Genome Evolution | First, a Bang Then, a Shuffle

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."

"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.²The 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.

References
1. A. Courseaux, J.-L. Nahon, "Birth of 2 chimeric genes in the Hominidae lineage," Science, 291:1293-7, 2001.

2. S. Ohno, Evolution by Gene Duplication, Heidelberg, Germany: Springer-Verlag, 1970.

3. J. Bennetzen, "Opening the door to comparative plant biology," Science, 296:60-3, 2002.

4. A. Wagner, "Asymmetric functional divergence of duplicated genes in yeast," Molec Biol Evol, 19:1760-8, October 2002.

5. D.E. Comings, "Evidence for ancient tetraploidy and conservation of linkage groups in mammalian chromosomes," Nature, 238:455-7, 1972.

6. J. Spring, "Genome duplication strikes back," Nat Genet, 31:128-9, 2002.

7. D. Larhammar et al., "The human hox-bearing chromosome regions did arise by block or chromosome (or even genome) duplications," Genome Res, 12:1910-20, December 2002.

8. X. Gu et al., "Age distribution of human gene families shows significant roles of both large-and small-scale duplications in vertebrate evolution," Nat Genet, 31:205-9, 2002.

9. J.A. Bailey et al., "Recent segmental duplications in the human genome," Science, 297:1003-7, Aug. 9, 2002.

The problem is we don't know the rate of mutation in any species as it isn't set . It is a random variable and its speed is set by a variety of factors. A virus, a random mutation, or a cancer can cause all sorts of mutations but when all factors act in a short time (several generations) then mutations occur at a higher rate. You also miss a main point Viruses not only reshuffle what is already there they can add genetic material from their own DNA or carry DNA from other creatures.They can also link genes in different ways.

In fact I would even go so far as to suggest if Christians are hunting for GOD they look toward the lowly virus as the architect of most higher lifeforms today. :)

Again rate of mutation is due to environmental factors that cause mutation when all the factors are working at once mutation occurs quickly but when a person says quickly it could mean hundreds or thousands of years.

As you can see no rate of change can be set. If we know all variables that may be possible. I however doubt we as scientists know all factors that can cause mutation yet. The Viral factor in evolution is brand new and there are even more cutting edge hypothesis that may or may not change what we already know.

What kind of links are you looking for I placed links that are easy to understand rather than technospeak that the average reader would fall asleep over?

I agree that we have a lot more to learn about what virii have done to the genome, but that also means it is not reasonable to attribute what many regard as God-like powers to them.

Let's approach this another way. I have gone with ya'lls numbers every step of the way to make it fit. I have not asked any of you to budge a bit even though gore3000 makes a good case that your numbers are suspect.

If we look at the total number amount of difference in the humane genome then maybe we can find the average human mutation rate REGARDLESS if it was caused by radiation, virii, or whatever. It then does not matter how the mutation occured- it takes virus and every other kind of mutation into account. We can then compare that to human-chimp differences and see how likely it is that they split.

Let me show you what I mean: I will not do your homework for you, as some have suggested, but I will do a sample problem for you. I will pretend like I am on your side, and generate some numbers that supports your case.....

A study by Doritz found eight base pair differences out of 397 studied from mtDNA from ethnic groups around the world. Using this study, we can calculate that there is about 2 percent variablity in this hyper-mutational region of mtDNA (8 /397= .02).

Does all of the human genome vary by this amount? IF the mutation rate of this region were applied to all CHROMOSOMAL DNA then a 42 million bpd divided by .02 equals an expected humane genome size of 2.1 billion base pairs. That number of base pairs and higher means that variablity in the human genome can account for it. As one goes lower than that number, the idea that natural factors alone are responsible goes down.

Compared to the actual count of 3 billion bp, you are well within the ballpark of saying the differences can happen as a result of naturalistic mechanisms.

OK, end of Darwins-advocate mode.

The only catch in the above is DOES TOTAL CHROMOSOMAL variability in humans equal or exceed that 2% figure I cited? NO. I don't know what the real difference is though. How much % wise do we all differ from one another in our total CHROMOSOMAL DNA? How do our 42 million (or 150 million using g3ks calculations) bpd's from chimps compare to the number of pbd we have from one another?

If we evolved, shouldn't that calculation give us the average chimp-human mutation rate? Conversely, if we are super-similar to one another compared to our differences with chimps, wouldn't that imply that WE DON'T mutate fast enough to explain the difference?

Do any of you have this information? I invite any of you to plug the real number (not the 2% figure I used, but the real abount of %bp difference in the human genome) into the process I have outlined above and let's see what the numbers show us. Any takers?

If not, does my brainstorm example lead you into any ideas as to how you could model mathematically the reasonableness of the man-chimp connection?

Not at all. At 45 I thought you were running away from trying to get meaningful numbers, even though you had commented that the original post was "fact based" when you thought those man-chimp numbers were in your favor. I understood your sudden reluctance to acknowledge the value of mathematical models as the result of your foresight that taken to their reasonable conclusion, the numbers don't support the evolution of man.

A couple of posts later you said I had misread you on that, and I took you at your word.

I hope you are not going to the position that I presumably mistakenly attributed to you back on #44. If the post does represent a "fact based" study, then number estimates on man-chimp genomes are fair game.

I am trying to take these numbers to their logical conclusion, practically begging any and all of you to present your models as I have mine. Rather than attempt to refute my numbers based on fact- which you cannot do since I have used your own numbers at every step of the process, I see a desire to move away from any attempts at measurement. Is that "science"?

I hope I am "misreading" you again. You don't expect us to accept the "science without numbers" mind-set that resists any attempt at quantification?

That can't be your position. It is not a rational one. It is PURE FAITH beyond that of my position that God made man. I am offering mathematical models to support my contentions, whilst I have been offered nothing in return but hypotheticals that are to be accepted on faith.

If my models are flawed, point out the flaws- I have been very reasonable throughout this entire thread about accepting numbers from your side. Don't just side-step the whole issue of quantifying the probability of the evolutionary hypothesis, offer your model in return.

At 45 I thought you were running away from trying to get meaningful numbers, even though you had commented that the original post was "fact based" when you thought those man-chimp numbers were in your favor.

Which thread are you reading, man?

which

45 posted on 02/07/2003 12:27 PM EST by Condorman

I don't know what the real difference is though. How much % wise do we all differ from one another in our total CHROMOSOMAL DNA? How do our 42 million (or 150 million using g3ks calculations) bpd's from chimps compare to the number of pbd we have from one another?
83 posted on 02/15/2003 3:36 PM EST by Ahban

Never said that. I wanted to establish a baseline. If chimps are 95% the same a man, what does that mean? How does that compare to intra-human genome comparisons? How close are humans to, say, goldfish? Without any kind of reference point, 5% is a meaningless figure.

I understood your sudden reluctance to acknowledge the value of mathematical models as the result of your foresight that taken to their reasonable conclusion, the numbers don't support the evolution of man. A couple of posts later you said I had misread you on that, and I took you at your word.

Once again, here is the context of that remark.

I don't think the first group of scientists should demand that the second group produce the bodies of those long gone researchers as "proof" of the design hypotheis. The second group should be able to use stats to show how absurd is the idea of evolution in this case, especially within 500 years.
46 posted on 02/07/2003 1:34 PM EST by Ahban

Only if the second group was fully conversant with the initial conditions at the period in time when the glow-in-the-dark mice first appeared in the animal kingdom. Without that info, calculating statistical improbability it just guesswork with a slide rule.
47 posted on 02/07/2003 4:09 PM EST by Condorman

I am trying to take these numbers to their logical conclusion, practically begging any and all of you to present your models as I have mine.

Where have you been? We have! Sexual reproduction, gene duplication, transposition, and viral action have all been presented and identified as mechanisms for genetic modification. You sought to dismiss virii by referring to my remarks as "C-man's mystery virus" until Sentis expounded on the concept, but have since been content to let the matter drop. Nebullis appeared and made note of the fact that mutation rates appear to be consistent with the observed genetic differences between chimps and man given the time frame.

But here's the rub, even if those mechanisms are shown to be inadequate, this IN NO WAY provides support for a designer. Your only argument at the point appears to be "What we know can't account for the changes, it must have been the Designer." What you forget is that unless we have evidence to the contrary, we have to exhaust all the possible natural alternatives before a Designer might be considered.

I made the same point in post 63 and concluded with this question: If a Designer is responsible for the chimp-human divergence, how did he do it, and would we humans be able to distinguish Designer-induced genetic changes from those occuring naturally? You claimed that I'm attempting to sidestep the issue.

I'm sorry, but I think I'm starting to lose interest in this thread. I do appreciate your efforts, but your responses indicate that you don't appear to be comprehending the points I'm trying to make. Maybe I'm not being clear, maybe you don't understand, maybe it's a combination of the two. Whatever the case, I seem to be spending more time regurgitating our conversations than making any progress forward.

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