All,
I've noticed before that if someone writes a big article in the
newspaper and it doesn't get much response, what the newpaper does it
to follow with an article about their own article.
In that spirit, let me make the guess here that I'm not by any means
the first to think of a transposon insertion in a regulator gene as a
possible big step in the transition from pre-modern to modern H.
sapiens.
I would guess that those people who sequenced the Neanderthal genome
are searching it carefully right now for just such places where there
is a LINE-1 element or retrovirus fragment or something similar in
the human genome but not the Neanderthal, especially in interesting
looking regulatory genes.
Stay tuned.
Preston
>All,
>
>Here I am to make trouble again. :)
>
>------
>This a bit long, and, I won't have time to defend it (or even
>explain it), which I don't really care about doing anyway - it's
>just a bunch of ruminations in a thought process that is going on
>along with a lot of other things right now for me. So let it stir
>the pot, or not.
>------
>I'm just talking science right now, not theology or Biblical
>studies, or even preaching (and the congregation said, "Amen to
>that!")
>
>There is a form of genetic change that occurs in one step and can
>cause radical effects, and needn't cause any problem for subsequent
>fertility.
>
>Some transposable elements contain powerful gene activator elements
>within them. There are millions of these things in all mammalian
>genomes. They make copies of themselves at essentially random places
>all the time in somatic cells - it is a known mechanism for cancer
>progression, either by activating a neighboring growth activating
>gene or disrupting a tumor suppressor gene.
>
>Transposition seems to be largely suppressed in the germ line cells,
>but some do sneak through, and fairly regularly a transposable
>element at a new position appears in a child (I'm not sure what the
>current estimate is for the rate, I vaguely recall about one new one
>in about every 30th kid, but I'm not at all sure.)
>
>Mostly they are essentially neutral in effect - they land somewhere
>in the genome where they have no effect, and with even a moderate
>population size, most of these will be lost in a few generations due
>to the random walk nature of the process. If you walk randomly near
>a cliff, you are very likely to fall off before long.
>
>A small percentage get fixed in the population by "chance," and they
>accumulate over millions of years, accounting for the fact that
>about 45% of the human genome (and large percentages of many other
>genomes) is composed of remnants of these things.
>
>An occasional transposition will be strongly negative in effect, if,
>for instance, it lands in the coding region of a single copy gene
>that is dose sensitive. I spent 10 years studying the protein coded
>for by a single copy tumor suppressor gene that would probably
>behave that way if a transposon landed in the coding region.
>Germline mutations compromising it's protein function are very rare
>if they can be found at all, despite the fact that somatic mutations
>in the gene occur in the majority of malignancies.
>
>Even more rarely, a transposon will land somewhere where it causes
>an effect that enhances differential reproduction. If that happens,
>it is likely to be fixed in the population, or perhaps rise to an
>intermediate frequency if it turns out to be harmful in the
>homozygous state.
>
>If a transposon with such an element were to insert itself in the
>control region of a gene that codes for a protein or RNA that
>controls the expression of many other genes, say genes expressed
>specifically in certain areas of the brain, it could cause major
>changes in the expression of many genes in one step.
>
>It's quite conceivable that such a change could be necessary,
>although I doubt sufficient, for expression of a moral sense. It
>could, alternately, or at the same time, cause an increase in
>intelligence, foresight, social intelligence, bone structure of the
>head, any number of things, depending on how many and which
>downstream genes are affected. In the cases that have been studied,
>it is often not obvious what the common theme is for all the genes
>that are controlled by a master regulator gene.
>
>There are many precedents now for simple transpositions or
>rearrangements that cause widespread changes in the expression of
>many genes. A friend of mine is facing a terrible and extremely rare
>cancer that is caused by a single recombination event that joins a
>protein module that binds to a widely distibuted small DNA sequence
>element with a very powerful gene activator domain. The result is a
>powerful oncogene that ups the expression dramatically for at least
>60 other genes. There are plenty of instances where a transposon or
>virus insertion does the same kind of thing - activating a large
>number of genes by activating an activator. A gene therapy
>experiment went bad a few years ago and caused leukemia by such a
>mechanism.
>
>Thus you could get a profound change in the brain and behavior and
>other things very quickly.
>
>This effect could be either dominant (so potent that it would
>saturate downstream mechanisms and an additional copy would add
>nothing to the effect) or co-dominant (dose dependent in its
>strength - one copy has some effect, 2 copies has more) or even
>nearly recessive (one copy has little or no effect, but 2 copies
>achieves a threshold by activating something with strong positive
>cooperativity).
>
>Since there is no chromosomal translocation involved, there are no
>chromosomes being torn apart in meiosis and no problems with the
>recombination events that must occur in meiosis. If the regulator
>gene doesn't affect the expression of any genes involved in
>fertility, there needn't be any problem with fertility, but it could
>create some barrier to fertility with individuals who don't have the
>transposon insertion. I think there are precedents for something
>like this, but my memory is vague. I'll get to the implications of
>this below.
>
>If this big change is not to create a mixed population of
>descendents of the first couple, some with extremely inferior
>abilities, it must be dominant and homozygous in some mating pair or
>their descendents, or it must be co-dominant and homozygous.
>
>If it is dominant and heterozygous, some individuals will be born
>without the allele and be like the earlier subspecies. If it is
>codominant and heterozygous, it creates a three tiered set of
>descendants (with none, 1 or 2 copies of the new allele). Here are
>the all the permutations:
>
>
> Homozyg Heterozyg
>Dominant uniform popul 2-tiered
>
>Co-Dominant uniform popul 3-tiered
>
>Recessive same as what preceded 2-tiered
>
>
>Homozygosity could be accomplished by "chance" (whatever that is),
>by two closely related individuals who had both become homozygotes,
>mating. Or it could be that one of them was homozygous and the other
>heterzygous, but (by "chance") they only have homozygous children.
>
>Or if you're not bothered by the need for consistency that someone
>said is the hobgoblin of little minds (this is a private joke with
>Bernie), you could have God (or a pre-incarnation of Francis Crick
>or an alien or whoever appeals to you) do a cloning experiment with
>a rib and duplication of Adam's X and elimination of his Y to get
>Eve.
>
>(And that is why (Y) she doesn't sit around wondering why the
>universe is the way it is - she just wants you to do the chores, or
>dance - but I'm getting in real trouble now, so I'll stop.)
>
>That way you get homozygosity of all loci, not just the fancy new
>one with its transposon insertion. And that means nearly complete
>equality (except for that boring redundancy of the X and lack of
>that, oh so important, Y) so maybe I'd rather you be right about
>this one, Bernie.
>
>It's conceivable that something like all this could be behind the
>shift to modern humans (Homo sapiens sapiens) from Homo erectus or
>whatever came before.
>
>Now, if the locus is to remain homozygous in the new population, or
>nearly so, there must be no successful reintroduction of the old
>allele to the new population. If anyone looked at the announcement
>of the first draft of the Neanderthal genome the other day, it seems
>the experts now think that very little distinctively Neanderthal DNA
>got into our genome. David O. referred to this news account:
>
>http://www.economist.com/science/displaystory.cfm?story_id=13139627
>
>I will assume for the moment that this is correct. It will certainly
>get modified and argued about.
>
>(For some reasons that Neanderthal DNA in general might be strongly
>selected against in the offspring of mixed matings who live among
>the new men, see this:
>
>Nasty, Brutish and Short: Neanderthals Died Young
>http://blogs.sciencemag.org/newsblog/2009/02/nasty-brutish-and-short-neande.html)
>
>This could be achieved by a barrier to fertility between the two
>populations, or by co-dominant selection, or both. If the transposon
>containing allele is strongly dominant, then the presence of the old
>allele doesn't cause any loss of fitness except in those homozygous
>for it. Thus by interbreeding with Neanderthals the old allele could
>be reintroduced and rise to significant levels and carry other
>Neanderthal DNA with it. However, if the new allele is co-dominant
>in its phenotypic expression, heterozygotes will be at a
>disadvantage in competing with homozygotes for the new allele.
>Combine this with some decreased fertility of the mixed matings, and
>you have a pretty strong barrier to Neanderthal DNA getting into the
>new population. David is much better at this kind of reasoning than
>I am, and he can shoot me down if he wants to.
>
>For a guess at how this might work in practice, think about how a
>large, very aggressive guy who had a C average in high school might
>be dealt with if he somehow got into MIT. The smart little guys
>might get some bruises at first, but they would win the fight in the
>end.
>
>Now, what does this do to mating in the other direction? This has to
>do with the striking observation that when the new men encounter the
>Neanderthals in Europe in 40,000 B.P., the Neanderthals go extinct
>before long. They had been fine for hundreds of thousands of years.
>But encountering the new man seems to finish them off. Why?
>
>Here's a guess. The new man likes the look of the Neanderthal's
>daughter and goes over and gets her pregnant, but leaves the child,
>male or female, among the Neanderthals. So you get an unusally smart
>child compared to the surrounding tribe. In the first generation,
>the child may be smaller than the others, but is considerably
>smarter and may well live longer than his fellows. He takes a
>Neanderthal girl for a mate. Over a few generations with some
>marrying among close kin, you get the possibility of a homozygote
>for the new allele, who has also picked up Neanderthal genes for
>size and strength. Now you have something that is always awesome to
>behold, a very large and strong and very smart guy. (It could work
>the same way, with more emphasis on the intelligence, for a woman.)
>
>Now that kind of person could be very good or very bad, but they are
>likely to be a leader in that population, for good or ill. If
>Genesis 6 could be taken, among other things, as a cultural memory
>of something that probably happened many times over millenia, the
>effects were not usually good. An unusually smart and large man in a
>society that is pretty violent to start with, becomes a "mighty
>man," a mafioso, a Nephilim, a Nimrod. He stirs up his not so smart
>fellows for his own benefit, and they all go out and attack the
>smart little guys from MIT, and it doesn't turn out well. The
>survivors, if there are any, aren't happy and someone or some little
>group has to get out of Dodge, and they "go to the East." But maybe
>for the Neanderthals, the effect of the increased violence
>internally and externally is eventual extinction. The new gene(s)
>introduced into their society destabilizes it and it just can't
>recover.
>
>Well, this set of hypotheses has grown in the telling. This all
>seems plausible to me as a scientist - I'm not a specialist in human
>genetics, but I have read quite a lot on the subject over the last
>30 years or so, both out of personal interest and in relation to my
>work first in yeast genetics and then in cancer research. (All this
>before the grants dried up and I started figuring out what to do now
>at 57 years old.) Spinning hypotheses is the easy part.
>
>Having said what I did above, I have to turn around and say I don't
>think that that is anything like the whole story, even just
>scientifically. There is at least one big weakness in what I spun
>above, and I can suggest how to test it.
>
>It seems unavoidable to me that the genetic changes necessary to
>make the differences between the late hominids and us didn't occur
>in one big step. There's the whole FOXP2 gene story, whatever it
>means. And there are bound to be more such cases. (I haven't have
>time or regular full text access to look at these things for a
>couple of years.) And as far as behavior, Glenn Morton used to point
>out on this group that the evidence indicates that religious
>behavior goes back a long way, hundreds of thousands of years,
>probably.
>The genetics and archeology and physical anthropology just look to
>be more complicated than that.
>
>Here's the weakness. All the population genetic evidence that I know
>of (and it's not my field, so I stand to be corrected) indicates
>that there never was any population bottleneck of 2 people, and
>certainly not in the last 6000 or 30000 or 200,000 years.
>
>"Mitochondrial eve" is just what David said, the last female common
>ancestor of all the human mitochondrial genomes that exist today.
>She may have been part of a small or a not so small population, but
>she wasn't the Eve of the Bible - at least it seems very unlikely to
>me. The level of genetic diversity over the whole genome, not just
>the MHC, is just too high.
>
>But that is a rather vague argument and really just the opinion of an amateur.
>
>There is likely a much stronger argument.
>
>David and James have argued here (if I understand them) that perhaps
>the large number of alleles at many loci in the MHC that are present
>in, say, chimps, could be regenerated in the descendents of Adam and
>Eve. (They would have to be regenerated, because only 4 alleles per
>locus could be carried through a bottleneck of 2 individuals, and
>only 2 alleles if there was a cloning experiment to make Eve.) Since
>there are only 4 possible bases at each position, it is suggested,
>and since one might guess that specific alleles are strongly
>selected for, maybe all those hundreds of alleles could be
>recapitulated pretty closely in about 10^5 years starting with a set
>of 2 or 4 for each locus. Maybe the selection is so powerful that a
>very closely related set would emerge.
>
>This would be a massive example of convergent evolution, but
>supposedly it would be driven by selection. Modern humans do have to
>deal with a set of pathogens that overlaps quite a bit with those of
>other primates, and presumably that's what drives the selectable
>changes at the MHC.
>
>If this were the case, when you construct a tree using the sequence
>of multiple alleles of multiple species at any locus, you should see
>all the human alleles arising as a monophyletic root system coming
>off someplace near the chimp allele ssequences and closely
>resembling the allele set for chimps or whatever primate species
>where there is a lot of data for that locus. I doubt that that is
>what the tree looks like.
>
>And even if it does, you test this by then using only the sequence
>at positions that are silent - third position in some codons. And
>you include a bunch of nearby positions in introns - they are very
>easy to align in species as closely related as higher primates and
>human. And you include any transposons and Alu sequences and small
>insertions and delections that you can find that have appeared at
>nearby positions within the last few million years.
>
>I would be willing to bet that if you do that, you will not see a
>monophyletic root system of human allele sequences coming off as
>described above. You will see that each human allele at a particular
>locus is derived most directly from that same allele in the chimp or
>whatever species has had a lot of sequencing of different alleles at
>the locus you are testing.
>
>It is always possible to maintain that the positions you are testing
>really aren't neutral, but if you include enough of them deep into
>introns and transposable elements, it starts to look unlikely that
>the majority are selected for.
>
>And of course, you can always maintain that for some reason God just
>reproduced all those mutations at the third codon position and in
>introns and in all those transposon insertion sites and specific
>truncations and rearrangements of the transposons that occur during
>specific transposition events.
>
>Cornelius Hunter made the argument on this list some years ago, that
>all species were created separately and millions of transposon
>insertions and chromosomal rearrangements were reproduced exactly
>and independently to the extent that they are the same in every
>mammalian species, and the pattern of those events between different
>species just happened to match the phylogeny deduced by other means.
>
>It occurred to me later that this must be the most massively
>anti-parsimonious hypothesis in the history of science. William of
>Ockham probably achieved something approaching infinite angular
>velocity in his grave on hearing it. (The physics is wrong, but you
>get the idea.)
>
>So what do I think happened back there? I don't know. This is as far
>as I've gotten with the science. Someone needs to look at loci where
>there are large numbers of alleles and do something like what I
>outlined above. I don't have the time or the experience with the
>software or the grant money - who's going to give grant money for
>something like that - the ASA? :)
>
>I'm inclined to agree with Bernie that the science just doesn't
>allow for an Adam and Eve who are the last common ancestors of all
>people today. I'm inclined to agree with David that if you are
>willing to balance on enough heads of logical pins that you can
>preserve the possibility that they are (but modern science was the
>result of losing patience with that sort thing), and I'm inclined to
>agree with James (and Dante) that a moral capacity is a qualitative
>and defining human gift:
>
>Dante, The Paradiso, Canto V (Mandelbaum translation):
>
> The greatest gift the magnanimity
>of God, as He created, gave, the gift
>most suited to His goodness, gift that He
> most prizes, was the freedom of the will;
>those beings that have intellect - all these
>and none but these - received and do receive
>this gift.
>
>But now I've left the science. And I've probably achieved my latest
>goal, to afflict the comfortable, comfort the afflicted, annoy the
>annoying (usually me) and bless everyone, at least a little, even if
>they don't know it yet.
>
>I'm going to go and get ahold of the neck of a bottle and do the
>mundane thing, drink something out of it.
>
>Preston
>
>
>
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Received on Wed Feb 25 23:43:31 2009
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