Higher order thinking

The one thing you must read today is David Dobbs’ Die, Selfish Gene, Die. It’s good to see genetic accommodation getting more attention, but I’m already seeing pushback from people who don’t quite get the concept, and think it’s some kind of Lamarckian heresy.

It’s maybe a bit much to ask that the gene-centric view of evolution die; it’s still useful. By comparison, for instance, it’s a bit like Mendel and modern genetics (I’ll avoid the overworked comparison of Newton and Einstein.) You need to understand simple Mendelian genetics — it gives you a foundation in the logic of inheritance, and teaches you a few basic rules. But once you start looking at real patterns of inheritance of most traits, you discover that it doesn’t work. Very few traits work as Mendel described, and one serious concern is that we tend to select for genes to study that behave in comprehensible ways.

And every geneticist knows this. Mendel was shown to have got some things wrong within a decade of his rediscovery: Mendel’s Law of Independent Assortment, for instance, simply does not hold for linked genes, and further, linkage turns out to hold important evolutionary implications. But I still teach about independent assortment in my genetics course. Why? Because you need to understand how to interpret deviations from the simple rules; it’s an “a-ha!” moment when you comprehend how Morgan and Sturtevant saw the significance of departures from Mendel’s laws.

Most of genetics seems to be about laying a foundation, and then breaking it to take a step beyond. Teaching it is a kind of torture, where you keep pushing the students to master some basic idea, and then once they’ve got it, you test them by showing them all the exceptions, and then announcing, “But hey! Here’s this cool explanation that tells you what you know is wrong, but there’s some really great and powerful ideas beyond that.”

That’s what’s fun about genetics: compounding a series of revelations until the students’ brains break, usually right around the end of the term. Over the years I’ve learned, too. Undergraduate genetics students usually collapse in defeat once I introduce epistatic interactions — the idea that the phenotype produced by an allele at one locus is dependent on the alleles present at other loci — but it’s always great to see the few students who fully grasp the idea and see how powerful it is (future developmental biologists identified!).

And that’s how I see the gene-centric view: absolutely essential. You must understand Mendel, and Fisher, and Wright, and Hamilton, and Williams, and once you’ve mastered that toolkit, you can start looking at the real world and seeing all the cases where it’s deficient, and develop new tools that let you see deeper. The new idea that Dobb’s describes, and that is actually fairly popular with many developmental biologists, is that phenotype comes first: that organisms are fairly plastic in response to the environment in ways that can’t be simplified to pure genetic determinism, and that the genes lag behind, acting to consolidate and make more robust adaptive responses.

I’ve written about genetic assimilation/accommodation before, and have given one lovely example of phenotypic change occurring faster than the generation of new mutants can explain. It’s always baffled me about the response to those ideas: most people resist, and try to reduce them to good old familiar genes. It’s a bit like watching students wrestle with epistatic modulation of gene expression when all they understand is Mendel, and rather than try to grasp a different way of looking at the problem, they instead invent clouds of simple Mendelian factors that bring in multi-step discrete variations. They can make the evidence fit the theory — just add more epicycles!

I’m seeing the same responses to Dobbs’ article — it’s still all just genes at the bottom of it, ain’t it? Oh, sure, but the interesting parts are the interactions, not the subunits. We need to take the next step and build tools to study networks of genes, rather than reducing everything to the genes themselves.

A rather remarkable deficiency

There’s a much ballyhooed article from Science going around that promotes the surprising conclusion that dogs were first domesticated in Europe. Dan Graur points out that there is one little problem with the data:

The take home message of the Thalmann et al. paper is simple: Dogs were not domesticated in the Middle East or China as previously claimed; they were domesticated in Europe. Let me repeat the main result of this paper: Dogs were domesticated in Europe; previous claims on the domestication of dogs in the Middle East or China are wrong and have been refuted.

Interestingly, on page 873, it is written:

“Notably, our ancient panel does not contain specimens from the Middle East or China, two proposed centers of origin (5, 6).”

So, the origin of dogs was moved from the Middle East or China to Europe by the simple expedient of omitting any sample from the Middle East or China.

Well, the paper does have the primary prerequisites for getting published in Science: superficially sexy data sets, involving a familiar large and photogenic animal, an unexpected result, with a high probability of drawing the attention of the mass media. That’s what we mean by “significant research,” right?

Say, isn’t that also the formula for a TED talk?

Remedial reading for big-time scienticians

I don’t understand how this happens. You’ve got a good academic position. You’re bringing in reasonable amounts of grant money. You’re publishing in Nature Genetics and Nature Structural and Molecular Biology. And you don’t even understand the basic concepts in your field of study.

For instance, here’s a press release titled “Cause of genetic disorder found in 'dark matter' of DNA”.

For the first time, scientists have used new technology which analyses the whole genome to find the cause of a genetic disease in what was previously referred to as "junk DNA". Pancreatic agenesis results in babies being born without a pancreas, leaving them with a lifetime of diabetes and problems digesting food. In a breakthrough for genetic research, teams led by the University of Exeter Medical School and Imperial College London found that the condition is most commonly caused by mutations in a newly identified gene regulatory element in a remote part of the genome, which can now be explored thanks to advances in genetic sequencing.

Regulatory elements are not and have never been considered junk DNA. The researchers have identified a regulatory region called PTF1A that has allelic variations that cause a failure of the pancreas to form. That’s really interesting! But then you read what they have to say about it, and they are completely oblivious to the literature on genetic structure and gene regulation. Isn’t that something you’d expect them to have studied thoroughly before even proposing this project?

Or how about this press release, “Un-junking junk DNA”. It’s gotten to the point where I just cringe when I see the phrase “junk DNA” in a press release, because it is a sure sign of flamboyant ignorance to come.

"This study provides answers for a decade-old question in biology," explained principal investigator Gene Yeo, PhD, assistant professor of Cellular and Molecular Medicine, member of the Stem Cell Research Program and Institute for Genomic Medicine at UC San Diego, as well as with National University of Singapore. "When the sequence of the human genome was fully assembled, under a decade ago, we learned that less than 3 percent of the entire genome contains information that encodes for proteins. This posed a difficult problem for genome scientists – what is the other 97 percent doing?"

The role of the rest of the genome was largely a mystery and was thus referred to as "junk DNA." Since then sequencing of other, non-human, genomes has allowed scientists to delineate the sequences in the genome that are remarkably preserved across hundreds of millions of years of evolution. It is widely accepted that this evidence of evolutionary constraint implies that, even without coding for protein, certain segments of the genome are vital for life and development.

So many misconceptions. No, noncoding DNA is not synonymous with junk DNA; junk DNA was not so called because its function was mysterious; it is absolutely no surprise that some regions of the genome are vital, even without coding for proteins — haven’t they heard of tRNA or miRNA? Developmental biologists have been yapping for decades about the importance of the switches that control gene regulation…are we just ignored?

I worry that this is a symptom of a serious rot in science education — that we’re turning out great technicians and masters of the arcane art of grant writing who don’t actually understand biology, and in particular have no perspective on what the questions actually are. They may be excellent middle managers, but the comprehension and vision are lacking.

I have a suggestion. If you’re going to do research that leads you to say anything about junk DNA, I urge you to read carefully one or all of the following books: The Origins of Genome Architecture by Michael Lynch; Fundamentals of Molecular Evolution by Dan Graur and Wen-Hsiung Li; or The Logic of Chance: The Nature and Origin of Biological Evolution by Eugene Koonin. Those aren’t lightweight texts — I wouldn’t assign them to your average undergraduate — but hey, you’re a big-time professional scientist. There’s no excuse for not knowing this stuff.

How to make a funny-looking mouse

I’m going to tell you about a paper that was brought to my attention by some poor science journalism, so first I have to complain about the article in the Guardian. Bear with me.

This is dreadfully misleading.

Though everybody’s face is unique, the actual differences are relatively subtle. What distinguishes us is the exact size and position of things like the nose, forehead or lips. Scientists know that our DNA contains instructions on how to build our faces, but until now they have not known exactly how it accomplishes this.

Nope, we still don’t know. What he’s discussing is a paper that demonstrates that certain regulatory elements subtly influence the morphology of the face; it’s an initial step towards recognizing some of the components of the genome that contribute towards facial architecture, but no, we don’t know how DNA defines our morphology.

But this is disgraceful:

Visel’s team was particularly interested in the portion of the genome that does not encode for proteins – until recently nicknamed “junk” DNA – but which comprises around 98% of our genomes. In experiments using embryonic tissue from mice, where the structures that make up the face are in active development, Visel’s team identified more than 4,300 regions of the genome that regulate the behaviour of the specific genes that code for facial features.

These “transcriptional enhancers” tweak the function of hundreds of genes involved in building a face. Some of them switch genes on or off in different parts of the face, others work together to create, for example, the different proportions of a skull, the length of the nose or how much bone there is around the eyes.

NO! Bad journalist, bad, bad. Go sit in a corner and read some Koonin until you’ve figured this out.

Junk DNA is not defined as the part of the genome that does not encode for proteins. There is more regulatory, functional sequence in the genome that is non-coding than there is coding DNA, and that has never been called junk DNA. Look at the terminology used: “transcriptional enhancers”. That is a label for certain kinds of known regulatory elements, and discovering that there are sequences that modulate the expression of coding genes is not new, not interesting, and certainly does not remove anything from the category of junk DNA.

Alok Jha, hang your head in shame. You’re going to be favorably cited by the creationists soon.

But that said, the paper itself is very interesting. I should mention that nowhere in the text does it say anything about junk DNA — I suspect that the authors actually know what that is, unlike Jha.

What they did was use ChIP-seq, a technique for identifying regions of DNA that are bound by transcription factors, to identify areas of the genome that are actively bound by a protein called the P300 coactivator — which is known to be expressed in the developing facial region of the mouse. What they found is over 4000 scattered spots in the DNA that are recognized by a transcription factor. A smaller subset of these 4000 were analyzed for their sequential pattern of activation, and three of these potential modulators of face shape were selected for knock out experiments, in which the enhancer was completely deleted.

The genes these enhancers modulate were known to be important for facial development — knocking them out creates gross deformities of the head and face. Modifying the enhancers only leaves the actual genes intact, so you wouldn’t expect as extreme an effect.

One way to think of it is that there are genes that specify how to make an ear, for instance. So when these genes are switched on, they initiate a developmental program that builds an ear. The enhancers, though, tweak it. They ask, “How big? How high? Round or pointy? Floppy or firm?” So when you go in and randomly change the enhancers, you’d expect you’d still get an ear, but it might be subtly shifted in shape or position from the unmodified mouse ear.

And that’s exactly what they saw. The mice carrying deletions had subtle variations in skull shape as a consequence. In the figures below, all those mouse skulls might initially look completely identical, because you aren’t used to making fine judgments about mousey appearance. Stare at ‘em a while, though, and you might begin to pick up on the small shifts in dimensions, shifts that are measurable and quantifiable and can be plotted in a chart.


This is as expected — tweaking enhancers (which are not, I repeat, junk DNA) leads to slight variations in morphology — you get funny-looking mice, not monstrous-looking mice. Although I shouldn’t judge, maybe these particular shifts create the Brad Pitt of mousedom. That’s also why I say that implying that we now know exactly how DNA accomplishes its job of shaping the face is far from true: Attanasio and colleagues have identified a few genetic factors that have effects on craniofacial shaping, but not all, and most definitely they aren’t even close to working out all the potential interactions between different enhancers. You won’t be taking your zygotes down to the local DNA chop shop for prenatal genetic face sculpting for a long, long time yet, if ever.

Attanasio C, Nord AS, Zhu Y, Blow MJ, Li Z, Liberton DK, Morrison H, Plajzer-Frick I, Holt A, Hosseini R, Phouanenavong S, Akiyama JA, Shoukry M, Afzal V, Rubin EM, FitzPatrick DR, Ren B, Hallgrímsson B, Pennacchio LA, Visel A. (2013) Fine tuning of craniofacial morphology by distant-acting enhancers. Science 342(6157):1241006. doi: 10.1126/science.1241006.

microRNAs and cancer

I’m trying to raise money for the The Leukemia & Lymphoma Society, and I promised to do a few things if we reached certain goals. I said I’d write a post microRNAs and cancer if you raised $7500. And you did, so I did. I kept my clothes on this time, though, so here’s a more serious picture of yours truly: this is what my students see, which is slightly less terrifying, nicht wahr?


If you want more, go to my Light the Night fundraising page and throw money at it. If we reach our goal of $10,000, I’ll organize a Google+ Hangout to talk about cancer. Note that we’re also getting matching funds from the Todd Stiefel Foundation, so join in, it’s a good deal.

It’s all epigenetics. Now I’ve gone and done it: I’ve used the “e” word, epigenetics. Nothing seems to fire off well-meaning misconceptions from otherwise sensible pro-science folks than epigenetics — it’s a major new revolution in evolution! It changes everything! It’s a way to get inheritance of acquired characteristics!


Epigenetics is routine and has been taken for granted by cell biologists for at least 6 decades. It is simply a principle of gene regulation — switching genes off and on — that persists over multiple cell generations. You aren’t surprised that when liver cells divide, they produce more liver cells, are you? They’ve simply inherited transcription factors and patterns of modification of DNA from their parent cell that restricts their cell fates. There are also patterns of gene expression induced in gametes within parents that modulate initial patterns of gene expression in the fertilized zygote — that is, the state of the parental cells affects the state of the embryo’s cells — which is exactly what you’d expect.

What seems to set people off is that it is an effect of the environment on the state of the genome, and there is this bizarre bias floating around that that can’t happen. Of course it can! Every summer when you get a tan, every winter when you put on another five pounds, every time stress at work makes you prone to get sick…those are environmental factors influencing your biology.

In previous installments of this series, I told you about oncogenes, genes that when over-expressed or over-active switch on cellular processes (like proliferation) that promote cancer, and tumor suppressor genes, which protect against cancer, and which in cancers, are often found to be inactivated or down-regulated. Over-expressed? Down-regulated? That sounds like the sorts of things epigenetic changes can do.


Further, here’s an interesting observation. Everyone knows the standard pathway: genes in DNA are transcribed into RNA which is then translated into protein. One might naively imagine, then, that the amount of RNA produced would be roughly correlated with the amount of protein produced. It’s not. In analyses of cancers, only 20% of the mRNAs involved showed any correlation between the quantity of mRNA and the quantity of protein — there is something else that is modulating either the amount of translation or the turnover of proteins in the cell, and the fact that 80% of the genes playing a role in cancer show such variation tells us that these kinds of regulatory effects are important.

There must be something stepping in and interfering somewhere between transcription of the gene into messenger RNA, and translation of messenger RNA into protein. One of the somethings is microRNA.

These are tiny little snippets of RNA, typically 22 nucleotides long, that have complementary sequences to their target gene mRNA — they bind to matching RNAs and inhibit translation. Thousands of these microRNAs have been discovered in the last few years, and they’ve also been found to play important roles in regulating gene expression in blood cell lineages, brain activity, insulin secretion, and fat cell development…and in cancer.

As you might guess from the previous articles in this series, there are obvious ways microRNAs could promote cancers. A microRNA that blocks tumor suppressor genes from being expressed could be modified to be produced at a higher level, or a microRNA that would hamper an oncogene’s activity could be mutated to be unable to recognize its target. Easy! Simple! Well, except that this is biology, and nothing is simple in biology (trust me, if you don’t enjoy problems blowing up in your face and getting harder and harder, don’t become a biologist.)

One reason this is complicated is that there are so many details to be worked out — swarms of microRNAs are involved, we don’t know the majority of them, and we don’t know what we’ll learn as we discover more. As Weinberg says,

…the discovery of hundreds of distinct regulatory microRNAs has already led to profound changes in our under- standing of the genetic control mechanisms that operate in health and disease. By now dozens of microRNAs have been implicated in various tumor phenotypes, and yet these only scratch the surface of the real complexity, as the functions of hundreds of microRNAs known to be present in our cells and altered in expression in different forms of cancer remain total mysteries. Here again, we are unclear as to whether future progress will cause fundamental shifts in our understanding of the pathogenetic mechanisms of cancer or only add detail to the elaborate regulatory circuits that have already been mapped out.

But also, we’ve learned that it’s not simply a matter of a few short bits of RNA getting transcribed and dumped into the cytoplasm — there is a whole elaborate cellular apparatus dedicated to microRNA processing. Behold!


Don’t panic, I’ll hold your hand and we’ll walk through it. miRNA genes are first transcribed into RNA by RNA polymerase II; notice that the transcript, which is called a pri-miRNA (or primary microRNA) contains some long stretches of internal complementarity, and that the RNA folds into a hairpin loop. This RNA is grabbed by an RNA binding protein, Pasha, and an RNA cutting enzyme, Drosha, which snips off some excess bits to produce a smaller stem-loop structure about 70 nucleotides long, which is partially double stranded RNA. It also gets a new name: Pre-miRNA. Pre-miRNA is then exported out of the nucleus and into the cytoplasm by a channel protein, Exportin-5.

Once in the cytoplasm, another RNA cutting enzyme, aptly named Dicer, snips off a few more bits to reduce it to two very roughly complementary RNA strands, now called the miRNA:miRNA* duplex. One of these strands is then loaded into a set of proteins to form the miRNA-associated multiprotein RNA-induced silencing complex, thankfully called miRISC for short.

The short, 22-nucleotide long strand of RNA in the miRISC is what gives it specificity — the miRISC proteins carry it along as a template to match against messenger RNAs they encounter. If the miRNA makes a perfect match to some unfortunate strand of messenger RNA, the miRISC cuts up the mRNA to destroy it. If it’s an imperfect match over just some significant fraction of the 22-nucleotide sequence, it it just locks up the RNA and represses its translation.

The way these can affect cancer is illustrated below. If a microRNA that inhibits an oncogene is mutated (b), that oncogene will increase the amount of protein produced from the available RNA; the oncogene could even be normal in sequence and function, and just the boost in its signal could contribute to tumorigenesis. Alternatively, a mutation in a microRNA gene that affects a tumor suppressor could amplify its production (c), producing a greater inhibition of a healthy gene that acts to prevent tumorigenesis.

MicroRNAs can function as tumour suppressors and oncogenes. a | In normal tissues, proper microRNA (miRNA) transcription, processing and binding to complementary sequences on the target mRNA results in the repression of target-gene expression through a block in protein translation or altered mRNA stability (not shown). The overall result is normal rates of cellular growth, proliferation, differentiation and cell death. b | The reduction or deletion of a miRNA that functions as a tumour suppressor leads to tumour formation. A reduction in or elimination of mature miRNA levels can occur because of defects at any stage of miRNA biogenesis (indicated by question marks) and ultimately leads to the inappropriate expression of the miRNA-target oncoprotein (purple squares). The overall outcome might involve increased proliferation, invasiveness or angiogenesis, decreased levels of apoptosis, or undifferentiated or de-differentiated tissue, ultimately leading to tumour formation. c | The amplification or overexpression of a miRNA that has an oncogenic role would also result in tumour formation. In this situation, increased amounts of a miRNA, which might be produced at inappropriate times or in the wrong tissues, would eliminate the expression of a miRNA-target tumour-suppressor gene (pink) and lead to cancer progression. Increased levels of mature miRNA might occur because of amplification of the miRNA gene, a constitutively active promoter, increased efficiency in miRNA processing or increased stability of the miRNA (indicated by question marks). ORF, open reading frame.

MicroRNAs can function as tumour suppressors and oncogenes. a | In normal tissues, proper microRNA (miRNA) transcription, processing and binding to complementary sequences on the target mRNA results in the repression of target-gene expression through a block in protein translation or altered mRNA stability (not shown). The overall result is normal rates of cellular growth, proliferation, differentiation and cell death. b | The reduction or deletion of a miRNA that functions as a tumour suppressor leads to tumour formation. A reduction in or elimination of mature miRNA levels can occur because of defects at any stage of miRNA biogenesis (indicated by question marks) and ultimately leads to the inappropriate expression of the miRNA-target oncoprotein (purple squares). The overall outcome might involve increased proliferation, invasiveness or angiogenesis, decreased levels of apoptosis, or undifferentiated or de-differentiated tissue, ultimately leading to tumour formation. c | The amplification or overexpression of a miRNA that has an oncogenic role would also result in tumour formation. In this situation, increased amounts of a miRNA, which might be produced at inappropriate times or in the wrong tissues, would eliminate the expression of a miRNA-target tumour-suppressor gene (pink) and lead to cancer progression. Increased levels of mature miRNA might occur because of amplification of the miRNA gene, a constitutively active promoter, increased efficiency in miRNA processing or increased stability of the miRNA (indicated by question marks). ORF, open reading frame.

This is not simply a hypothetical possibility, either. Dozens of miRNA genes have been implicated in human cancers — they show abnormal variations in expression in specific cancers and also have known oncogene/tumor suppressor targets.


These microRNAs are a relatively new scientific phenomenon — they weren’t even a blip on the radar when I was a graduate student, and when I did start hearing about them in the 1990s, they were thought of as a weird mechanism found in highly derived nematodes. Now we’re seeing them everywhere, and beginning to recognize their importance in controlling all kinds of genes. The process of developing tools to control miRNAs is underway in the laboratory, but it has a long way to go before we have effective clinical tools to combat cancer with miRNAs or antagonists to miRNAs. At the very least, it’ll be another tool we can use.

Calin GA, Croce CM (2006) MicroRNA-cancer connection: the beginning of a new tale. Cancer Res. 66(15):7390-4.

Esquela-Kerscher A, Slack FJ (2006) Oncomirs – microRNAs with a role in cancer. Nat Rev Cancer 6(4):259-69.

Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144(5):646-74.

This cat is going to be insufferable

You may have heard we’ve got this satanic feline padding about the house now, getting into mischief — she has discovered my collection of cephalopodiana, and her favorite toy is one of my stuffed octopuses that she wrestles and bats around the floor. It’s like she’s rubbing it in.

Anyway, a new paper in Nature Communications describes a comparative analysis of the genomes of tigers, lions, snow leopards, and…housecats. I’m not letting her read it, lest she acquire delusions of grandeur (oh, wait, she’s a cat — she already has that.)

There’s nothing too surprising in the data; as usual, we discover that mammals (well, animals, actually) have a solid core of shared genes and the divergence between species is accounted for by changes in a small number of genes. They also exhibit a high degree of synteny — the arrangement of genes on chromosomes are similar.

(a) Orthologous gene clusters in mammalian species. The Venn diagram shows the number of unique and shared gene families among seven mammalian genomes. (b) Gene expansion or contraction in the tiger genome. Numbers designate the number of gene families that have expanded (green, +) and contracted (red, −) after the split from the common ancestor. The most recent common ancestor (MRCA) has 17,841 gene families. The time lines indicate divergence times among the species.

(a) Orthologous gene clusters in mammalian species. The Venn diagram shows the number of unique and shared gene families among seven mammalian genomes. (b) Gene expansion or contraction in the tiger genome. Numbers designate the number of gene families that have expanded (green, +) and contracted (red, −) after the split from the common ancestor. The most recent common ancestor (MRCA) has 17,841 gene families. The time lines indicate divergence times among the species.

But note the cladogram on the right, and this bit of information we must keep from the cats.

The tiger genome sequence shows 95.6% similarity to the domestic cat from which it diverged approximately 10.8 million years ago (MYA); human and gorilla have 94.8% similarity and diverged around 8.8 MYA.

The difference between a housecat and a tiger is a mere ten million years. If only they knew…

I plan to allow this cat to continue to play with my cephalopods. Distraction, you know.

Cho YS, Hu L, Hou H, Lee H, Xu J, Kwon S, Oh S, Kim H-M, Jho S, Kim S, Shin Y-A,Kim BC, Kim H, Kim C-u, Luo SJ, Johnson WE,Koepfli K-P, Schmidt-Küntzel A, Turner JA, Marker L et al. (2013) The tiger genome and comparative analysis with lion and snow leopard genomes. Nature Communications 4, Article number: 2433 doi:10.1038/ncomms3433

Magic RNA editing!

One of those wacky Intelligent Design creationists (Jonathan McLatchie, an arrogant ignoramus I’ve actually met in Scotland) has a theory, which is his, to get around that obnoxious problem of pseudogenes. Pseudogenes are relics, broken copies of genes that litter the genome, and when you’ve got a gang of ideologues who are morally committed to the idea that every scrap of the genome is designed and functional, they put an obvious crimp in their claims.

So here’s this shattered gene littered with stop codons and with whole exons deleted and gone; how are you gonna call that “functional”, creationist? McLatchie’s solution: declare that it must still be functional, it’s just edited back into functionality. He uses the example of GULOP, a gene responsible for vitamin C synthesis, which is pretty much wrecked in us. Nonfunctional. Missing big bits. Scrambled. With missing regulatory elements, so it isn’t even transcribed. No problem: it’s just edited.

As I mentioned previously, the GULO gene in humans is rendered inactive by multiple stop codons and indel mutations. These prevent the mRNA transcript of the gene from being translated into a functional protein. If the GULO gene really is functional in utero, therefore, presumably it would require that the gene’s mRNA transcript undergo editing so that it can produce a functional protein. It’s not at all difficult to understand how this could occur.

Yes, RNA editing is a real thing. RNA does get processed before it’s translated into protein. McLatchie has a teeny-tiny bit of knowledge and is abusing it flagrantly.

I’ve hammered out dents in a car, and I’ve touched up rust spots with a little steel wool and a can of spray paint. My father was also an auto mechanic and could do wonders with a wrench. Auto repair exists, therefore…


…patching up that vehicle should be no problem at all, right? I expect to see it cruisin’ down the highway any time now.

Maybe two cans of spray paint this time…?

Short, sharp summary

Larry Moran has a simple list of the 5 basics you need to understand about junk DNA. It’s short and sweet; I’d like to see a creationist, who are often weirdly antagonistic to the whole idea of junk DNA, deal with these basic facts before they start ranting against the observations and conclusions.

  1. Genetic Load

    Every newborn human baby has about 100 mutations not found in either parent. If most of our genome contained functional sequence information, then this would be an intolerable genetic load. Only a small percentage of our genome can contain important sequence information suggesting strongly that most of our genome is junk.

  2. C-Value Paradox

    A comparison of genomes from closely related species shows that genome size can vary by a factor of ten or more. The only reasonable explanation is that most of the DNA in the larger genomes is junk.

  3. Modern Evolutionary Theory

    Nothing in biology makes sense except in the light of population genetics. The modern understanding of evolution is perfectly consistent with the presence of large amounts of junk DNA in a genome.

  4. Pseudogenes and broken genes are junk

    More than half of our genomes consists of pseudogenes, including broken transposons and bits and pieces of transposons. A few may have secondarily acquired a function but, to a first approximation, broken genes are junk.

  5. Most of the genome is not conserved

    Most of the DNA sequences in large genomes is not conserved. These sequences diverge at a rate consistent with fixation of neutral alleles by random genetic drift. This strongly suggests that it does not have a function although one can’t rule out some unknown function that doesn’t depend on sequence.

I’m also relieved to see that the anti-junk fanatics tend to gravitate towards Larry’s blog and leave the rest of us mostly alone.

The MFAP Hypothesis for the origins of Homo sapiens

I know you’re thinking we’ve had more than enough discussion of one simplistic umbrella hypothesis for the origin of unique human traits — the aquatic ape hypothesis — and it’s cruel of me to introduce another, but who knows, maybe the proponents of each will collide and mutually annihilate each other, and then we’ll all be happy. Besides, this new idea is hilarious. I’m calling it the MFAP hypothesis of human origins, which the original author probably wouldn’t care for (for reasons that will become clear in a moment), but I think it’s very accurate.

A list of traits distinguishing humans from other primates
Naked skin (sparse pelage)
Panniculus adiposus (layer of subcutaneous fat)
Panniculus carnosus only in face and neck
In “hairy skin” region:
 - Thick epidermis
 - Crisscrossing congenital lines on epidermis
 - Patterned epidermal-dermal junction
Large content of elastic fiber in skin
Thermoregulatory sweating
Richly vascularized dermis
Normal host for the human flea (Pulex irritans)
Dermal melanocytes absent
Melanocytes present in matrix of hair follicle
Epidermal lipids contain triglycerides and free fatty acids

Lightly pigmented eyes common
Protruding, cartilaginous mucous nose
Narrow eye opening
Short, thick upper lip
Philtrum/cleft lip
Glabrous mucous membrane bordering lips
Heavy eyelashes

Short, dorsal spines on first six cervical vertebrae
Seventh cervical vertebrae:
– long dorsal spine
– transverse foramens
Fewer floating and more non-floating ribs
More lumbar vertebrae
Fewer sacral vertebrae
More coccygeal vertebrae (long “tail bone”)
Centralized spine
Short pelvis relative to body length
Sides of pelvis turn forward
Sharp lumbo-sacral promontory
Massive gluteal muscles
Curved sacrum with short dorsal spines
Hind limbs longer than forelimbs
– Condyles equal in size
– Knock-kneed
– Elliptical condyles
– Deep intercondylar notch at lower end of femur
– Deep patellar groove with high lateral lip
– Crescent-shaped lateral meniscus with two tibial insertions
Short malleolus medialis
Talus suited strictly for extension and flexion of the foot
Long calcaneus relative to foot (metatarsal) length
Short digits (relative to chimpanzee)
Terminal phalanges blunt (ungual tuberosities)
Narrow pelvic outlet

Diverticulum at cardiac end of stomach
Valves of Kerkring present in small intestines
Mesenteric arterial arcades
Multipyramidal kidneys
Heart auricles level
Tricuspid valve of heart
Laryngeal sacs absent
Vocal ligaments
Prostate encircles urethra
Bulbo-urethral glands present
Os penis (baculum) absent.
Absence of periodic sexual swellings in female
Ischial callosities absent
Nipples low on chest
Bicornuate uterus (occasionally present in humans)
Labia majora

Brain lobes: frontal and temporal prominent
Thermoregulatory venous plexuses
Well-developed system of emissary veins
Enlarged nasal bones
Divergent eyes (interior of orbit visible from side)
Styloid process
Large occipital condyles
Primitive premolar
Large, blunt-cusped (bunodont) molars
Thick tooth enamel
Helical chewing

Nocturnal activity
Particular about place of defecation
Good swimmer, no fear of water
Extended male copulation time
Female orgasm
Short menstrual cycle
Terrestrialism (Non-arboreal)
Able to exploit a wide range of environments and foods

Heart attack
Cancer (melanoma)

First, the author of this new hypothesis provides a convenient list of all the unique traits that distinguish humans from other primates, listed on the right. It falsely lists a number of traits that are completely non-unique (such as female orgasm and cancer), or are bizarre and irrelevant (“snuggling”, really?). It’s clearly a selective and distorted list made by someone with an agenda, so even though some items on the list are actually unusual traits, the list itself is a very poor bit of data.

But set those objections to the list aside for a moment, and let’s consider the hypothesis proposed to explain their existence, the MFAP Hypothesis of Eugene McCarthy, geneticist. I will allow him to speak for himself at length; basically, though, he proposes that the way novel traits appear in evolution is by hybridization, by crosses between two different species to produce a third with unique properties.

Many characteristics that clearly distinguish humans from chimps have been noted by various authorities over the years. The task of preliminarily identifying a likely pair of parents, then, is straightforward: Make a list of all such characteristics and then see if it describes a particular animal. One fact, however, suggests the need for an open mind: as it turns out, many features that distinguish humans from chimpanzees also distinguish them from all other primates. Features found in human beings, but not in other primates, cannot be accounted for by hybridization of a primate with some other primate. If hybridization is to explain such features, the cross will have to be between a chimpanzee and a nonprimate — an unusual, distant cross to create an unusual creature.

For the present, I ask the reader to reserve judgment concerning the plausibility of such a cross. I’m an expert on hybrids and I can assure you that our understanding of hybridization at the molecular level is still far too vague to rule out the idea of a chimpanzee crossing with a nonprimate. Anyone who speaks with certainty on this point speaks from prejudice, not knowledge.

Let’s begin, then, by considering the list in the sidebar at right, which is a condensed list of traits distinguishing humans from chimpanzees — and all other nonhuman primates. Take the time to read this list and to consider what creature — of any kind — it might describe. Most of the items listed are of such an obscure nature that the reader might be hard pressed to say what animal might have them (only a specialist would be familiar with many of the terms listed, but all the necessary jargon will be defined and explained). For example, consider multipyramidal kidneys. It’s a fact that humans have this trait, and that chimpanzees and other primates do not, but the average person on the street would probably have no idea what animals do have this feature.

Looking at a subset of the listed traits, however, it’s clear that the other parent in this hypothetical cross that produced the first human would be an intelligent animal with a protrusive, cartilaginous nose, a thick layer of subcutaneous fat, short digits, and a naked skin. It would be terrestrial, not arboreal, and adaptable to a wide range of foods and environments. These traits may bring a particular creature to mind. In fact, a particular nonprimate does have, not only each of the few traits just mentioned, but every one of the many traits listed in th sidebar. Ask yourself: Is it is likely that an animal unrelated to humans would possess so many of the “human” characteristics that distinguish us from primates? That is, could it be a mere coincidence? It’s only my opinion, but I don’t think so.

Look at the description of the putative non-primate parent in the last paragraph above. What animal are you thinking of? It’s probably the same one McCarthy imagined, which is why I’ve decided that this explanation for human origins must be called the Monkey-Fucked-A-Pig hypothesis, or MFAP for short.

Let’s be perfectly clear about this. McCarthy’s hypothesis is that once upon a time, these two met and had sex,


And that they then had children that were…us.

That’ll learn me. I thought this South Park clip was a joke.

One thing that struck me in reading McCarthy’s claim is how they are so similar to the claims of the soggy ape fans — they even use the very same physiological and anatomical features to argue for their delusion. For instance, I’ve read aquatic ape proponents’ arguments that the shape of our nose is adaptive for streamlining and for preventing water from flowing into the nostrils while propelling ourselves forward through the water…but compare that to the MFAP.

Neither is it clear how a protrusive cartilaginous nose might have aided early humans in their “savannah hunter lifestyle.” As Morris remarks, “It is interesting to note that the protuberant, fleshy nose of our species is another unique feature that the anatomists cannot explain.” This feature is neither characteristic of apes, nor even of other catarrhines. Obviously, pigs have a nose even more protuberant than our own. In a pig’s snout, the nasal wings and septum are cartilaginous as ours are. In contrast, a chimpanzee’s nose “is small, flat, and has no lateral cartilages”. A cartilaginous nose is apparently a rare trait in mammals. Primatologist Jeffrey Schwartz goes so far as to say that “it is the enlarged nasal wing cartilage that makes the human nose what it is, and which distinguishes humans from all other animals.” The cartilaginous structure of the pig’s snout is generally considered to be an “adaptation” for digging with the nose (rooting). Rooting is, apparently, a behavior pattern peculiar to pigs. Other animals dig with their feet.

Point, MFAP. Of course, just as I would point out to aquatic ape people, we do have an explanation for the nose: recession of the facial bones associated with reduced dentition, along with retention of the bones associated with the respiratory apparatus. The protuberant nose is simply a ridge made apparent by the receding tide of our chewing apparatus. McCarthy uses evidence as badly as does every wet ape fan.

Now, why won’t this hybridization claim work? Well, there are the obvious behavioral difficulties, even if it were cytogenetically possible. We’d have to have pigs and chimps having sex and producing fertile offspring, and those human babies (remember, this is a saltational theory, so the progeny would have all the attributes of a third species, ours) would have to be raised by chimps. Or pigs. I don’t think either is a reasonable alternative, and a band of chimps would probably be no more charitable to a helpless fat blob of a baby than Mr Wu’s pigs.

However, no one reasonably expects pigs and chimps to be interfertile. The primate and artiodactyl lineages have diverged for roughly 80 million years — just the gradual accumulation of molecular differences in sperm and egg recognition proteins would mean that pig sperm wouldn’t recognize a chimpanzee egg as a reasonable target for fusion. Heck, even two humans will have these sorts of mating incompatibilities. Two species that haven’t had any intermingling populations since the Cretaceous? No way.


But further, even if the sperm of one would fuse with the egg of another, there is another looming problem: chromosome incompatibilities. Pigs have 38 chromosomes, chimpanzees have 48. Cells are remarkably good at coping with variations in chromosome number, and even with translocations of regions from one chromosome to another; and further, pigs and people even retain similar genetic arrangements on some of their chromosomes. There are pig chromosomes that have almost the same arrangement of genes as a corresponding human chromosome.

But there are limits to how much variation the cell division machinery can cope with. For instance, with fewer chromosomes than we primates have, that means you need to line up multiple primate chromosomes to match a single pig chromosome (this pairing up is essential for both mitosis and meiosis). Look at pig chromosome 7, for instance: it corresponds to scrambled and reassembled bits of human chromosomes 6, 14, and 15.

Blocks of conserved synteny between pig and human. (a) Pig SSC7 to human chromosomes 6, 14 and 15. (b) HSA13 compared to pig chromosome 11. Block inversions between pig and human are denoted with broken lines. Contig coverage is depicted by bars in the center of SSC7 and HSA13.

Blocks of conserved synteny between pig and human. (a) Pig SSC7 to human chromosomes 6, 14 and 15. (b) HSA13 compared to pig chromosome 11. Block inversions between pig and human are denoted with broken lines. Contig coverage is depicted by bars in the center of SSC7 and HSA13.

Maybe that would work in mitosis within the hybrid progeny — you’d have three chromosomes from the human/chimp parent twisted around one chromosome, but they would be able to pair up, mostly, and then separate to form two daughter cells. But meiosis would be total chaos: any crossing over would lead to deletions and duplications, acentric and dicentric chromosomes, a jumble of broken chromosomes. That would represent sterile progeny and an evolutionary dead end.

But we wouldn’t have to even get that far. Human and chimpanzee chromosomes are even more similar to one another, and there are no obvious chromosomal barriers to interfertility between one another. If hybridization in mammals were so easy that a pig and a chimp could do it, human-chimp hybrids ought to be trivial. Despite rumors of some experiments that attempted to test that, though, there have been no human-chimp hybrids observed, and I think they are highly unlikely to be possible. In this case, it’s a developmental problem.

For example, we have bigger brains than chimpanzees do. This is not a change that was effected with a single switch; multiple genes had to co-evolve together, ratcheting up the size in relatively incremental steps. So you could imagine a change that increased mitotic activity in neural precursors that would increase the number of neurons, but then you’d also need changes in how those cells are partitioned into different regions, and changes in the proliferation of cartilage and bone to generate a larger cranium, and greater investment in vascular tissue to provide that brain with an adequate blood supply.

Development is like a ballet, in which multiple players have to be in the right place and with the right timing for everything to come off smoothly. If someone is out of place by a few feet or premature by a few seconds in a leap, the dancers could probably compensate because there are understood rules for the general interactions…but it would probably come off as rough and poorly executed. A hybrid between two closely related species would be like mixing and matching the dancers from two different troupes to dance similar versions of Swan Lake — everything would be a bit off, but they could probably compensate and muddle through the performance.

Hybridizing a pig and a chimp is like taking half the dancers from a performance of Swan Lake and the other half from a performance of Giselle and throwing them together on stage to assemble something. It’s going to be a catastrophe.

But here’s the deal: maybe I’m completely wrong. This is an experiment that is easily and relatively cheaply done. Human sperm is easily obtained (McCarthy probably has a plentiful supply in his pants), while artificial insemination of swine is routine. Perhaps McCarthy can report back when he has actually done the work.

Humphray SJ, Scott CE, Clark R, Marron B, Bender C, Camm N, Davis J, Jenks A, Noon A, Patel M, Sehra H, Yang F, Rogatcheva MB, Milan D, Chardon P, Rohrer G, Nonneman D, de Jong P, Meyers SN, Archibald A, Beever JE, Schook LB, Rogers J. (2007) A high utility integrated map of the pig genome. Genome Biol. 8(7):R139.

Do the creationist shuffle and twist!

Don’t you hate it when you get up in the morning and the first thing you read on the internet is the news that your entire career has been a waste of time, your whole field of study has collapsed, and you’re going to have to rethink your entire future? Happens to me all the time. But then, I read the creationist news, so I’ve become desensitized to the whole idea of intellectual catastrophes.

Today’s fresh demolition of the whole of evolutionary theory comes via Christian News, which reports on a paper in the journal Molecular Biology and Evolution which challenges the ape to human evolutionary theory. Wait, that’s a journal I read regularly. What did I miss?

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