Re: Some junk ain't junk


<whitesickle@xxxxxxx> wrote in message news:drlnav$2e2q$1@xxxxxxxxxxxxxxxxxxxxxx
>
>
> I came across this information on the internet and am paraphrasing it
> since publishing it requires permission. It is from an earlier article
> than Nature Genetics 38, 223 - 227 (2005) "Conserved noncoding
> sequences are selectively constrained and not mutation cold spots" Joel
> N Hirschhorn et al. I learned that genomic regions conserved between
> primate and rodent groups show higher relative concentration within
> rodents than within primates. This is due to genome-wide relaxation of
> selective constraint in primate lineage which is hypothesized to have
> resulted from a smaller effective population.

Ok. That sounds reasonable to me. And it is exactly the subject
at issue in my last 'dust-up' with Jim McGinn.

> The researchers
> discovered this relaxation is much more profound in conserved
> non-coding regions than in protein-coding regions, and that mutations
> at a large proportion of sites in conserved non-coding regions are
> associated with very small fitness effect. It is noted data on
> polymorphism is consistent with very weak selection. This staggering
> enrichment in sites at the borderline of neutrality can be explained by
> assuming an important role for synergistic epistasis in the evolution
> of non-coding regions. The results suggest that most individual
> mutations in conserved non-coding regions are only slightly deleterious
> but are numerous and may have a significant cumulative impact on
> fitness.

I am aware of at least one hypothesis that might explain this weak
synergistic epistasis. Forsdyke's ideas on 'stem-loop' potentials.
http://post.queensu.ca/~forsdyke/speciat2.htm
No doubt there are other possibilities.

> As of YET I have yet to see an authoritative study come out and provide
> solid evidence of important functional variation of the non-coding
> region.

There is plenty of authoritative evidence for functional variation
in parts of the genome which don't code for proteins. For example,
there are the parts of the genome that code for rRNA and tRNA,
the centromeres, etc., etc. What you have not seen is authoritative
evidence for functional variation in parts of the genome that we
don't know about yet.

> If polymorphism is consistent with very weak selection and many
> individual mutations are slightly deleterious then what would be the
> signifigant cumulative impact on fitness? It should be noted "genomic
> regions conserved between primate and rodent groups show higher
> relative concentration within rodents than within primates". What can
> we learn from the rodent that has produced signifigant cumulative
> impact on fitness?
>
> I've never been scientific minded so would appreciate input but I will
> make a few observations. While performing research on the non-coding
> region is valid and necessary there are those scientists and others who
> either privately or publicly have a bias against genetic engineering.
> By stressing the importance of the non-coding region (either real or
> bogus) they seek to show how the non-coding region is indispensable and
> how either tinkering with it or the coding region of DNA is
> counterproductive, if not impermissible.

I think you are being paranoid here. Interest in possible functions
of non-coding DNA is mostly fueled by a hope to discover something new
and exciting.

> I believe in the future, assuming we ever get past the evolution-ID
> so-called debate or in tandem, focus on the non-coding region will
> increase as a rationale against genetic engineering. Evolutionary
> biology is a conserved discipline. For example, the researchers are
> arguing such conserved non-coding regions may contribute to signifigant
> cumulative fitness. We are no longer "fit" but this operates on just
> Darwinian evolution, not taking into account numerous other factors.
> Does the conserved non-coding region possibly have undiscovered
> important functional variation which pertains to our biology and
> diseases? Probably so. And maybe we could learn more. However, what is
> more likely to eliminate single gene diseases, merely exploring the
> conserved non-coding region or implementing genetic engineering?

Well, I would point out that one possible approach to gene therapy -
the idea of 'RNA interference' - turned out to be more difficult than
expected precisely because we didn't know enough about the kinds
of interactions that take place within the cell between RNA molecules.
And at least some of the motivation for studying the conserved
non-coding regions comes from a desire to get that kind of approach
to therapy back on track. At least that is what this layman thinks
he understands.

[snip]


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