DNA error rates

Keith Robison robison1 at husc10.harvard.edu
Sat May 16 11:02:59 EST 1992


bradbury at sftwks.UUCP (Robert Bradbury) writes:

>In article <9205121706.AA07357 at rust.zso.dec.com> french at RUST.ZSO.DEC.COM writes:
>>In article <9205071432.AA10616 at genbank.bio.net> 
>>rbradbur at hardy.u.washington.edu (Robert Bradbury)
>>
>>>
>>> This means by the time you hit 80, your mutation frequency is 
>>> 2.2 x 10^-5 in a single gene.  Multiply by 5000 active
>>> genes per cell and you have 1 in 10 cells with a broken gene...
>>> 
>>> Hmmmm, so damaging .2% of a gene makes it non-functional.  Due to the
>>> degenerate code from DNA to proteins and the large portions of proteins
>>> which aren't critical to structure/function you can make a case that a
>>> large fraction of the DNA for a protein can be damaged without harming the
>>> protein.  ...
>>>
>>> If we say that 10x the critical active area is important for 
>>> general functioning then every cell in the body has a gene suffering a 
>>> loss of function due to DNA damage!  
>>
>>If the DNA coding sequences really are redundant, wouldn't you divide 
>>the mutation frequency by 10 instead of multiplying it by 10?  If so, 
>>then by age 80 only 1 in 100 cells would be suffering loss of function
>>due to DNA damage.  This defect rate appears to be too low to account 
>>for the effects of aging.
>>
>I should probably try to be more complete but I worry about the bandwith
>problem.  Proteins are complex in terms of what is important and what
>isn't.  Proteins which are enzymes (as opposed to structural components)
>have one or more active sites where they do their dirty work.  These sites
>have a small number (2-10?) of amino acids which are critical to the
>catalytic activity of the enzyme.  Change one of these and the enzyme
>is broken!  There are a number of other sites which are involve in the
>protein maintaining its shape and in aligning molecules properly for
>catalysis to occur, these are perhaps a much larger fraction (10-30%?).
>And there may be additional places which are normally unimportant to
>the functioning of the protein but if you stick something wrong (large
>amino acid replaces small amino acid, hydrophobic replaces hydrophilic,
>etc) in that location things are impacted as well.

>Now, we are lucky that we have repair processes that keep things from
>changing very much.  And when they do the redundancy of the code keeps
>things from becoming too messed up.  If I read my RNA codon->Protein
>chart correctly, you can change the 1st, 2nd and 3rd bases of a codon
>3.1%, 1.6% and 81% of the time respectively without changing the protein.
>So if we were to assume base mutations all occur with equal frequency
>(which is untrue) then about 29% of the time a base change does not
>affect the protein.

>So, to take a real (perhaps extreme) example this time.  In CuZn superoxide
>dismutase, 38 out of 151 (25%) of the amino acids are conserved across 19
>species (from bacteria to plants and mammals).  Such a high conservation
>rate would argue that all of the a.a. are critical.  If we take the numbers
>from my previous article for 4x10^-8 for the mutation rate of the amino
>acid responsible for sickle cell anemia, estimate 1 order of magnitude
>increase due to age (quibble here if you want) gives you 4x10^-7 times
>38 / 2 copies per cell gives a mutation rate in critical amino acids of
>SOD at approx. 10^-5 or one in 100,000 cells have broken SOD genes.

Go back to stat class.  If the probability of losing one copy of SOD
is 2*10^-5, then the probability of losing both copies is that value
_SQUARED_, not halved!  So your final fraction is 4*10^-10 (a mighty
small number).  I don't have the figures in front of me, but 1 in
40 trillion would be much less than 1 cell/person.

>-- 
>Robert Bradbury			uunet!sftwks!bradbury






Keith Robison
Harvard University
Program in Biochemistry, Molecular, Cellular, and Developmental Biology

robison at ribo.harvard.edu 




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