Humans slow mutation rate (Science)

Ingrid Jakobsen ingrid at helios.anu.edu.au
Thu Apr 27 22:46:20 EST 1995

In article <Pine.3.05.9504270834.E10529-b100000 at mcz>, dmw at MCZ.HARVARD.EDU (Daniel Weinreich) writes:
|> On 24 Apr 1995, Grier Page wrote:
|> >This question is being addressed in a series of papers form Dr. W-H Li's lab. 
|> I again confess my former ignorance of these studies!  In response to my
|> original post I received (and forwarded to this list) a note from W.-H. Li
|> which gave some of these recent references (Nature 362:745, PNAS 91:827,
|> JME 40:70). 
|> > [The putatively faster Y-clock] is not the result of what enzymatic
|> > differences but due to difference in the number of divisions a egg goes
|> > through verses a sperm.
|> Putting aside the extremely difficult question of whether the level of
|> purifying selection acting on homologous X- and Y-linked introns is
|> identical, I'm still intrigued by an alternate explanation offered to the
|> list by Ingrid Jakobsen (ingrid at helios.anu.edu.au), who wrote: 
|> > DNA in sperm is methylated, while in ova it is not.  This would mean
|> > that genes on the Y chromosome would experience more C to T transitions
|> > independently of any effect that may be caused by cell division.
|> There are indeed some C->T transitions from ZFY to ZFX (e.g. see Fig 1c of
|> the Nature paper).  If one controls for this effect (e.g. by discarding
|> such transitions, or at least down-weighting them) does the whole
|> phenomenon of "male-drive" go away?  I doubt it; but has anyone run the
|> numbers? 

Okay, I didn't realise it was going to be followed up on so I should
provide a few more details. Methylation takes place at CpG dinucleotides
so what you are looking for is CpG going to TpG or to CpA
(C->T on the other strand). These mutations are likely to be caused
by methylation of the C, which when it deaminates, appears to be a
T rather than a U and so is not picked up by the "U removal machinery".
(I'm sure there is a nicer name for it than that, but I can't remember)

 This issue has been looked at in Factor VIII deficiency in humans. 
 The reference is:

Ketterling,R.P., Vielhaber,E., Bottema,C.D.K., Schaid,D.J., Cohen,
M.P., Sexauer,C.L., and Sommer,S.S.
Amer.J.Hum.Genet. 52: 152-166 (1993)
Germ-line origins of mutation in families with hemophilia B: the
sex ratio varies with the type of mutation.

They found a 3.5 (?) fold higher rate of point mutation in males 
which was entirely accounted for by an 11-fold higher rate of 
transitions at CpG dinucleotides. They suggest that CpG methylation,
rather than number of cell generations, is the reason for the higher
rate of point mutation in males in this gene at least.

This group has since found a higher rate of chromosome inversion
leading to factor VIII deficiency in males, but they suggest that 
this is because the factor VIII gene is on the X chromosome and in 
females, pairing with the other X chromosome during meiosis might
 reduce those kinds of errors.


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