A Wedgie for Creationists

The creationists have got their panties in bunches over Richard Lenski's recent paper on bacterial evolution and evolutionary contingency. In brief, over the course of 44,000 generations, Lenski's lab of e. coli acquired the ability to metabolize citric acid. It appears that at least 3 mutations were involved.

Now, on one hand, you have Andrew Schlafly (of Phyllis and "Conservapedia" fame) demanding a right to Lenski's data and bacterial cultures. Lenski was partially funded by the government, and Schlafly is a taxpayer. It appears that Schlafly sees the paper as a severe affront to his beliefs, and strongly suspects some kind of fraud. Never mind that he is not qualified to read such technical papers, much less analyze the bacteria for himself. The whole brouhaha is detailed here and here.

On the other hand, you have Michael Behe, an intelligent design creationist, poo-pooing the paper. After all, he says, the machinery to metabolize citric acid was dormant in e. coli's DNA. The only mutations required were those to allow it through the bacterial membrane. A handful of point mutations (most likely) over 20 years is nothing to get excited about, according to Behe.

Obviously, there's quite a disparity between Schlafly's and Behe's views. Is the paper such a blow to creationism that it surely must be fraudulent? Or are the results entirely ho-hum?

Now (July 9), we've got "Answers in Genesis" chiming in with an interpretation that Lenski's results are neither ho-hum or fraudulently evolution-affirming, but pro-creationism. Such disparities are fairly commonplace in the world of creationism, where the only guiding principle is to attack evolution on every possible front. In the spirit of fraternity, it seems that debate between the various schools of creationism is supposed to be minimized. But the logical chasms are huge.

I'm not only referring to creationist arguments against evolution, but also to their own religious dogmas. It seems, for example, that these folks are rather divided over the existence of satan, and/or his role in evolution. There was a time, though creationists have conveniently forgotten it, when satan was accused of planting un-biblical dinosaur bones in the soil. Remnants of this view can still be found on the net. Unfortunately, it seems that flimsy creationists tracts that may have existed in laundromats 40 years ago have gone the way of soft-bodied pre-Cambrian worms. Now, of course, you've got a "creation museum" with displays of folks saddled on the behemoths, and satan is normally left out of creationist arguments against evolution (Lewis Black on creationists: "these folks think the Flintstones is a documentary").

My point: scientists should make a point of questioning the creationists, a tactic that is normally ignored. Of course, there's a good argument to be made that scientists should never debate these buffoons in the first place. But if we must debate, then the scientist needn't merely play the role of creationist error correcter. My own experience is that, given a quasi-earnest nudge, these folks are foaming at the mouth to spew the most ludicrous supernaturalisms. Such a process may reveal inconsistencies in their views toward both evolution and religion, leaving them to fend off not only the scientists, but other believers.

Some other questions for the creos:

*How often has the Designer interceded? While most young-earthers would say "once", and others might say "always", creationist darling Behe implies that he does so intermittently. (Question for Behe: do you think your "science" could pin down when these intercessions occured?)

*If you claim that ID is a science, could you offer up a handful of experiments that might falsify it?

The Thailand Bowling Resort

About three years ago, I had this notion of putting together the "Thailand Bowling Resort". Enthusiasm for my latest brilliant idea normally wanes within a week or two, but I was hyped for several months. I put together the graphics (see the bowling balls in the coconut trees?) and a five page business proposal, and even made some meager attempts to contact folks with big bucks.

I envisioned myself as the Willy Wonka of global bowling. Given the relatively cheap costs of bowling in Thailand, you could send members of your league over here, toss a few games, and then drink cocktails on the beach. There'd be 200 foot lanes, and lanes with Evel Knievel style "loop the loops". Banked, race-track style lanes. Lanes with 15 or 21 pins. For the serious bowlers, you'd be able to choose from any number of lane conditions, and actually toss all sorts of balls...not just cheap plastic house balls. Video would be available so you could check out your form. Etc.

It never happened, of course. All you venture capitalists can feel free to grab the idea. But you gotta give me rein to mysteriously wander the premises in the wee hours, with tuxedo, top hat, and cane.

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Actually, I haven't tossed a bowling ball for nearly half a year now. My new focus is on Himalayan climbing...I'd really like to get up over 8,000 meters someday. More on that later. But it's not like all my bowling balls are going to waste...I build leg strength and endurance by stuffing the balls into my backpack and "trekking" up and down the stairs in the condo.

Not quite ready to compete with the guys below, though...

Fun with Gene Expression (for Bio-Nerds Only)

Hop on over here and you'll be greeted with an awesome gene expression resource. It's a database of about 33,000 cDNA sequences that correspond to virtually every gene in the body. You could type something like "204285_s_at" (that's how these cDNA sequences are identified) in the search field. Alternatively, you could type something like "top2a" (which happens to be the symbol for topoisomerase 2A). Then you hit enter, and you see all sorts of expression data for that gene. You might see that it's heavily expressed in the pancreas, but not in the brain. You'll see links for papers that reference that gene. Etc.

Folks gawk at the achievement of sequencing entire genomes. Impressive, but personally I'm astonished with these DNA microarrays that tell you which genes, out of 20,000 or more, are being expressed in the tissue sample. Biochemists have been sequencing DNA for something like 50 years now, with various increments in efficiency along the way. But these microarrays required a whole new approach. Specifically, biochemists had to collaborate with experts in semiconductor lithography to create these "gene chips".

"How much would you pay for your own genome sequence?" is a question sometimes offered to various scientists. Currently, it would cost a few million dollars, I would think. But a fairly affluent individual can have a tissue sample analyzed via microarray right now, and the results would probably be quite a bit more useful (at this junction in history, at least).

It also amazes me that so many of these genes and their protein products have been analyzed in depth. Choose any of 20,000 genes. Which diseases are connected with its mutations? What sort of protein family/structure are we talking about? What is its function? How heavily is it expressed in any of 100 different tissues and cancers? Who has written papers on the subject? Nobody will win a Nobel prize here, because tens of thousands of researchers have contributed to this huge knowledge-base. And much of the data is freely available to anyone nerdy enough to probe it.

I'm one of those nerds. Having downloaded the aforementioned database, transformed the data, and squished it through my own statistical sausage machine, I now offer up the winners of the "Gene Expression Awards". Before continuing, I should make it clear that I'm taking the expression data at "face value", ignoring error bars, and the simple fact that heavy/light mRNA concentrations don't necessarily translate into heavy/light protein concentrations.

First, the award for Most Consistently Expressed Gene. Here, we're talking about a gene that is expressed across all sorts of tissues, not just a few. The winner is...Insulin-Like Growth Factor Binding Protein 6! You find it everywhere in the body. Runner-Up candidates include "proline arginine-rich end leucine-rich repeat protein", "phosphoinositide-3-kinase, class 3", and "glypican 4". Special mention should go to proteins like "gelsolin" and "growth arrest-specific 6", which are not only consistently expressed, but also heavily expressed.

How about the Least Consistently Expressed Gene? Here, we'll go with "myosin, heavy polypeptide 7, cardiac muscle, beta", found almost entirely in muscle tissue. Another good candidate would be "protamine 2", which is only expressed in testis tissue.

How about "Most Overexpressed in Cancer Cells"? Let's go with "phorbol-12-myristate-13-acetate-induced protein 1" as the champion. Runner ups include "neuromedin U", "topoisomerase (DNA) II alpha 170kDa", "phorbol-12-myristate-13-acetate-induced protein 1", "DNA replication complex GINS protein PSF2", "ribonucleotide reductase M2 polypeptide", "activator of S phase kinase", and more.

There are plenty of proteins that are essentially unexpressed in cancer cells. There's always a slim chance that these proteins must be actively suppressed in order for cancer cells to proliferate. Some examples: clusterin, fibronectin 1, v-fos FBJ murine osteosarcoma viral oncogene homolog, and insulin-like growth factor binding protein 7.

"Most Overexpressed in Adult Tissue" (i.e. least expressed in fetal tissue): "major histocompatibility complex, class II, DP alpha 1", followed by any number of other immunoglobulin-related proteins. "Prostaglandin D2 synthase 21kDa (brain)" should also figure in the list.

Conversely, there's "Most Underexpressed in Adult Tissue": "alpha-2-HS-glycoprotein", "glycophorin A ", "hemoglobin, gamma G", and more.

Some Trivia...

*genes that are generally heavily expressed tend not to be expressed in testis germ cells. Rather odd.

*want to know which genes are heavily expressed in the appendix? Look for genes that are also heavily expressed in the superior cervical ganglia. Why in hell should there be a relation between these two tissues? Heavy expression in the ovaries also correlates strongly with expression in the appendix...low expression in the ovaries correlates with low expression in the appendix.

*Heavy expression in the Spinal Cord correlates overwhelmingly with expression in the Olfactory Bulb. More reasonably, heavy expression in the Prefrontal Cortex and Hypothalamus also correlate strongly with with Olfactory Bulb expression.

*Various brain tissues cross-correlate very strongly. Strong expression in the whole brain is very well correlated with heavy expression in the amygdala, followed by the prefrontal cortex, occipital lobe, etc. The differences between these tissues are fairly subtle, apparently.

*Gene expression in the prostrate is strongly correlated to expression in the lung! Huh?

*Despite the proximity of the organs, expression in the prostrate is negatively correlated with expression in the testis.

*Heavy expression in the atrioventricular node (of the heart) corresponds to heavy expression in the skin!

*Heavy/low expression in the blood is negatively correlated with heavy/low expression in the brain. There are also inverse correlations between testis expression and whole blood expression.

*Low expression in the adrenal cortex is correlated with heavy expression in the Medulla Oblongata.

*If it's heavily expressed in smooth muscle, it's probably expressed in low quantities in skeletal muscle. This correlation isn't strong, but it's a bit surprising nevertheless.

*Proteins heavily expressed in adipocytes (fat cells) tend to be expressed in smooth muscle. Collagen and collagen binding proteins, for example, but also "melanoma associated gene" (ds2448), laminin, and more.

One-Step Woo Identification

Who are the woo-meisters? They're easy to identify. Given two sides, they're the ones that cite conspiracies.

Creationism: Here, it's the "Expelled" play. Legions of brilliant ID/creationist scientists are supposedly being fired or denied tenure. The possibility that these folks are simply inept, inane, or insane is not explored. The fact that this entire issue seems restricted to the U.S.A. is also ignored...no other country in the world would waste as much time and effort debating whether all viewpoints under the sun should be offered up for scientific debate. It's a democracy, we've got Oprah, and even the illiterates are "entitled to their opinions".

Below, the trailer for "Expelled". Check it out...eminent game-show-host/Nixon-speech-writer Ben Stein doesn't waste any time (16 seconds, to be precise) blaming "BIG SCIENCE" for the world's ills.



Global Warming: As above, thousands of institutions have conspired to shut the gates on the aspiring Einsteins of global warming denial. This argument is momentarily suspended, of course, when the denialists cite academic polls that supposedly show that large numbers of scientists agree with their point of view.

Anti-Vaccine Nuttery: Here it's Big Pharma. The multinationals want to poison our children and turn them autistic because...because...actually, I'm not sure why. It's not like the drug companies have expensive, existing treatments for autism. Maybe they're working on some. Perhaps Big Pharma is attempting to create a new generation of savants who can be employed by Big Pharma, churning out ever more insidious malady/treatment combos.

Given my tongue-tiedness, let's hear eminent scientists Jim Carrey and Jenny McCarthy elaborate...


The Moon Landing Hoax: Here it's NASA. Thousands of scientists, government officials, and Hollywood types were hired to fake six moon landings. Toss in one failure (Apollo 13) for realism, and the chance for future sequels. Kill off anyone who shows signs of whispering the truth to the public. Kill off all the NASA scientists who weren't aware of the absence of wind on the moon, too. And punch out the intrepid sleuths who are honing in on the truth....


9/11: Again, huge volumes of government officials conspired to 1) cause four large airplanes laden with Laden zombies (and a lot of fuel) to crash into various structures which 2) wouldn't have toppled without the assistance of planted explosives in order to 3) cause world-wide hatred of Muslims and sympathy for America, ushering in a new Golden Age for democracy. Forgetting about the tendency of metal reinforcement to weaken, if not melt, in high heat, George Bush's response...that of taking any and all actions that might inhibit expressions of sympathy...makes it clear that he had no foreknowledge of these sinister schemes.

HIV Denial: Again, Big Pharma with a malady/treatment combo that.....targets babies!!! Ingeniously, they cause AIDS with a cheapo drug called AZT, brainwash both the scientists and the public into believing the killer drug is actually the cure, and sell more of the drug. Fortunately, one progressive and enlightened society has seen through the lies...Thabo Mbeki's South Africa.

Suppression of Alien Technology: Who is behind this conspiracy? Is it the Russians? The Chinese? It's certainly not a traditional society where ghosts have long been engrained as the spooks of choice (Q: Why aren't there any aliens in Thailand? A: Because the aliens are afraid of the ghosts). It's the Americans, of course, who have appropriated and reverse-engineered all sorts of black technology from the myriad alien vehicles that never seem to crash-land outside the homeland. With the extraordinary efficiency of our efforts in Iraq and Afghanistan, how could anyone really doubt the presence of an alien assist?

A "Penalty Decision" from China, 1987

My father dug up this little treasure and sent it to me. Seeing it, I chuckle. It's a "penalty decision" for trespassing into off-limit areas in China.

The town was Yecheng. It's about 200 kilometers south of Kashgar, and maybe 1,000 kilometers north of Tibet. My goal was to get into Tibet from Kashgar, and passing through Yecheng was the only efficient way to do it. The alternatives might have added 5,000 kilometers to the trip.

My traveling partner, Mani, and I found a hotel in Yecheng. It wasn't long before a policeman arrived and roused us (I feigned sleep when he entered the hotel room...somehow that wasn't an effective strategy). We were donkey-carted off to the police station where we were hit with the above penalty, which didn't amount to much by Western standards. Nobody could speak English, but the police were able to communicate by opening a little notebook in which handwritten explanations of various offenses were available in English. The manual was quite detailed...they even had foreseen the various objections that offenders might offer, with rebuttals following.

I was also asked to write an "auto-confession"...an apology to the People's Republic of China. I could have written just about anything, given the total lack of English skills. I wrote that my ancestors would be ashamed of me.

Back out on the street, we purchased bus tickets back to Kashgar for the following day. If the police accosted us, we could simply show the tickets as proof that we certainly planned to head north. Of course, we didn't. Around 4:00 in the morning, we exited the hotel. Unfortunately, there was a chain link fence surrounding the hotel, and we had to quietly bust open the gate to get out.

We wandered south for a couple hours before catching a truck heading into Tibet. That's another longggg story....

Some Video From Nepal

Below are a few clips from my aforementioned trek in Nepal. The scenery is fairly generic Himalayan trekking territory. The twist that might make these clips a tad different is the presence of my ebullient traveling partner Kanchana. Check her out as she takes over a Nepali kitchen, dances, gets exhausted, and generally absorbs Nepali culture with wide-open eyes.







I've got a total of nine such clips over on YouTube: http://www.youtube.com/user/ngongmahk .

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Kan left a bubbly impression on everyone in her path, with the exception of one Nepali guest-house owner who was stupid enough to incur her wrath by offering up his impressions of Thai prostitutes he encountered in Germany. Kan responded with a profanity-laced harangue which I enjoyed immensely as I downed my rakshi. It seems that his wife, lingering over the stove, savored the exchange as well....she certainly didn't attempt to intercede. Regretfully, there's no video.

My own approach, as usual, was more introspective. The mountains are amazingly beautiful, but the beauty only seems to register in nanosecond bursts. As soon as you start thinking "it's so amazing", it all begins dissipating. You call your compadres over to share the experience. You pull out the camera and seek out the most postcard-perfect angle possible. And if you actively refrain from pulling out the camera, the act of trying to hold onto the moment will probably kill it as well. It's a bit of a koan that I carry in these sorts of mind-blowing places.

When I first trekked in Nepal in 1987, I didn't even bring a camera. That's how strongly I strived to extend these moments. But then, there are family members and friends who would sincerely like to see what you've been up to. So the policy has changed.

Even now, though, you'll notice that I rarely point the camera on myself. That's not a case of camera-shyness. I just want to show a decent approximation of what I'm seeing and experiencing.

Some possibilities for novel mutation-checking mechanisms

Nature has set up a number of well-known mechanisms for keeping mutations in check. The first that comes to mind is the one by which mismatched base pairs are recognized, with the older, methylated strand serving as template. Despite these mechanisms, mutations do slip by at the rate of about 1/10^8 to 1/10^9 base pairs per generation¹ in the human population.

Stepping into the realm of science fiction, one can try to imagine improvements. One could imagine an organism utilizing triple-stranded DNA. If such an organism actually existed, mismatches would easily be recognized because only 1 of the 3 strands would contain an error. The two consensus strands would be assumed to be correct, and the error in the other would be repaired.

More realistically, one might imagine a system that somehow compares DNA strands in cases where a gene has two or more copies. If a mismatch is found, the cell might be directed to apoptose. Up until recently, the comparison of two strands seemed a bit fanciful. However, with "RNA interference" and "RNA activation", we know of mechanisms whereby two strands from disparate locations in the genome may be compared.

In the case of RNAi, an mRNA that pairs with a smaller RNA strand (miRNA or siRNA) may be degraded or otherwise "silenced" in the cytoplasm. An RNAi mechanism that seeks out slight mismatches (via a single base pair difference) and then instructs the cell to self-destruct or fail to thrive is unknown. Such a mechanism is not horribly fanciful...it is well-understood that perfectly matching targets, imperfectly matching targets, and non-matching targets can have different fates.

In the case of RNA activation (RNAa), however, we have a known mechanism by which strand comparison can occur...instead of silencing, two properly matched strands interact to promote translation². Mismatched strands result in poor translation, which may then hamper cell viability.

Should such an error checking system become established, what consequences might result? In addition to negative and neutral mutations, positive mutations would be minimized. On one hand, organisms inhibited from positive mutations will tend to be outcompeted over the long haul. On the other hand, genes love to be replicated with full fidelity. We have a battle, worthy of mathematical modeling, between the drive for fidelity and the need for improvement. Is it possible that the extinction of some species is being driven by such overactive strand-comparison systems? Conversely, rapidly evolving species might see a dearth of such mechanisms.

It has been documented that the deletion or alteration of some ultra-conserved DNA results in no obvious negative effects to the organism³. This seems odd, until one considers the possibility that the extraordinary persistence of such DNA may be due to an efficient strand-comparison system, not because it has any particular function, or because the existent version is tremendously better than any others. Such mechanisms do not benefit the organism and may be thought of as "ultra-selfish".

Determining whether ultraconserved sequences might be targets for "strand comparison" might be a tad tricky. When knockouts of ultraconserved sequences result in no apparent harm to the organism, strand comparison is a possibility. Computationally, in the relatively few cases where an miRNA targets an exon, one might expect that every third base pair in a reading frame would have a lower mutation rate than would be ordinarily expected. Conversely, sequences that are ultraconserved via the importance of various protein domains for which they code would tend to have a higher mutation rate in the third base pair.

Known cases of RNAi/a are restricted to relatively small strands of mature RNA (19-23 nt). Thus we have no means of ensuring the copy-fidelity of an entire gene via a single miRNA. There are cases, however, where multiple miRNAs target different areas of a gene.

In animals, miRNA's are often found in ultra-conserved introns⁴. This conservation may be explained as simply as follows: if a mutation forces a mismatch between the miRNA and its target, the germ cell fails to thrive. Note that the mutation may actually be beneficial, but is eliminated. Again, this points to the possibility of "ultra-selfish" RNAi/a.

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Another sort of hypothetical mutation-detection system might involve tying sperm function to proteins that are used in other tissues. Imagine, for example, that a protein necessary for brain function is also necessary for sperm motility. The brain disfunction associated with this mutation is never seen because sperm carrying this mutation never reach their destination.

Proteins that have important functions in a wide variety of tissues might not be under pressure to be tied into sperm function. Why? Because even if the sperm reaches its destination with these lethal mutations, the embryo will not be viable. Little parental investment has been lost. On the other hand, genes whose effects might only manifest later in development might be candidates for "sperm function pleiotropy".

Genes tied to brain function, then, would seem to be likely candidates for this sperm function linkage. A good deal of parental investment may have been incurred by the time it is understood that a child is mentally handicapped to the extent that his/her chances for reproductive success are strongly diminished. It's interesting to note that some computational studies have shown a high overlap between brain mRNA and testis mRNA⁵.

Other studies have not shown a strong brain mRNA/testis mRNA overlap. My own perusal of gene expression data leads me to believe that "sperm function linkage" occurs only to a limited extent. Some of the inferred overlaps between testis and brain expression may be more related to the fact that neither tissue is particularly secretory, and both tissues maintain degrees of immune privilege and blood barriers. In other words, many of the observed similarities may be more a matter of what isn't expressed, than what is. Good candidates for "sperm function linkage" might be transcription factors, which needn't be expressed in large quantities, or miRNA's, for which no public tissue-specific data seems to be available at the moment.

One might object that males are typically profligate with sperm, and would not be under any additional evolutionary pressure to screen out, say, DNA that carries a brain-development mutation. This is, however, only true to the extent that the male of the species does not invest in the child's upbringing.

The linkage between sperm function needn't only relate to, say, the construction of flagellum. It could also involve all sorts of proteins involved in spermatogenesis. In fact, we only need to overlap one important early function with a later developmental function to reduce the likelihood that a mutation would be preserved in further generations . Here, we have a pressure that would tend to favor reuse of proteins, rather than the creation of novel ones. Sperm would be under particular pressure to adopt these overlaps because we here have a mechanism whereby mutations are eliminated before any parental investment.

Some candidates for "sperm function linkage":

206581_at: basonuclin
209443_at: serine (or cysteine) proteinase inhibitor, clade A (alpha-1 antiproteinase, antitrypsin), member 5
220744_s_at: WD repeat domain 10
207144_s_at: Cbp/p300-interacting transactivator, with Glu/Asp-rich carboxy-terminal domain, 1
220110_s_at: nuclear RNA export factor 3
214183_s_at: transketolase-like 1
206310_at: serine protease inhibitor, Kazal type 2 (acrosin-trypsin inhibitor)

The extent to which sperm cells are subject to apoptosis is notable, with apoptosis sometimes occuring in "waves"⁶. The most common explanation of this phenomenon is that the apoptosis maintains a crucial ratio of Sertoli cells and pre-meiotic germ cells, but the issue is far from settled⁷. Of the 50 genes under strongest positive selection in the human genome, a good number code for sperm functions"⁸. Could some sort of "weeding out" process be involved here? With somatic cells, mutations can be masked via diploidy. Conveniently, this isn't the case with spermatids, which are haploid. The task of mutation-checking is thus simplified.

Note that, unlike the "strand comparison" system surmised above, beneficial mutations aren't necessarily entirely eliminated in sperm-function linkage. However, it is known that testis-specific mouse genes do evolve quite a bit more rapidly than testis genes that are also expressed elsewhere⁹. In other words, these genes may have more freedom to mutate because of the absence of pleiotropy.

The overlapping proteins might have structural importance for sperm function, but they might also simply activate other enzymes in a chain. Oddly, in sperm function linkage, we have a mechanism by which evolution may favor a degree of complexity that would otherwise seem unnecessary. Complexity is favored because the individual enzymes in a long chain are "tested" along the way. Here, some proteins or substrates necessary for sperm function are only produced through Rube Goldberg contraptions. However, the gun that's fired as part of a ludicrously long chain of events that results in the garage door being opened is perfectly useful when you want to shoot a thief. Including the gun in the Goldberg device means that it's likely to function correctly when you need it.



As a side note, it's interesting that "intelligent design" proponents are fond of citing cilia as an example of the sort of assembly that couldn't possibly be a result of natural selection. In addition to the usual, powerful arguments against this position, I'd argue for the possibility that evolution is doing its damnedest to make the process of creating functional sperm as ridiculously complex as possible.

One PLOS paper details a study of pleiotropy in C. Elegans, finding that 50% of genes involved in embryogenesis are pleiotropic. What's more, these genes tend to occupy central (rather than initial or final) positions in protein pathways¹⁰. Pleiotropy, when viewed in the light of evolution, is usually discussed as a constraining factor. That is, a single mutation may be beneficial or neutral in one tissue, but harmful in another, increasing the likelihood that pleiotropic gene mutations would be selected against. The effect of pleiotropy needn't always be one of constraint, however. For example, in the case of parsimonious pleiotropy¹¹, "knowing" that a mutation that fails to harm sperm is also unlikely to harm the brain, the sperm may relax strict mutation checking controls a tad. Note that evolutionary pressures favoring pleiotropy tend to negate the popular notion of "modularity" in gene expression.

1. Rates of spontaneous mutation: http://www.genetics.org/cgi/content/full/148/4/1667

2. RNAa: Small dsRNAs induce transcriptional activation in human cells http://www.pnas.org/cgi/content/abstract/0607015103v1

3. More than 1 mb of non-coding DNA, much of it conserved between mice and humans, knocked-out: http://repositories.cdlib.org/cgi/viewcontent.cgi?article=3767&context=lbnl

4. Ultraconserved elements in insect genomes: A highly conserved intronic sequence implicated in the control of homothorax mRNA splicing. http://www.genome.org/cgi/content/full/15/6/800

5. In silico analysis indicates a similar gene expression pattern between human brain and testis: http://content.karger.com/ProdukteDB/produkte.asp?doi=10.1159/000076290

6. An early and massive wave of germinal cell apoptosis is required for the development of functional spermatogenesis. http://www.nature.com/emboj/journal/v16/n9/abs/7590214a.html

7. Involvement of apoptosis in the control of Sertoli and pre-meiotic germ cell numbers in the developing rabbit testis. http://www.blackwell-synergy.com/doi/abs/10.1046/j.1439-0272.2002.00464.x?cookieSet=1&journalCode=and

8. A Scan for Positively Selected Genes in the Genomes of Humans and Chimpanzees. http://biology.plosjournals.org/perlserv/?request=get-document&doi=10.1371/journal.pbio.0030170#JOURNAL-PBIO-0030170-B33

9. Rates of Protein Evolution Are Positively Correlated with Developmental Timing of Expression During Mouse Spermatogenesis http://mbe.oxfordjournals.org/cgi/content/full/22/4/1044

10. Systematic Analysis of Pleiotropy in C. elegans Early Embryogenesis. http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1000003

11. Seven types of pleiotropy. http://www.ijdb.ehu.es/web/paper.php?doi=9654038