Posted on 01/31/2003 4:19:03 PM PST by jennyp
Picture an imperfect hall of mirrors, with gene sequences reflecting wildly: That's the human genome. The duplications that riddle the genome range greatly in size, clustered in some areas yet absent in others, residing in gene jungles as well as within vast expanses of seemingly genetic gibberish. And in their organization lie clues to genome origins. "We've known for some time that duplications are the primary force for genes and genomes to evolve over time," says Evan Eichler, director of the bioinformatics core facility at the Center for Computational Genomics, Case Western Reserve University, Cleveland.
For three decades, based largely on extrapolations from known gene families in humans, researchers have hypothesized two complete genome doublings--technically, polyploidization--modified by gene loss, chromosome rearrangements, and additional limited duplications. But that view is changing as more complete evidence from genomics reveals a larger role for recent small-scale changes, superimposed on a probable earlier single doubling. Ken Wolfe, a professor of genetics at the University of Dublin, calls the new view of human genome evolution "the big bang" followed by "the slow shuffle."
It's a controversial area.
"There has been a lot of debate about whether there were two complete polyploid events at the base of the vertebrate lineages. The main problem is that vertebrate genomes are so scrambled after 500 million years, that it is very difficult to find the signature of such an event," explains Michael Lynch, a professor of biology at Indiana University, Bloomington, With accumulating sequence data from gene families, a picture is emerging of a lone, complete one-time doubling at the dawn of vertebrate life, followed by a continual and ongoing turnover of about 5-10% of the genome that began in earnest an estimated 30-50 million years ago. Short DNA sequences reinvent themselves, duplicating and sometimes diverging in function and dispersing among the chromosomes, so that the genome is a dynamic, ever-changing entity.
Duplication in the human genome is more extensive than it is in other primates, says Eichler. About 5% of the human genome consists of copies longer than 1,000 bases. Some doublings are vast. Half of chromosome 20 recurs, rearranged, on chromosome 18. A large block of chromosome 2's short arm appears again as nearly three-quarters of chromosome 14, and a section of its long arm is also on chromosome 12. The gene-packed yet diminutive chromosome 22 sports eight huge duplications. "Ten percent of the chromosome is duplicated, and more than 90% of that is the same extremely large duplication. You don't have to be a statistician to realize that the distribution of duplications is highly nonrandom," says Eichler.
The idea that duplications provide a mechanism for evolution is hardly new. Geneticists have long regarded a gene copy as an opportunity to try out a new function while the original sequence carries on. More often, though, the gene twin mutates into a nonfunctional pseudogene or is lost, unconstrained by natural selection because the old function persists. Or, a gene pair might diverge so that they split a function.
Some duplications cause disease. A type of Charcot-Marie-Tooth disease, for example, arises from a duplication of 1.5 million bases in a gene on chromosome 17. The disorder causes numb hands and feet.
INFERRING DUPLICATION ORIGINS A duplication's size and location may hold clues to its origin. A single repeated gene is often the result of a tandem duplication, which arises when chromosomes misalign during meiosis, and crossing over distributes two copies of the gene (instead of one) onto one chromosome. This is how the globin gene clusters evolved, for example. "Tandem duplicates are tandemly arranged, and there may be a cluster of related genes located contiguously on the chromosome, with a variable number of copies of different genes," says John Postlethwait, professor of biology in the Institute of Neuroscience at the University of Oregon, who works on the zebrafish genome.
In contrast to a tandem duplication, a copy of a gene may appear on a different chromosome when messenger RNA is reverse-transcribed into DNA that inserts at a new genomic address. This is the case for two genes on human chromosome 12, called PMCHL1 and PMCHL2, that were copied from a gene on chromosome 5 that encodes a neuropeptide precursor. Absence of introns in the chromosome 12 copies belies the reverse transcription, which removes them.1 (Tandem duplicates retain introns.)
The hallmarks of polyploidy are clear too: Most or all of the sequences of genes on one chromosome appears on another. "You can often still see the signature of a polyploidization event by comparing the genes on the two duplicated chromosomes," Postlethwait says.
Muddying the waters are the segmental duplications, which may include tandem duplications, yet also resemble polyploidy. "Instead of a single gene doubling to make two adjacent copies as in a tandem duplication, in a segmental duplication, you could have tens or hundreds of genes duplicating either tandemly, or going elsewhere on the same chromosome, or elsewhere on a different chromosome. If the two segments were on different chromosomes, it would look like polyploidization for this segment," says Postlethwait. Compounding the challenge of interpreting such genomic fossils is that genetic material, by definition, changes. "As time passes, the situation decays. Tandem duplicates may become separated by inversions, transpositions, or translocations, making them either distant on the same chromosome or on different chromosomes," he adds.
QUADRUPLED GENES Many vertebrate genomes appear to be degenerate tetraploids, survivors of a quadrupling--a double doubling from haploid to diploid to tetraploid--that left behind scattered clues in the form of genes present in four copies. This phenomenon is called the one-to-four rule. Wolfe compares the scenario to having four decks of cards, throwing them up in the air, discarding some, selecting 20, and then trying to deduce what you started with. Without quadruples in the sample, it is difficult to infer the multideck origin. So it is for genes and genomes.
"How can you tell whether large duplications built up, or polyploidy broke down? People are saying that they can identify blocks of matching DNA that are evidence for past polyploidization, which have been broken up and overlain by later duplications. But at what point do blocks just become simple duplications?" asks Susan Hoffman, associate professor of zoology at Miami University, Oxford, Ohio.
The idea that the human genome has weathered two rounds of polyploidy, called the 2R hypothesis, is attributed to Susumu Ohno, a professor emeritus of biology at City of Hope Medical Center in Duarte, Calif.2 The first whole genome doubling is postulated to have occurred just after the vertebrates diverged from their immediate ancestors, such as the lancelet (Amphioxus). A second full doubling possibly just preceded the divergence of amphibians, reptiles, birds, and mammals from the bony fishes.
Evidence for the 2R hypothesis comes from several sources. First, polyploidy happens. The genome of flowering plants doubled twice, an estimated 180 and 112 million years ago, and rice did it again 45 million years ago.3 "Plants have lots of large blocks of chromosomal duplications, and the piecemeal ones originated at the same time," indicating polyploidization, says Lynch. The yeast Saccharomyces cerevisiae is also a degenerate tetraploid, today bearing the remnants of a double sweeping duplication.4
Polyploidy is rarer in animals, which must sort out unmatched sex chromosomes, than in plants, which reproduce asexually as well as sexually. "But polyploidization is maintained over evolutionary time in vertebrates quite readily, although rarely. Recent examples, from the last 50 million years ago or so, include salmonids, goldfish, Xenopus [frogs], and a South American mouse," says Postlethwait. On a chromosomal level, polyploidy may disrupt chromosome compatibility, but on a gene level, it is an efficient way to make copies. "Polyploidy solves the dosage problem. Every gene is duplicated at the same time, so if the genes need to be in the right stoichiometric relationship to interact, they are. With segmental duplications, gene dosages might not be in the same balance. This might be a penalty and one reason why segmental genes don't survive as long as polyploidy," Lynch says.
Traditional chromosome staining also suggests a double doubling in the human genome's past, because eight chromosome pairs have near-dopplegängers, in size and band pattern.5 A flurry of papers in the late 1990s found another source of quadrupling: Gene counts for the human, then thought to be about 70,000, were approximately four times those predicted for the fly, worm, and sea squirt. The human gene count has since been considerably downsized.
Finally, many gene families occur in what Jurg Spring, a professor at the University of Basel's Institute of Zoology in Switzerland, dubs "tetrapacks."6 The HOX genes, for example, occupy one chromosome in Drosophila melanogaster but are dispersed onto four chromosomes in vertebrate genomes.7 Tetrapacks are found on every human chromosome, and include zinc-finger genes, aldolase genes, and the major histocompatibility complex genes.
"In the 1990s, the four HOX clusters formulated the modern version of the 2R model, that two rounds of genome duplication occurred, after Amphioxus and before bony fishes," explains Xun Gu, an associate professor of zoology and genetics at Iowa State University in Ames. "Unfortunately, because of the rapid evolution of chromosomes as well as gene losses, other gene families generated in genome projects did not always support the classic 2R model. So in the later 1990s, some researchers became skeptical of the model and argued the possibility of no genome duplication at all."
THE BIG BANG/SLOW SHUFFLE EVOLVES Human genome sequence information has enabled Gu and others to test the 2R hypothesis more globally, reinstating one R. His group used molecular-clock analyses to date the origins of 1,739 duplications from 749 gene families.8 If these duplications sprang from two rounds of polyploidization, the dates should fall into two clusters. This isn't exactly what happened. Instead, the dates point to a whole genome doubling about 550 million years ago and a more recent round of tandem and segmental duplications since 80 million years ago, when mammals radiated.
Ironically, sequencing of the human genome may have underestimated the number of duplications. The genome sequencing required that several copies be cut, the fragments overlapped, and the order of bases derived. The algorithm could not distinguish whether a particular sequence counted twice was a real duplication, present at two sites in the genome, or independent single genes obtained from two of the cut genomes.
Eichler and his group developed a way around this methodological limitation. They compare sequences at least 15,000 bases long against a random sample of shotgunned whole genome pieces. Those fragments that are overrepresented are inferred to be duplicated.8 The technique identified 169 regions flanked by large duplications in the human genome.
Although parts of the human genome retain a legacy of a long-ago total doubling, the more recent, smaller duplications provide a continual source of raw material for evolution. "My view is that both happen. A genome can undergo polyploidy, duplicating all genes at once, but the rate of segmental duplications turns out to be so high that every gene will have had the opportunity to duplicate" by this method also, concludes Lynch. It will be interesting to see how the ongoing analyses of the human and other genome sequences further illuminate the origins and roles of duplications.
Ricki Lewis (rickilewis@nasw.org) is a contributing editor.
No. Let's look at how the original one was done:
I thought my explanation in #41 was quite clear, and I can't make it any clearer: Britten's original study, by its nature, would never be able to detect sequence differences due to insertion or deletion mutations. The new technique can, and found an extra 3.9% difference in the sequences. But since a single insertion or deletion mutation can affect hundreds or thousands of base pairs with a single mutation, the extra sequence differences add a miniscule amount to the number of mutations necessary to account for them.
Which is why there are 42 million mutations separating us from the chimps, which caused 150 million base-pair differences.
As we have seen, interbreeding often is limited to the members of local populations. If the population is small, Hardy-Weinberg may be violated.
I am well aware of such statements being made by numerous evolutionists. I reject them because they contain numerous half truths. The first half truth (and a half truth is really a complete lie that because it contains and element of truth makes it more believable and thus a better sounding lie) is the implication that while Hardy-Weinberg can be violated in a small population, this makes it likely that a neutral mutation will take over the whole species from that blast off point is false.
You know, I'll bet that Hardy-Weinberg were two evolutionists! In fact, I'll bet they knew quite well that their equations were only valid for large populations.
Let's continue with the example of the population of a million in the species and let's say that the 'tribe' of 100 gets a neutral mutation and it spreads through it. Well, if the 'tribe' gets mixed into the general population (somehow, sometime, somewhere) then Hardy-Weinberg will be in effect again and those carrying the neutral mutation will be only 1/10,000 of the species and will remain so BECAUSE THIS MUTATION IS NEUTRAL. So again this neutral mutation will not take over the population or even become a significant part of the overall genome pool of the species. So this argument is bunk.
No, you're assuming the population of 1 million consists of 1 semi-isolated tribe of 100 and another mass of 999,900. I'm talking about a species that tends to live in tribes in the first place. So we're talking about a species of 1 million individuals who are split up into 10,000 tribes of 100 each. Every time the mutation gets introduced into a new tribe, it has just as good a chance of fixating within that tribe as it did in the first tribe.
There is an even bigger problem though with these mutations becoming through a small inbred group a part of the genome pool of the whole species. It is a scientific fact that harmful mutations far exceed all other mutations. It is a scientific fact that inbreeding is harmful for the tightly inbred group. What this means is that the inbred group will become much less viable due to the inbreeding and that any neutral mutations within it will (if the group does not die off due to the harmful mutations) will dissappear when (or if) it joins the larger group and those harmful mutations show that the inbred group is less viable and less 'fit' than the main group.
No, the scientific fact is that most mutations are neutral. You're thinking of the mutations that have some effect on the organism - they are mostly harmful. But virtually all of the harmful mutations aren't counted among the 42 million mutations that separate us from chimps anyway, since the proto-chimps & proto-humans who carried those mutations quickly died out. I think we can safely assume all those 42 million mutations were either neutral or beneficial. (Almost all of them neutral.)
As for inbreeding, you're now forcing yourself to argue that any species that habitually lives in tribes will die out! That's just absurd.
Are you two busy, or do you just have no estimates? To determine if the differences between man and chimp are reasonably due to chance we need defensable estimates on two things:Hmmmm... I don't think they'll ever know something like that with any degree of specificity. How could they?1) How big was the early population of humans and 2) How many population bottlenecks did humans go through (times when they were reduced to less than a 20 breeding members.
See, here is where we start to disagree. There are several theories for population bottlenecks, none of them definitive yet. For example, see here for the theorized European bottleneck, or the recent FR thread on the Asian descendents of Ghengis Kahn, and I would tend to doubt (a prejudice, I grant) a 20-count human population anywhere but at the very beginning of the species.
The "Out of Africa" theory is, from what I've gathered, just a start to human population history. If we base this exercise on human population bottlenecks for gene fixation, then we are necessarily limited on the conclusions we can draw. I propose a different strategy: We KNOW that chimps and humans are different. The question we are trying to answer, I think, is how did that happen?
I think it would be more informative to identify, investigate, and expand upon the mechanisms of genetic variation. To claim that the chimp-human differences are due to chance is, IMO, to miss an investigative opportunity. "Chance" is not a mechanism. For that matter, neither is "Designer." Gene duplication and replication errors during meiosis and mitosis-- THOSE are mechanisms. The recent work on the role of virii in altering the genetic code is reported to be extremely interesting. For your side, if a Designer did the work, HOW did he do it, are we be able to distinguish "Designed" genetic change from that which occurs naturally, and if so, how would we go about doing that?
I did not say it was not clear, I said it was wrong. As I said, the proof of the pudding that the 5% is indeed the real genetic difference between man and chimp is that Britten, who had done the original study claiming the 1.5% or so, refuted himself. The question has always been about the genetic difference between the two. As I showed you also, the person who wrote the article you are following is a hack with no credibility. No legitimate scientist can say any longer that non-coding DNA is junk like that guy said.
You know, I'll bet that Hardy-Weinberg were two evolutionists! In fact, I'll bet they knew quite well that their equations were only valid for large populations.
Yup, Hardy, Weinberg, Fisher and Wright, the most famous figures in population genetics were all evolutionists. They worked for decades trying to figure out a way to get out of the problems posed by Mendelian genetics to the theory of evolution. They were pretty good mathematicians, but since they were lacking the scientific basis to apply their mathematical ideas they were very wrong. Specifically the problem came about with the discovery of DNA. The problem DNA posed was quite simple and quite awesome. It disproved for good the idea that one single mutation could effect a great change in function. With a single base pair being the result of a mutation, new species from one mutation became totally impossible. Evolution had always assumed that just one change could effect a large change in a species. The population geneticists, working on that assumption believed that a single mutation could have a large enough change in the selectivity to overcome the stasis of Hardy-Weinberg. However, with DNA showing that you would need numerous favorable mutations to achieve any significant change. These mutations would be first of all be subject to being unfavorable and kill the organism, secondly be neutral and be very likely to die off soon after arising, and the few, few favorable ones, because they had such a low or non-existent selective value until many more mutations would be added to it, would also face a high degree of chance of being lost.
What all the above means in essence is that since mutations start in a single organism:
1. Hardy-Weinberg makes the spread of mutations very unlikely to the whole population.
2. Neutral and slightly favorable mutations (those with a low selection coefficient) are likely to not only not spread, but to die off completely within a few generations.
3. And here's the kicker - because due to DNA insuring that a single mutation cannot have any large effect on an organism, all mutations are essentially neutral mutations and likely to die within a few generations.
The only 'out' from the above problem proposed by evolutionists (like you are doing here), is the small inbred population. There is a good scientific reason why calling someone an 'inbred' is an insult. Inbreeding causes harmful mutations to thoroughly make the inbred population less viable. That's a scientific fact and there is no talking their way out of it for evolutionists.
And all that tells us is that we probably don't know everything about the mechanisms of genetic variation yet. This in no way strengthens any other particular hypothesis.
C-man is forced to appeal to some mystery virus.
You are appealing to incredulty to make your case. I bring up viral action as a mechanism of variation. "Mystery" is YOUR addition. Sentis is the one who originally referenced the recent work in virus-induced variation, so I am pinging him to the thread. I believe Nebullis may also be able provide some information on the topic.
Chimps and humans are genetically different. I'm saying let's try to figure out how it happened. 42 million differences? Great! First, are we sure, and second, how do we get there from here (or, how did we get here from there)? I read your posts as suggesting that a natural explanation is impossible.
The mutational burden, so to speak, of the human-chimp difference doesn't rest on the human branch alone. The chimp branch also diverged from a common ancester. So, the numbers shrink further.
Are those numbers reasonable from what we know about mutation rates in humans, today? Yes. Researchers studied the mutation rate at a number of different loci and found that these rates agree with the rates implied by the human-chimp genetic difference.
True, and Condorman pointed that out. jennyp already had that one covered though, she is using 10 million year divergence instead of five million to take into account that you have two groups that are diverging. All of these estimates that we are making have that factored in.
Along with "C", I will be glad to take a look at any link you have on human mutation rates. I would especially like to know about the FIXATION of such mutations in the population.
I don't mean the fixation of some existing Alelle in some sub population, but a truly novel mutation establishing itself in a group. That is what we need to know, not just the mutation rate, but the novel mutation rate, and not just the novel mutation rate, but the fixation rate.
Molecular clock estimates range from 5-8 million years from the human-chimp ancestor. A conservative estimate of 5 million years ignores the recent circa 7 million yo hominid find. It doesn't change much regarding the estimates of about 1% difference in coding regions between chimps and humans. That difference is perfectly reasonable with what we know about mutation rates.
I would especially like to know about the FIXATION of such mutations in the population.
I invite you to do your own homework. You might not be aware, but within that percentage difference, neutral substitutions, that is, mutations that are not fixed, are included.
Here I am. :)
It all boils down to what one chooses to believe. Some scientists claim they have always 'known' something, then when questioned, you find out they only assumed it.
That is a lot to hang on one find that may or may not have that age. I am using numbers provided by jennyp and agreed to by Condorman. They will attest I'm sure that I have been more than fair on the numbers, giving in to their own numbers at every turn.
It doesn't change much regarding the estimates of about 1% difference in coding regions between chimps and humans. That difference is perfectly reasonable with what we know about mutation rates.
I don't see where it is reasonable. I know some mtDNA regions are hyper mutational, but not chromosomal DNA. I don't see how the observed difference squares with the H-W laws we have been discussing on this thread. Even the outrageous pro-evo assumptions I made generate a differece of less than 1% of the observed differences (400K vs. 42 million). And its not 1%, its AT LEAST 1.4% (a 40% difference) in useful genes alone even if all of the non-coding genes are true junk, which is unlikely.
I invite you to do your own homework
Since when is supporting evolution MY homework? The assignment falls to those who proclaim evolution. My homework has convinced me that the scenarios needed to close the gene gap by known natural causes in the time allowed are unreasonable. You were invited to this thread by C-man in hopes that you had some hard data that indicated otherwise.
If you in fact have such data, you might as well present it. If not, I think it is fair for thread participants and observors to conclude that the chimp-man common ancestor hypothesis is unlikley.
within that percentage difference, neutral substitutions, that is, mutations that are not fixed, are included
OK, let's make sure we are meaning the same thing by our terms. I consider a gene pattern "fixed" when it is found throughout a population, regardless of whether it is neutral or helpful.
If you are arguing that all 1.42 million fixed differences are favorable rather than neutral then you are arguing gore3000's original position. It was one of the things that I gave in on, as jennyp argued that the 1.42 million represented fixed neutral as well as favorable mutations.
If there are that many FAVORABLE mutations fixed, then there must have been thousands of times that many neutral ones. That makes the chimp-man scenario even more unlikely.
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