The most interesting thing to an evolutionist is not that APOE4 increases the risk of Alzheimer’s disease

Neurologists were immensely excited by the discovery 25 years ago that the APOE4 variant of APOlipoprotein E increases the risk of Late Onset Alzheimer’s Disease (LOAD). 24,000 papers later (Google Scholar) we still don’t know how it does it. Should all this work have been done ? Of course ! !  Once we know the mechanism(s) by which APOE4 increases Alzheimer’s risk we’ll have new ideas to help us attack.

The APOE gene has 3 variants (alleles) APOE2, 3 and 4. The protein is average sized (299 amino acids). The 3 alleles differ at two positions (amino acids #112 and #158) where either cysteine or arginine can be found. The frequency of APOE4 is 14% in the adult white population, that of E3 is 78% and that of E2 is 8%.

Fascinating as this all is, it’s not what’s interesting from an evolutionary point of view.

[ Proc. Natl. Acad. Sci. vol. 113 pp. 17 – 18, 74 – 79 ’16 ] Postmenpausal longevity in females is not limited to humans. Humans, orcas and pilot whales are the only vertebrate species known to have prolonged postreproductive lifespans. Our fertility ends at about the same age that fertility ends in other female hominids (the great apes). However, apes rarely live into their 40s (even in captivity).

Unlike APOE4, APOE2 and APOE3 protect against late onset Alzheimer’s.

The fascinating point is that APOE2 and APOE3 aren’t found in the great apes. They are a human invention. Now LOAD occurs well past reproduction, so there should be no reason in terms of reproductive success for them to arise and be more common in human populations than the original APOE4.

Even more interesting is some work on another protein CD33, found on immune cells and glia in the brain [ Neuron vol. 78 pp. 575 – 577, 631 – 643 ’13 ] A minor allele (21% frequency in human populations) of CD33 (SNP rs 3865444) protects against Alzheimer’s. The allele is associated with reductions in CD33 expression in microglia, and also with reduction in levels of insoluble Abeta42 in (Alzheimer’s) brain. The numbers of CD33+ microglia correlate with insoluble Abeta42 levels and amyloid plaque burden. So decreasing (or inhibiting) CD33 function might help Alzheimer patients.

Again the protective allele is only found in man. The great apes don’t have it just the major (nonprotective) allele.

Again, there is no way that having the allele directly improves your reproductive success. By the time it is protecting you, you’re infertile.

What in the world is going on? Why did alleles protective against Alzheimer’s arise in two very different proteins in the course of human evolution?

“There is something fascinating about science. One gets such wholesale returns of conjecture out of such a trifling investment of fact.” — Mark Twain.

The reason these alleles probably arose gets us in to an ancient battle in evolutionary theory — what is the actual unit of selection? It may be the group rather than the individual. Face it, human infants and children are helpless for longer than other primates, and need others to care for them, for at least 5 years. Who better than grandma and grandpa? So the fact that with granny around more children survive to reproduce constitutes group selection (I think).

As Theodosius Dobzhansky said “Nothing in Biology Makes Sense Except in the Light of Evolution”

The road to the Boltzmann constant

If you’re going to think seriously about cellular biophysics, you’ve really got to clearly understand the Boltzmann constant and what it means.

The road to it starts well outside the cell, in the perfect gas law, part of Chem 101. This seems rather paradoxic. Cells (particularly neurons) do use gases (carbon monoxide, hydrogen sulfide, nitric oxide, and of course oxygen and CO2) as they function, but they are far from all gas.

Get out your colored pencils with separate colors for pressure, energy, work, force, area, acceleration, volume. All of them are combinations of just 3 things mass, distance and time for which you don’t need a colored pen,

The perfect gas law is Pressure * Volume = n R Temperature — the units don’t matter at this point. R is the gas constant, and n is the number of moles (chem 101 again).

Pressure = Force / Area
Force = Mass * Acceleration
Acceleration = distance / (time * time )
Area = Distance * distance

Volume = Distance * distance * distance

So Pressure * Volume = { Mass * distance / (time * time * distance * distance ) } * { distance * distance * distance }

= mass * distance * distance / ( time * time )

This looks suspiciously like kinetic energy (because it is )

Since work is defined as force * distance == mass * acceleration * distance

This also comes out to mass * distance * distance / ( time * time )

So Pressure * Volume has the units of work or kinetic energy

Back to the perfect gas law P * V = n * R * T

It’s time to bring in the units we actually use to  measure energy and work.

Energy and work are measured in Joules. Temperature in degrees above absolute zero (e.g. degrees Kelvin) — 300 is close to body temperature at 81.

Assume we have one mole of gas. Then the gas constant (R) is just PV/T or Joules/degree kelvin == energy/degree kelvin.

Statistical mechanics thinks about molecules not moles (6.022 * 10^23 molecules).

So the Boltzmann constant is just the Gas constant (R) divided by (the number of molecules in a mole * one degree Kelvin ) — it’s basically the energy each molecule posses divided by the current temperature — it is called k and equals 8.31441 Joules/ (mole * degree kelvin)

Biophysicists are far more interested in how much energy a given molecule has at body temperature — to find this multiply k by T (which is why you see kT all over the place.

At 300 Kelvin

kT is
4 picoNewton * nanoMNeters — work
23 milliElectron volts
.6 kiloCalories/mole
4.1 * 10^-21 joules/molecule — energy

Now we’re ready to start thinking about the molecular world.

I should do it, but hopefully someone out there can use this information to find how fast a sodium ion is moving around in our cells. Perhaps I’ll do this in a future post if no one does — it’s probably out there on the net.

Maybe there is something to it after all

Nearly 8 years ago I wrote a post (see below) about a rather fantastic paper, that said that in order to turn on gene transcription, the DNA had to be damaged first. This caused all sorts of repair enzymes to rush to the damaged site, opening up the chromatin there and allowing RNA polymerase II (which is large) to get to the DNA and transcription to proceed. I wrote the original author who was Italian, who said he was ill, but nothing further appeared about the idea (as far as I know). Remember what Carl Sagan said “Extraordinary claims require extraordinary evidence.”

Now Science (vol. 351 p. 147 ’16 ) has an abstract of an article in Nat. Commun. 6, 10191 (2015). “Curiously, DNA repair factors have been found associated with tran- scriptionally paused, inducible genes. Bunch et al. show that the activation of paused and inducible genes in human tissue culture cells triggers DNA breaks at the RNA polymerase pause site. The subsequent recruitment and signaling activity of DNA repair factors is critical for DNA repair, release of the RNA polymerase, and the transition to the transcrip- tion elongation phase of gene expression.”

Here’s the relevant portion of the post from 2/08. How about that ! ! ! DNA breaks are even more spectacular than 8 oxo-guanine

An incredible article appeared last month in the journal Science. (see below for the abstract). If it can be verified and if it applies generally, our conception of just how genes coding for protein are turned on will be radically changed (yes, there are many other kinds of genes other than those coding for proteins). If DNA compaction, nucleosomes, histones, lysine methylation and demethylation, the histone code, nuclear hormone receptors (particularly the estrogen receptor), DNA glycosylase and topoisomerase aren’t old friends have a look at the first comment on this post for the background you need (it’s back on the Skeptical Chymist). Don’t worry, there is plenty of chemistry to follow.

Some histone code modifications are reversible, particularly acetylation of the epsilon amino group of lysine. Enzymes acetylating histone lysines are called histone acetylases, those removing it are called histone deacetylatases (HDACs). However, lysine methylation was thought to be permanent until ’04 when several enzymes able to demethylate lysine were found. One such enzyme is called LSD1 (it has nothing to do with the hallucinogen). It removes the two methyl groups from lysine #9 of histone #3 (H3K9me2). If this modification is present on a nucleosome near a gene, the gene is silenced, so the methyls must be removed so the protein it codes for can be made.

The estrogen receptor + estrogen complex bound to the ERE (the estrogen response element – a 15 nucleotide DNA sequence) triggers H3K9me2 removal. The process of demethylation is oxidative (how else would you split a nitrogen to hydrocarbon bond?). Hydrogen peroxide is produced, a loose cannon which oxidizes the juicy electron-rich bases of DNA nearby, forming in particular 8 oxo-guanine, as guanine is the most easily oxidized DNA base. Since 21% of the DNA bases in our genome are guanine, H2O2 doesn’t have far to look. This calls in some fairly heavy artillery (DNA glycosylase to remove the 8 oxo-guanine, topoisomerase IIbeta to unwind the DNA so it can be repaired, the repair enzymes, etc, etc…). Naturally this opens up the compacted DNA structure around the gene allowing RNA polymerase II to do its work transcribing the estrogen responsive gene into mRNA (once the damage is repaired).

So according to this paper, estrogen turns on gene transcription by damaging DNA. This is fantastic (if true). There’s more. The estrogen receptor is but one member of a group of proteins called nuclear hormone receptors. The name comes from the fact that other hormones (progesterone, androgen, thyroid, glucocorticoids, mineralocorticoids) have their own proteins that turn on (or turn off) genes the same way. Subsequently it was found that some vitamin metabolites (vitamin D3, vitamin A) have similar receptors even though they aren’t hormones. The human genome contains 48 such proteins. Less than half of them have known ligands. Those with known ligands have their finger in just about every metabolic pie in the cell.

One final point. It has been estimated that 8-oxoguanine is formed 100,000 times each day in every cell. Perhaps its formation is physiologic rather than pathologic. Where does that leave antioxidant therapy, which has been touted to do everything but cure hemorrhoids? Well, one such trial was done on 29,000 Finnish men at high risk for lung cancer (they were smokers) [New England J. Med. vol. 330 pp. 1029-1035 (1994)] Alpha tocopherol (one antioxidant used in the study) didn’t decrease the incidence of lung cancer, and there was an 18% higher incidence of lung cancer among the men receiving beta carotene (another antioxidant). In medicine, theory is great but data trumps it every time.

Science vol. 301 pp. 202 – 206 ’08, B. Perillo et. al.

Modifications at the N-terminal tails of nucleosomal histones are required for efficient transcription in vivo. We analyzed how H3 histone methylation and demethylation control expression of estrogen-responsive genes and show that a DNA-bound estrogen receptor directs transcription by participating in bending chromatin to contact the RNA polymerase II recruited to the promoter. This process is driven by receptor-targeted demethylation of H3 lysine 9 at both enhancer and promoter sites and is achieved by activation of resident LSD1 demethylase. Localized demethylation produces hydrogen peroxide, which modifies the surrounding DNA and recruits 8-oxoguanine–DNA glycosylase 1 and topoisomeraseIIβ, triggering chromatin and DNA conformational changes that are essential for estrogen-induced transcription. Our data show a strategy that uses controlled DNA damage and repair to guide productive transcription.

If a Harvard professor said it, it can’t be wrong

Harvard professors are always right, so here’s a quote from one about immigrants.

” It may be doubted, as a gen­eral rule, whether the young Irish-American is a better or safer citizen than his parent from Cork. He can read, but he reads nothing but sensation stories and scandalous picture-papers, which fill him with preposterous notions and would enfeeble a stronger brain than his and debauch a sounder conscience. He is generally less industrious than his sire, and equally careless of the public good.”

This is Francis Parkman (Harvard 1844) Professor of Horticulture at Harvard writing in 1878.

Got that Donald !

Smoke, mirrors and statistical mechanics

This will be the year I look at PChem and biophysics. What comes first? Why thermodynamics of course, and chemists always think of molecules not steam engines, so statistical mechanics comes before thermodynamics

The assumptions behind statistical mechanics are really so bizarre that it’s a miracle that it works at all, but work it does.

Macrostates are things you can measure — temperature, pressure, volume.

Microstates give rise to macrostates, but you can’t measure them. However even though you can’t measure them, you can distinguish different ones and count them. Then you assume that each microstate is equally probable, even though you have no way in hell of experimentally measuring even one of them, and probability is what you find after repeated measurements (none of which you can make).

Amazing.

An uplifting way to start the New Year

This not a scientific post. Going to a memorial service for an old friend hardly seems like an uplifting way to begin the new year. And yet it was. David and I had been friends since ’58 when we were in the same eating club. He also became an M. D. and unfortunately passed away of a slowly dementing illness, probably Alzheimer’s. As a neurologist I could do nothing for him. What little I did accomplish was discussing the scientific aspects with with his wife, explaining the latest breakthroughs she’d read about (which never were). She was a rock, standing by him until the end. Having taken care of many such patients, and having an uncle die of it, I know just how hard this is.

What in the world could be uplifting about something like this? Seeing how David’s intelligence and personality has now marched on through 4 children and (at least) 4 grandchildren. So in a way he really isn’t gone. What was uncanny was seeing David’s eyes staring at me out of his oldest daughter. It really is remarkable, given what we think we know about genetics, and that 10,000 or so of our 20,000 protein coding genes come from one parent, that an offspring will resemble just one parent and not be an amalgam of both. Perhaps just a few genes determine what we look like.

The grandchildren I talked to ranged in age from about 8 to 17. All were smart and articulate. I tried to push them to use their obvious brains to go into research and perhaps prevent or treat what happened to their grandfather. The littlest one said that he was going to be a particle physicist.

I don’t remember talking religion with David or anyone else back in college. There were devout members of the club who would march in glowing after Sunday church, only to be treated by hungover club mates to a chorus of “Onward Christian Soldiers”. One classmate did become the Lutheran Bishop of Western New York, but he certainly didn’t push his religiosity. The most religious one I do remember became a physics professor at Berkeley.

Of course there were remembrances, that of his oldest daughter being the most interesting (to me). She is a religious Christian who clearly loved her father very much, even though he was a professed atheist, although with a strong sense of right and wrong. They used to argue about the existence or nonexistence of God. She and I agreed that he would never do anything that he thought was wrong, probably one of the reasons I liked him (remember the hungover reprobates of a few paragraphs ago). I suppose his daughter now has the last word, but such an argument really has no end.

It was pretty hard to be a doc back in the 60s and 70s watching good people suffer and die, and still conceive of a benevolent creator. “The Plague” by Camus with its hideous death scene of a child pretty much sums up the argument against one.

And yet, now that we know so much more molecular biology, cellular and organismal biochemistry and physiology, our existence seems totally miraculous. I at least have achieved a sense of peace about illness, suffering and death. These things seem natural. What is truly miraculous is that we are well and functional for so long.

You can take or leave the argument from design of Reverend Paley — here it is

“”In crossing a heath, suppose I pitched my foot against a stone, and were asked how the stone came to be there; I might possibly answer, that, for anything I knew to the contrary, it had lain there forever: nor would it perhaps be very easy to show the absurdity of this answer. But suppose I had found a watch upon the ground, and it should be inquired how the watch happened to be in that place; I should hardly think of the answer I had before given, that for anything I knew, the watch might have always been there. … There must have existed, at some time, and at some place or other, an artificer or artificers, who formed [the watch] for the purpose which we find it actually to answer; who comprehended its construction, and designed its use. … Every indication of contrivance, every manifestation of design, which existed in the watch, exists in the works of nature; with the difference, on the side of nature, of being greater or more, and that in a degree which exceeds all computation.”

The more chemistry and biochemistry I know about what’s going on inside us, the harder I find it to accept that this arose by chance.

This does not make me an anti-evoloutionist. One of the best arguments for evolution, is the evidence for descent with modification, one of its major tenets. The fact that we can use one of our proteins to replace one on yeast using our present genetic technology is hard to explain any other way.

Actually to me now, the existence or nonexistence of a creator is irrelevant. The facts of how we are built is not something you need faith about. The awe about it all comes naturally the more we know and the more we find out.

The old year goes out with a bang

A huge amount of cellular genomics will have to be redone if the following paper is replicated. Remember “Extraordinary claims require extraordinary evidence.” Carl Sagan.

What’s all the shouting about? Normally when you think about messenger RNA (mRNA) as it exists in the cytoplasm after the initial transcript is significantly massaged in the nucleus, you think about the part that codes for amino acids. This ‘coding region’ is the part that is translated into amino acids by the ribosome. But mRNA is invariably larger having nucleotides at each end (3′ and 5′) which have other uses. These are called the 3′ Untranslated Region (3′ UTR) and 5′ Untranslated Region (5′ UTR).

So if you do single cell RNA sequencing (which we can do now) it shouldn’t matter what nucleotide sequence you search for (5′ UTR, 3′ UTR or the coding region) as all mRNA contains one of each.

Not so says this paper [ Neuron vol. 88 pp. 1149 – 1156 ’15 ].

Given the mRNA for a given protein in a single cell, using a probe for the 3’UTR and a probe for the coding sequence should give you the same abundance for both. That’s not what they found at all for single neurons from the brain. In some cases there was much more RNA coding for the 3’UTR than for the coding segment of a given mRNA for a protein. In others there was much less. Even more impressively is that the 3’UTR/(3’UTR + coding) ratio for a given protein varies between different parts of the brain. Obviously this ratio should be .5 given what we knew about mRNA in the past. The ratio has to be between 0 and 1.

Well they looked at a lot of proteins. The did find around 1,400 genes with a ratio of .5 (as expected), but they found 700 showing a ratio of .2 (lots more 3’UTR than coding sequence), and 1,100 showing a ratio of .8. Overall plotting the ratio vs. number of genes with that ratio gives something looking like a bell curve (Gaussian distribution).

It’s long been known that mRNA levels don’t exactly correlate with the levels of proteins made from them. If there’s lots of 3’UTRs around the authors found that there was relatively little protein made from the gene.

A variety of brain atlases have published mRNA abundances for various regions of the brain. If they just used one probe (as they probably did) this is clearly not enough.

The 3’UTRs may be acting as ceRNAs (competitive endogenous RNAs). These have been known for years — I’ve included a post of 3 years ago on the subject (at the end).

So this work (if replicated) throws everything we thought we knew about mRNA into a cocked hat. It’s why I love science, there’s always something really new to think about. Happy New Year !!!

Chemiotics II
Lotsa stuff, basically scientific — molecular biology, organic chemistry, medicine (neurology), math — and music
Why drug discovery is so hard: reason #20 — competitive endogenous RNAs

The chemist will appreciate le Chatelier’s principle in action in what follows. We are far from knowing all the players controlling cellular behavior. So how in the world will we find drugs to change cellular behavior when we don’t know all the things affecting it. The latest previously unknown cellular player to enter the lists are competitive endogenous RNAs (ceRNAs). For details see Cell vol. 147 pp. 344 – 357, 382 – 395 ’11. The background the pure chemist needs for what follows can all be found in the category “Molecular Biology Survival Guide.

Recall that microRNAs are short (20 something) polynucleotides which bind to the 3′ untranslated region (3′ UTR) of mRNA, and either (1) inhibit its translation into protein (2) cause its degradation. In each case, less of the corresponding protein is made. The microRNA and the appropriate sequence in the 3′ UTR of the mRNA form an RNA-RNA double helix (G on one strand binding to C on the other, etc.). Visualizing such helices is duck soup for a chemist.

Molecular biology is full of such semantic cherry bombs as nonCoding DNA (which meant DNA which didn’t cord for protein), a subset of Junk DNA. Another is the pseudogene — these are genes that look like they should code for protein, except that they don’t because of lack of an initiation codon or a premature termination codon. Except for these differences, they have the nucleotide sequence to code for a known protein. It is estimated that the human genome contains as many pseudogenes (20,000) as it contains true protein coding genes [ Genome Res. vol. 12 pp. 272 – 280 ’02 ]. We now know that well over half the genome is transcribed into mRNA, including the pseudogenes.

PTEN (you don’t want to know what it stands for) is a 403 amino acid protein which is one of the most commonly mutated proteins in human cancer. Our genome also contains a pseudogene for it (called PTENP). Interestingly deletion of PTENP (not PTEN) is found in some cancers. However PTENP deletion is associated with decreased amounts of the PTEN protein itself, something you don’t want as PTEN is a tumor suppressor. How PTEN accomplishes this appears to be fairly well known, but is irrelevant here.

Why should loss of PTENP decrease PTEN itself? The reason is because the mRNA made from PTENP, even though it has a premature termination codon, and can’t be made into protein, is just as long, so it also contains the 3’UTR of PTEN. This means PTENP is sopping up microRNAs which would otherwise decrease the level of PTEN. Think of PTENP mRNA as a sponge.

Subtle isn’t it? But there’s far more. At least PTENP mRNA closely resembles the PTEN mRNA. However other mRNAs coding for completely different proteins, also have binding sites in their 3’UTR for the microRNA which binds to the 3UTR of PTEN, resulting in its destruction. So transcription of a completely different gene (the example of ZEB2 is given) can control the abundance of another protein. Essentially its mRNA is acting as a sponge, sopping up the killer microRNA.

It gets worse. Most microRNAs have binding sites on the mRNAs of many different proteins, and PTEN itself has a 3’UTR which binds to 10 different microRNAs.

So here is a completely unexpected mechanism of control of protein levels in the cell. The general term for this is competitive endogenous RNA (ceRNA). Two years ago the number of human microRNAs was thought to be around 1,000. Unlike protein coding genes, it’s far from obvious how to find them by looking at the sequence of our genome, so there may be quite a few more.

So most microRNAs bind the 3’UTR of more than one protein (the average number is unclear at this point), and most proteins have binding sites for microRNAs in their 3’UTR (again the average number is unclear). What a mess. What subtlety. What an opportunity for the regulation of cellular function. Who is going to be smart enough to figure out a drug which will change this in a way that we want. Absence of evidence of a regulatory mechanism is not evidence of its absence. A little humility is in order.

A lump of coal to the authors

The following sentence appeared in a paper in the Proceedings of The National Academy of Sciences USA this year. The names of the authors have been withheld to protect the guilty. The following is an exact quote

These languages were selected because they provide contrasts of transparent vs. opaque orthographies with alphabetic vs. logographic writing systems, which map into monomorphemic and monosyllabic words vs. morphologically complex and multisyllabic words, having concatenated linear morphology vs. nonconcatenated nonlinear morphology, with visually simple vs. complex print, which map into tonal vs. nontonal spoken forms.

Two Christmas Presents

Two Christmas presents for you.  Yes Christmas presents.  I refuse to be culturally castrated by the professionally aggrieved.

The first is a link to a great scientific website — https://www.quantamagazine.org. It’s primarily about math and physics, with some biology thrown in. Imagine the News and Views section of Nature or the Perspectives section of Science on steroids.

Quanta is an editorially independent division of the Simons Foundation. And what is that you enquire? It is the answer to “If you’re so smart, why ain’t you rich”. Jim Simons is both much smarter and much richer than you and I. You can read more about him in a book I’m about to review on the blog — “The Physics of Wall Street”

Simons was a very accomplished mathematician winning prizes with a friend James Ax in the 60’s and 70’s — not quite the Fields Medal but up there. The Simons Chern 3 form is part of string theory. The two founded Renaissance Technologies in the late 80’s a stock fund using mathematical techniques to beat the market. And beat it they did, averaging 40% a year (after fees which were hefty). Even in the most recent market blowout in 2008 they were up 80% for the year. The firm employs about 200 people, mostly mathematicians and physicists. It was described by an MIT math prof as ‘the best mathematics and physics department in the world”.

At any rate after becoming a multibillionaire, Simons established his foundation, of which Quanta is a small part. It’s very good, with some heavies writing for it — such as Ingrid Daubechies full prof of math at Princeton who did a good deal of the early work on wavelets.

I haven’t read it all but the math is incredible, mostly about the latest and greatest new results and why it is important placing it in context. Physics isn’t forgotten, and the lead article concerns the philosophy of science and how it’s a’changin’ a la string theory, which is light years away from an experimental test of any of it.

Your second Christmas present is a Joke

The pope visited Colorado 22 years ago. A little known fact about him is that he loved to drive. Although Colorado is famed for the Rockies, the eastern half is high plains, so flat that you can see Pike’s peak from 100 miles away across the plains. At any rate the pope was being driven by his chauffeur from Colorado Springs to Denver on the Interstate, when the pope asked if he could drive. “Only if we go out on the plains where no one will see you” said the chauffeur.

So they switched when they got about 30 miles out in the middle of nowhere with the pope driving and the chauffeur in the back seat both behind tinted opaque windows. The pope started driving, really enjoying it, going faster and faster. He got up to 85 when a state trooper pulled them over.

Where’s the fire saith the trooper. He blanched when the driver’s window came down and he saw who was driving, and called headquarters. Arrest him came the answer. The trooper said I’m not sure, this guy is very big. I don’t care how big he is, arrest him. Are you sure. Yes.

I dunno boss, this guy is so big he’s got the pope driving for him.

Merry Christmas and Happy New Year to all

It ain’t the bricks it’s the plan — take II

A recent review in Neuron (vol. 88 pp. 681 – 677 ’15) gives a possible new explanation of how our brains came to be so different from apes (if not our behavior of late).

You’ve all heard that our proteins are only 2% different than the chimp, so we are 98% chimpanzee. The facts are correct, the interpretation wrong. We are far more than the protein ‘bricks’ that make us up, and two current papers in Cell [ vol. 163 pp. 24 – 26, 66 – 83 ’15 ] essentially prove this.

This is like saying Monticello and Independence Hall are just the same because they’re both made out of bricks. One could chemically identify Monticello bricks as coming from the Virginia piedmont, and Independence Hall bricks coming from the red clay of New Jersey, but the real difference between the buildings is the plan.

It’s not the proteins, but where and when and how much of them are made. The control for this (plan if you will) lies outside the genes for the proteins themselves, in the rest of the genome (remember only 2% of the genome codes for the amino acids making up our 20,000 or so protein genes). The control elements have as much right to be called genes, as the parts of the genome coding for amino acids. Granted, it’s easier to study genes coding for proteins, because we’ve identified them and know so much about them. It’s like the drunk looking for his keys under the lamppost because that’s where the light is.

We are far more than the protein ‘bricks’ that make us up, and two current papers in Cell [ vol. 163 pp. 24 – 26, 66 – 83 ’15 ] essentially prove this.

All the molecular biology you need to understand what follows is in the following post — https://luysii.wordpress.com/2010/07/07/molecular-biology-survival-guide-for-chemists-i-dna-and-protein-coding-gene-structure.

The neuron paper is detailed and fascinating to a neurologist, but toward the end it begins to fry far bigger fish.

Until about 10 years ago, molecular biology was incredibly protein-centric. Consider the following terms — nonsense codon, noncoding DNA, junk DNA. All are pejorative and arose from the view that all the genome does is code for protein. Nonsense codon means one of the 3 termination codons, which tells the ribosome to stop making protein. Noncoding DNA means not coding for protein (with the implication that DNA not coding for protein isn’t coding for anything).

Well all that has changed. The ENCODE Consortium showed that well over half (and probably all) our DNA is transcribed into RNA — for details see https://en.wikipedia.org/wiki/ENCODE. This takes energy, and it is doubtful (to me at least) that organisms would waste this much energy if the products were not doing something useful.

I’ve discussed microRNAs elsewhere — for details please see — https://luysii.wordpress.com/2010/07/14/junk-dna-that-isnt-and-why-chemistry-isnt-enough/. They don’t code for protein either, but control how much of a given protein is made.

The Neuron paper concerns lncRNAs (long nonCoding RNAs). They don’t code for protein either and contain over 200 nucleotides. There are a lot of them (10,000 – 50,000 are known to be expressed in man. Amazingly 40% of them are expressed in the brain, and not just in adult life, but during embryonic development. Expression of some of them is restricted to specific brain areas. It is easier for an embryologist to tell what type a cell is during brain cortical development by looking at the lncRNAs expressed than by the proteins a given cell is making. The paper contains multiple examples of the lncRNAs controlling when and where a protein is made in the brain.

lncRNAs can contain multiple domains, each of which has a different affinity for a particular RNA (such as the mRNA for a protein), or DNA, or protein. In the nucleus they influence the DNA binding sites of transcription factors, RNA polymerase II, the polycomb repressor complex. The review goes on with many specific examples of lncRNA function — synaptic plasticity, neurotic extension.

Getting back to proteins, the vast majority are nearly the same in all mammals (this is where the 2% Chimpanzee argument comes from). Here is where it gets interesting. Roughly 1/3 of lncRNAs found in man are primate specific. This includes hundreds of lncRNAs found only in man. The paper gives evidence that hundreds of them have shown evidence of positive selection in humans.

So the paper provides yet another mechanism (with far more detail than I’ve been able to provide here) for why our brains are so much larger, and different in many ways than our nearest evolutionary ancestor, the chimpanzee. This is the largest molecular biological difference found so far for the human brain as opposed to every other brain. Fascinating stuff. Stay tuned. I think this is a watershed paper.

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