Toshihiko Shiroishi
National Institute of Genetic
Yata 1111

Dear Toshihiko Schroishi:
I have read your excellent and impressive article (Hybrid Breakdown Caused by Substitution of the X chromosome between Two Mouse Subspecies GENETICS vol. 166 February. 2004 pages 913 through 924).  I find it very interesting.

My own concern is the fertility of populations.  It is well established that for animals in general and for humans in particular kinship is required for normal fertility in the first and second generations.  (I can give you the references if you like.)  My very simple observation is that a large population, it seems to be something under 1,000, if it is subjected to random mating, will collapse.  I believe we are seeing that beginning to happen in humans. 

I had assumed that the cause was the same as the cause of hybrid breakdown.  Something in the genome is keeping track of kinship over multiple generations.  In mice and humans the phenomenon seems to run its course over five or six generations.  That is close to the time it takes hybrid breakdown to become severe. 

There are of course differences.  In hybrid breakdown there is a cross between two distinct lines.  After that members of the crossbred population are bred with members of one of the original lines and in time the line dies out.  What I think I see is that if members of the same line are bred but bred to non kin the fertility declines.  I could be wrong.  I could be looking at the hybrid breakdown effect without knowing it.  I have been wrong many times while looking at this issue.  But my data does not seem to force me to believe that hybrid breakdown occurs because of the same mechanism. 

A second difference is that it appears that hybrid breakdown affects only males.  Available evidence in humans suggests that women are affected as well.  If you go to you can look at graphs that Google has made available.  It is about statistics gathered from countries you can choose your coordinates and see how the values evolve over time.  If you choose total fertility for the horizontal axis (it is the first in the list of choices they give you) and age at first marriage for women as the vertical axis (it is the final choice under “population” and run the graph over the past century, there is a rather consistent pattern.  For the developed world, the circle that indicates the country wanders around until about 30 years ago.  Then it moves decisively to the left, falling below replacement level without a change in the age of marriage.  Then it rises rapidly as women get older at the time of first marriage but with fertility almost unchanged, falling only slowly.  In Japan there was a pause when replacement fertility was reached in about 1960 and the age at first marriage did not begin to rise until 1980.  China is now having such a pause.  But typically the rise in age starts very soon after the birth rate falls below replacement. 

The pattern is so consistent that there must be a mechanism.  Perhaps the original fall is due to male factors.  As for the women there is an old term “biological clock,” which implies that when a woman reaches a certain age she becomes very eager to have children.  It looks like the mechanism is slowing their biological clocks.  This would be something that would be hard to observe in the mice you studied. 

A third difference is that my own sense is that the process is simply too predictable and moves too fast for it to be due to gene interactions alone.  I suspect there is an epigenetic effect. 

And herein lies a possibility you may like.  You have created an excellent model for hybrid breakdown.  But suppose you were to remove any epigenetic effect with chemical agents.  If we are both looking at the same phenomenon then maybe you can erase the effect of hybrid breakdown that way.  You identified parts of the X chromosome that seemed to be involved.  This would not change that at all.  It would only give you a possible way of better understanding how those parts are called into play.

Everything I find about this issue I try to place eventually on my web log, which is  I shall post this letter there, too.

Please let me know what you think.  (And let me know whether you would like your reply to be posted or maybe I could just mention that you had answered if you like.) 


M. Linton Herbert MD 

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