Virology lecture #6: RNA-directed RNA synthesis

9 February 2010


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  • gsgs

    if flu makes 1-10 mutations per replication, then why do we only
    see 40 mutations per year ? and flu is even known to mutate much.
    Most mutations are synonymous, so are even those usually eliminated
    by selection ?

  • http://www.virology.ws profvrr

    Two reasons. First, not every change in the RNA (mutation) makes it
    into viruses. Some are lethal, for example. Second, sequencing only
    provides information on the consensus of the population. There are
    many genome changes not detected by sequencing because they are at
    sub-detectable levels in the population. Some believe that in any
    virus preparation there is no single particle that has the same genome
    sequence as the consensus determined by sequence analyses.

  • Ngunjiri_JM

    I like Prof. Racaniello's explanation. This poses a question: is valied to associate phenotypic changes of influenza virus or other RNA viruses on the basis of single amino acid substitutions?

  • gsgs

    ~85% of mutations are synonymous nucleotide mutations which don't change
    the amino-acid sequence.

    If most viruses have at least one mutation after one replication cycle,
    then even moster have at least one after 2 or more replication cycles
    and almost all should be mutated after 2-3 days, the average time
    to reach a new host.

    Unless selection eliminates the synonymously mutated viruses
    or the mutation rate is much lower.

    The mutations should accumulate in the next host,etc.
    Just wait a year until you sequence to see the then dominant variation.

  • http://www.virology.ws profvrr

    You are not listening to what I am saying. First, forget about amino
    acid changes. Think only about mutations – changes in the RNA. Then
    realize that when you sequence a viral RNA, you are getting a
    consensus which is not present in any given virus genome. The
    diversity is so great that it is not reflected in the sequence that we
    obtain by chemical methods. Therefore it's not possible to use the
    sequence that we obtain from viral isolates to see what is really
    going on in terms of variation.

  • gsgs

    OK, 85% of mutations are synonymous _because_ ~90% of non-synonymous mutations
    don't survive selection.
    So, ~70% of mutations are non-synonymous but only ~5% of these, 3.5% in total survive.
    While ~30% of mutations are synonymous (3rd codon) and ~75% of these , 23% in total surive,
    and we observe 6 times more synonymous mutations than non-synonymous.
    75% of mutations die
    We observe 40 per genome of 13000 nucleotides per year,
    that makes 2*10^-6 surviving mutations per nucleotide per cycle of 6hours.
    Or ~8*10^-6 total mutations including non-surviving.
    Still much less than the mentioned 2*10^-4

  • gsgs

    but mutations do accumulate in the nect cycle, the next host, regardless of the consensus.
    Just what virus happens to make it. At that point the mutated virus becames the
    new consensus. So, when you sequence after a big number of several cycles,
    then your old consensus is gone.

  • gsgs

    ~85% of mutations are synonymous nucleotide mutations which don't change
    the amino-acid sequence.

    If most viruses have at least one mutation after one replication cycle,
    then even moster have at least one after 2 or more replication cycles
    and almost all should be mutated after 2-3 days, the average time
    to reach a new host.

    Unless selection eliminates the synonymously mutated viruses
    or the mutation rate is much lower.

    The mutations should accumulate in the next host,etc.
    Just wait a year until you sequence to see the then dominant variation.

  • http://www.virology.ws profvrr

    You are not listening to what I am saying. First, forget about amino
    acid changes. Think only about mutations – changes in the RNA. Then
    realize that when you sequence a viral RNA, you are getting a
    consensus which is not present in any given virus genome. The
    diversity is so great that it is not reflected in the sequence that we
    obtain by chemical methods. Therefore it's not possible to use the
    sequence that we obtain from viral isolates to see what is really
    going on in terms of variation.

  • gsgs

    OK, 85% of mutations are synonymous _because_ ~90% of non-synonymous mutations
    don't survive selection.
    So, ~70% of mutations are non-synonymous but only ~5% of these, 3.5% in total survive.
    While ~30% of mutations are synonymous (3rd codon) and ~75% of these , 23% in total surive,
    and we observe 6 times more synonymous mutations than non-synonymous.
    75% of mutations die
    We observe 40 per genome of 13000 nucleotides per year,
    that makes 2*10^-6 surviving mutations per nucleotide per cycle of 6hours.
    Or ~8*10^-6 total mutations including non-surviving.
    Still much less than the mentioned 2*10^-4

  • gsgs

    but mutations do accumulate in the nect cycle, the next host, regardless of the consensus.
    Just what virus happens to make it. At that point the mutated virus becames the
    new consensus. So, when you sequence after a big number of several cycles,
    then your old consensus is gone.