Doubts and genes and chromosomes:
I suppose that, alas, if I have one strength it is the ability to make mistakes, mistakes never dreamed of before.  Wholesale.  Embarrassing.  Dumb mistakes.  Yes, I make them.  Another thing I do a lot of is doubt myself.  Well at least the two make a good set.  Of course I am more sure about some things than others.  So let me tell you what I am sure of.

1. If you take a large population of humans, and I am not sure how large but it looks like something in the hundreds to tens of thousands, and have them choose mates at random, there will be a catastrophic population within about ten generations.
2. The cause of this is genetic; that is it is caused by mating choice.
3. The world is going to go into a severe population decline because of this.

In these things I have no doubt.  I should be happy to stake my life on them.

Elsewhere I have doubts.

One thing I make much of is the fact that I have written a computer program that follows the laws of genetics and predicts the same relationship between kinship and fertility that is seen in animals and humans.  The program requires that for optimal fertility chromosomes and there genes must match to an adequate degree.  That is not a problem.  The problem to me is that the program is rather too good.  It predicts optimal growth around, say, a population of 200.  That’s pretty good when you compare it with real world experience.  It is about the size of a fertile subsistence farming community or village of hunter gatherers.  But the program assumes two chromosomes with 300 mutatable sites each.  In reality in humans there are 46 chromosomes with billions of mutatable sites.  The closeness of the match makes me squirm.

That is why I wish so fervently that more talent would be brought to bear on this important issue.  I am a doctor.  I take care of sick people.  The times when I have wished I did something different were when I made a decision without consulting enough others.  There has always been ample opportunity for that.  Generally it was just a stroll down a hall.  The consultation was available.  But here is something extremely important and I am not doing a good job of getting talent onto it. 

Maybe what exists in reality that is important is a tiny fraction of the genome.  Maybe it is what is bypassed when sperm are injected into eggs.  I don’t know.  I wish I did.

The second thing that makes me most uncomfortable is that I feel like fairly screaming, “Marry between second and fifth cousins if you want children.”  But I have no real business promising that.  I do not have clear cut data for a first generation effect.  The Icelandic data goes back ten generations.  The Danish data goes back two generations.  Clearly the effect of increasing genetic diversity is something that accumulates over more than one generation.  For all I know it accumulates only over more than one generation.  Even those thousand animal studies may be looking at more than one generation for all I can promise you.  That should be possible to tease out of the original data.  Does the same curve hold for animals with more than one years generation time if they are sampled annually as for animals with a shorter generation time sampled annually.  The data exist, but I do not have them.

A third thing is that the mechanism remains elusive.  Certainly I have a model.  And since my model is the only game in town that comes close to accounting for the data it is the best theory.  Hence it is scientific “proof” or at least it would be if I could get it into a journal.  But what is really going on?  Maybe it is the safety check by which certain sperm are excluded, maybe not.

Maybe it is a matter of mitosis.  When a cell gets ready to divide, the DNA, which usually is sitting around unwound and available for transcription and which has already been duplicated by the magic of cell chemistry, clumps up into visible chromosomes and the nuclear membrane disappears.  The chromosomes then move to a structure in the middle of the cell called the “metaphase plate.”  Structures called “spindles” appear on either side of the plate and attach to the centromeres of the chromosomes and pull them apart, one copy going to each side of the cell.  .  Then the cell divides, each new cell getting a nucleus as the nuclear membranes appear.  Well just suppose than when they get to the metaphase plate, they to not all arrive at the same time.  Or they don’t attach to the spindles at the same time.  This could throw off the timing of the whole thing.

Yes, that would seem to be a possible problem.  And it is testable.  With modern microscopy, might be able to watch it all happen in real time and detect any timing problem.

But my gut tells me that it is not mitosis that is a problem.  When you cross a mare with a jackass you get a mule.  A mule does not have normal sexual development.  But it makes other tissues just fine.  In fact it tends to be more muscular than either a horse or a donkey.  Building those tissues takes mitosis, so even in this rather extreme case of mixing chromosomes mitosis does not seem to be a problem. 

Maybe the problem is with meiosis.  “Meiosis” is a special kind of cell division.  The chromosomes clump up again and they then physically couple up so there are now basically four sets of genetic information in each “tetrad,” two copies of each of the two homologous chromosomes.  At this time, there either is (as in humans) or is not (as in fruit flies) a time of recombination where the two homologous chromosomes break and rejoin so that neither is any longer a faithful copy of either original but all the sites are still represented on each.  Two divisions later and there are four cells with only one set of the genetic information each.  These become egg and sperm which are ready to produce a new embryo. 

Well that seems rather promising.  At least the chromosomes get next each other, so they have a chance to compare notes, as it were.  But if the problem is with meiosis, why in the world does the mule not have normal development of sexual organs?  Almost none of the cells have undergone meiosis since it occurred under normal conditions in the gonads of the parents. 

Does a signal pass, “Help.  I can’t make sperm (or eggs).  Don’t bother preparing to put them to work”?  I really don’t know.  It makes me most uncomfortable.  Maybe that is why nobody much wants to talk about it.  But it is the things we don’t understand that are the most important to talk about.

So while there are a very few basics about which I feel quite certain and at least some things I feel pretty good about, there do remain questions that beg to be addressed.

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