Domiant/Recessive Genes

John Woods eanv20 at castle.ed.ac.uk
Thu Jan 6 09:00:28 EST 1994


Ryan wrote:

  I was wondering if anyone knew exactly why a cell chooses
  one gene over another in dominant genes (in some cases co-dominance). 
  Is there a specific nucleotide sequence in the DNA that tells if a
  gene/trait is to be dominant or recessive?  [...]

It doesn't really choose.  A carrier for sickle cell anaemia has half
normal haemoglobin and half HbS (sickling-haemoglobin).  Often the
recessive has zero functionality, and it appears that the dominant is
`chosen',  by default.

The answer to the question is provided by Metabolic Control Theory
and can be found in the excellent paper by Kacser & Burns (*).  Be
warned --- some of the terminology has now changed, especially the
symbols used.

ricke at rcf.mayo.edu wrote:

  Dominant diseases are caused by the presence of (almost always) a single
  mutational change which causes a loss of function or gain/modification of
  function.  There are multiple different mechanisms by which mutations 
  cause domiant diseases (many occur when mutant protein forms complexes
  with either the remaining normal allele or with different proteins).

Yes.  Loss of function is most often the case.  Most genes are fairly
sophisticated --- think what you'd do if you made a random change to a
motorbike --- you *might* improve it, but it's most likely to stop
working completely

ricke at rcf.mayo.edu wrote:

  Recessives diseases result when the remaining normal allele is sufficient
  to provide enough protein for the cell/organism to survive.

But it's interesting to note that the 50% gene dose usually seen
in heterozygotes does not often give rise to much phenotypic
difference compared to that of the 100% in the dominant homozygote.
So 50% is nearly always sufficient.

Let me stress that nothing is *completely* dominant.  Even Mendel
thought he could fancy some slight difference between his
heterozygotes and his dominant homozygotes.  Sure, a carrier for
albinism *looks* normal, but if you stick one in a liquidizer
youphotometrically determine that they are significantly paler.

* Rigor Checking Off *

But why do we see almost complete dominance all the time?  Lets take
an enzyme in a pathway.  Let's arbitrarily double it.  If the rate of
the entire pathway in which it was embedded doubled, we would say we
had a `rate-limiting' enzyme.  To be more realistic, consdier a 1%
change in enzyme.  A 1% change in flux would result for the above
case.  Now, define the term 'Flux Control Coefficient' (FCC) such that

         J    % change in flux of pathway
        C  =  --------------------------------  in the limit of % = 0
         v    % change in local rate of enzyme 

We can accept that a value of 1 represents `rate-limiting' and a value
of 0 represents `no control'.  We can prove by the `summation theorem' (**)
that no matter how long a pathway, the sum of all of these (one FCC for
each enzyme) is 1.  Most pathways have `n' enzymes, so the average FCC
is 1/n --- smaller as n increases.  For largish pathways, this means
that most FCCs are smaller, with the unsurpizing result that 50% -->
100% activity change shows little overall flux difference.  It also
gives us the reason for the lack of effect of >100% expression ---
explaining the failure of genetic engineering projects to increase,
say, yeast glycolysis by pumping up Phosphofructokinase, the textbook
`rate-limiting' enzyme.

* Rigor checking on *

There are several ramifications of the above, and special
qualification must be given to pathways containing channelling, high
enzyme concentrations, etc.  But we can see that the notion of
`rate-limiting' is a fiction.  Very many enzymes show little change on
flux when reduced down to even 33% or increased severalfold.  The
phenomenon of dominance is merely a result of this physiological fact.


				... John Woods



(*)
@ARTICLE{KAC81A,
    AUTHOR = "H. Kacser and J.A. Burns",
    JOURNAL = "Genetics",
    TITLE = "The Molecular Basis of Dominance",
    VOLUME = "97",
    PAGES = "639--666",
    YEAR = 1981}

(**)
@ARTICLE{KAC73A,
        AUTHOR = "H. Kacser and J. A. Burns",
        TITLE  = "The Control of Flux",
        YEAR = 1973,
        VOLUME = 27,
        JOURNAL = "Symp. Soc. Exp. Biol.",
        PAGES = "65--104"           }
-- 
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Forsan et haec olim meminisse iuvabit (Virgil)
[approx] Tr: The time may come when we will look back on these days and laugh
"



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