From: Josh Bembenek (jbembe@hotmail.com)
Date: Wed Apr 09 2003 - 12:15:20 EDT
P:
Not sure what your point is here. We know that there are retroviral
proviruses in the genome, so they must infect germ cells at a high enough
rate that some of those germ cells form people. They also must get fixed in
the population. There doesn't have to be positive selection - population
genetic theory predicts that some neutral mutations will get fixed.
Josh: Point is two parts: First, I was thinking through the probabilities
associated with vertical viral transfer. The limited number of chances
favors the propagation of the virus through vertical transfer as opposed to
horizontal (for insertion into same sites- if several species were infected,
and it very rarely inserts into gametes and is passed on, then one would not
expect to see similar site insertions between species due to simultaneous
infections). However, one virus inserted into a gamete could copy itself
during development and insert into all the preferred sites in subsequent
generations before becoming uncapable of reinserting itself through
mutation. This means the distribution occurs during the post infection
viral amplification and reinsertion, and not through vertical transfer at
sites with elevated site preference. Secondly, I don't think it is
perfectly clear how much site preference there is in the genome- it is an
assumption that I am questioning. A report in the recent March 21rst Cell
entitled "Global Chromosome Positions Are Transmitted Through Mitosis in
Mammalian Cells" indicates strongly that DNA is not equally packed or
accessible in the nucleus. Also, Gunter Bloebel presented a lecture at our
university yesterday and indicated that the heterochromatin/ euchromatin is
packed into the nucleus in a specific way in relation to the nuclear pores.
This would be one variable introducing some site specificity- it is possible
a virus cannot penetrate the chromitin far beyond the nuclear pore entry
sites. Additionally, in Sperm nuclei, the nuclear pores only locate to one
particular region of the nucleus, which coincides with DNA that is still
packaged with Histones (the rest is super-packed with a different sperm
specific molecule- I can't remember off the top of my head- and has no
nuclear pores, hence perhaps protected from viral entry). If a virus is to
be passed on through generations, it has to attack gametes, and this
organization of the sperm nucleus could strongly limit the sites available
for viral entry. Although again, the fact that viruses can jump and
reinsert largely confounds the issue.
P: My point was just that the leukemia result is explained by positive
selection, not a site specific mechanism of insertion. If you wanted to
invoke the same explanation for proviruses at the same site in different
species, you would have to say that there was positive selection for
incorporation of the same virus at the exact same site in both species.
Josh- Or that different viruses have different preferences due to unknown
variables that select subsets of available sites for genome integration.
The review I mentioned cites viruses that do have such assymetrical
insertion sites. See below.
P: It doesn't require a site preference, as I explained above, if one out
of 100,000 insertions is expected to be close enough to the gene to activate
it (that was the researchers' estimate) and they injected a million cells.
Frequent occurrence of the leukemia is expected even in the absence of a
site preference.
Although we don't have a full account of site insertions in this case, so we
cannot make conclusions on the probability of different insertions unless we
assume equal access to all sites within the genome.
P:
Insertion at exactly the same site in humans and other primates is I think
known to be the case for some retrovirus insertions where the region has
been sequenced in more than one species. Other transposable elements,
particularly L1 elements and Alu elements are present in mammalian genomes
in much larger numbers than retroviruses (L1 > 10^5; Alu > 10^6) and thus
provide thousands more examples of the same thing. These elements are so
frequent in the genome that almost any segment over a few kb that is
sequenced in both human and chimp or gorilla will have examples of this.
Some particular insertions can be shown to be present only after a certain
point in primate evolution. That is, they may be present only in chimps,
gorilla and human and not in more primitive primates or other mammals.
Josh: I will have to save the reading of the review you cited for a later
date. This is certaintly pertinent information.
P: Retroviruses just don't have the absolute site specificity that it would
take to hit the same place twice with 3 x 10^9 places to chose from.
Josh: The following quote is important for my general argument:
"Although HERVs are known to be preferentially integrated into GC- and Alu-
rich actively transcribed and early replicated areas of human chromosomes,
the patterns of various HERVs and their LTRs within the human genome are
diverse. For some, there is only slight unevenness in the distribution over
chromosomes... IN contrast 10,000-25,000 copies of HERV-K related LTRs are
highly over-represented on human chromosomes 3 and 16, and underrepresented
on chromosomes 8, 11, 13, and X." (Bioessays 22:161-171).
There seems to be more to this than complete random access to the genome.
Josh
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