subsection*{Genetic diversity of recent A(H3N2) viruses}
Clade A2 is defined by a series of amino acid substitutions in HA:T131K, R142K, R261Q.
This series of substitutions completed in mid-2016; no further amino acid changes were observed and the frequency of this clade remained fairly constant from late-2016 to mid-2017 (Fig.~\ref{fig:frequencies}).
In the 2017--2018 season in North America, however, an A2 HA subclade dominated the viruses circulating, yet lacked additional amino acid substitutions.
This subclade--which we denote as A2/re (Fig.~\ref{fig:2y_clades})---appears to have arisen as a result of a reassortment event, as discussed below.
This subclade---which we denote as A2/re (Fig.~\ref{fig:2y_clades})---appears to have arisen as a result of a reassortment event, as discussed below.
The rapid rise of subclade A2/re---coupled with an extraordinarily high incidence of that subclade in North America---stands out.
By the beginning of 2018, we find the clade viruses belonging to clade A2 increasing to make up almost 70\% of A(H3N2) circulating viruses, overtaking A1b as the dominant HA clade (Fig.~\ref{fig:frequencies}).

@@ -156,7 +156,7 @@ \subsection*{Genome reassortment events among circulating viruses leads to A2/re
The presence of all four pariwise cobinations of these two mutation states indicates that a reassortment event has occurred, as only three states can arise in the absence of reassortment.
In the HA phylogeny we use the mutation HA:T131K, and in NA we use NA:N329S.
In our data, the three non-reassortant genotypes were observed at frequencies around 10--20\% in 2016, but the A2/re genotype first appeared in February 2017.
By December 2017, this genotype had risen to above 70\% frequency in North America; this is a comparable rate to that at which the 3c3 clade rose to predominance during 2012-2013 (Fig.~\ref{fig:tangle}).
By December 2017, this genotype had risen to above 70\% frequency in North America; this is a comparable rate to that at which the 3c3 clade rose to predominance during 2012--2013 (Fig.~\ref{fig:tangle}).
For this analysis, we use only HA:T131K as an identifying mutation for the derived clade, though we can find the same results through using HA1 sites 142 and 261 as all three can be used to define define the transition from the ancestral state of HA---in our case the split of A2 from A1.

The HA phylogeny for A2/re viruses are also incongruent compared to A2 viruses within trees for the six other RNA segments (PB2, PA, NP, NA, MP, NS).

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