What makes us human (genetically at least) take 1

We are now able to watch natural selection mold and shape our recent ancestors.  The genomes of 1,500 ancient humans have now been sequenced.  They range in age from 1,000 years ago to 45,000 years ago (based on the geology of where they were found and optically stimulated luminescence).  Multiple genomes from the same site in space and time have been sequenced, so we have multiple sequences of the same protein gene allowing us to look for coding variants (alleles).  You can read all about it in Proc. Natl. Acad. Sci. vol. 120 e2213061120 pp. 1 –> 12 ’23.  Be warned, a lot of terms are undefined assuming that you are experts in genetics, so I’ll try to provide some background.

They estimate that the genomes are from 18 different populations spread across space (many in the Arabian Peninsula) and time. Most of them are from 5,000 to 10,000 years old.

The paper talks about ‘anatomically modern humans’ (AMHs e.g. us), excluding Denisovans and Neanderthals.

We know that primates have been migrating out of Africa for millions of years. However sometime between 30,000 and 1o0,000 years ago AMHs migrated out of Africa, interbreeding with close relatives (Neanderthals, Denisovans) who then died out.  Their DNA has been sequenced and now constitutes a small part of our own (1 – 5%) a process called introgression.

The 1,500 genomes were compared to the Yorubas of Nigeria.  So for each of their proteins we know how many variants (alleles) are present and at what frequency.

Suppose one allele of protein X (present at 5% in the Yorubas) was unhelpful in a cold climate.  If it disappeared in one of the 18 populations, we can say this was due to natural selection against it (negative selection).  The authors call this a selective sweep.

Another possibility for a selective sweep  would be a mutation in protein X not seen in the Yorubas appearing in nearly every member of one of the 18 populations.  This would be evidence for positive selection.

A technique to scan ancient genomes called SweepFinder2 (SF2) detected some 57 selective sweeps in the ancient population (none were found in the Yorubas)  Many of the genes in the sweeps were involved in fat metabolism (something likely important in cold adaptation).   Other selected genes were involved in skin pigmentation (another adaptation to strong sunlight or the lack of it).   The paper gives specific examples of these genes, but that would be too technical.   The cognoscenti should jump right in.  There’s tons more in the paper.

Our first evidence for evolution were fossils separated in time by millions of years.  The record remains sparse and fragmentary, and led to the idea the evolution and natural selection were very slow, slower in fact than glaciation.

The idea that we could actually witness natural selection was proved by the Grants, studying Darwin’s Finches in the Galapagos.  I seriously recommend “The Beak of the Finch” by Jonathan Weiner, if you’ve not heard of the Grants and their excellent work.

But here we are actually observing natural selection in action.  Clarence Darrow would have hated it.

What makes us human (genetically at least) take 0

For reasons unknown to me 3 groups of papers on what makes us different from other animals (and even our ancestors) have appeared in the past month.  They will appear in 3 consecutive posts

The first will deal with what makes us different from our human ancestors.     We now have over 1,500 genomes of people living thousands of years ago from all over Europe and Asia.  We can actually watch natural selection increase some genes (positive selection) and get rid of others (negative selection) over this time, showing natural selection can occur quickly.  The fossil record made it seem that changes were glacial only occurring after millions of years.

The second will deal with over 500 mammalian genomes.  To understand ourselves we need to see what genetic structures are common to all, and what is unique to us.

The third will deal with over 200 primate genomes.  Again, to understand ourselves we must look elsewhere.

Fascinating stuff.  Stay tuned

Transcriptional Chaff

The first results of the ENCODE project (ENCyclopdeia Of Dna Elements) were pretty controversial when they came out 16 years ago–https://en.wikipedia.org/wiki/ENCODE.  We knew that only 1 – 2% of our 3.2 billion basepair genome codes for protein, with well over half being made from repetitive elements (LINEs, Alu elements, transposons, satellite DNA, etc. etc.).

ENCODE said, ‘junk’ or not, careful study of the RNAs present in cells and matching them to the sequence of our DNA, showed that just about every position in our DNA was copied (technical term — transcribed) into RNA by the cell’s machinery — RNA polymerases I, II and III.

Could  all this RNA possibly have a function?  Or was it the turnings of a block of wood on a lathe, a byproduct of what was actually being made by the lathe, transcriptional chaff if you will.

A recent paper [ Nature vol. 617 pp. 395 – 402 ’12 ] describes a protein complex which chops up RNA produced from the 98% of the genome not coding for protein. It goes by the ugly acronym BAG6 complex (what it stands for is even uglier — BCL2 Associated Athanogene cochaperone 6).  The complex contains 3 proteins and it associates with ribosomes trying to translate RNA into protein (do distinguish translation from transcription).  Here BAG6 looks for newly made ribosomal protein products to bind to.

How does the BAG6 complex distinguish proteins or peptides made from the 98% of the genome not coding for protein?  Because such proteins have a lot of hydrophobic amino acids (leucine, isoleucine, valine, alanine, phenylalanine) which makes them excellent candidates for insertion into membranes (which are made of lipids and inherently hydrophobic).  However if they don’t get into membranes their hydrophobic amino acids make them insoluble in the cytoplasm, and persona non grata,   Once BAG6 finds such insoluble proteins or peptides, it calls an enzyme which adds ubiquitin to them, and off they go to the proteasome for destruction.

Here is where the paper becomes truly fascinating, showing me that despite decades of reading molecular biology, there is a Hell of lot that I didn’t know.  I’ll bet that most people reading this post didn’t know it either.

It turns out that there is an intrinsic nucleotide bias in the 98% of our genome not coding for protein.  It contains a lot of Uracil when transcribed into RNA from a Thymine  (RNA uses Uracil rather than Adenine).  RNA containing lots of U (Uracil) tends to code for hydrophobic amino acids.  Did you know that?  I didn’t.

It you look at our 20,000 proteins you’ll find that their carboxy terminal 30 amino acids or so avoid having hydrophobic amino acids in this position.

Just the opposite occurs in parts the nonCoding (for protein) of the genome — introns, 3′ untranslated regions, large noncoding RNAs (lncRNAs)  — they don’t exclude hydrophobic amino acids.

So the existence of the BAG6 complex is good evidence that the cell isn’t using all the RNA transcribed from the genome, and does work to get rid of it.

More fascination awaits.  The genomes of other animals (particularly primates) tells us a lot about our own.  A recent issue of Science had a lot of fascinating papers on this called Zoonomia (the subject of a future post).

So it’s easy to find human proteins unique to us, now that we have the genome of the Chimpanzee, out closest evolutionary relative, diverging from us 4 to 6 million years ago.  And guess what — they have the highest carboxy terminal hydrophobicity of all our 20,000 or so protein coding genes, essentially proving that they arose from the 98% of the genome previously not coding for protein.  Maybe that’s why we have so much DNA not coding for protein, evolutionary soil if you will for new protein formation

 

Lactic acid, the mitotic spindle killer

Nature vol. 616 pp. 790 – 797 ’23 is one of the most interesting papers I’ve read in the past year, both for its contents and for the two very large issues it raises (which the authors don’t really discuss).

Simply stated, the rise in cellular lactic acid levels from 6  milliMolar at mitosis onset, to 15 – 20 when mitosis is nearly over is what ’causes’ the breakdown of the mitotic spindle.

It’s now 100 years since Otto Warburg noted that tumors metabolize glucose by glycolysis producing 2 molecules of ATP per glucose (and two molecules of lactic acid) when, with plenty of oxygen around, they could get 38 molecules of ATP using their mitochondria.   This is called aerobic glycolysis.

Tumors are said to be energy hungry, so why do they use aerobic glycolysis? Simply because using oxygen to chew up glucose gives you lots of ATP along with CO2 and water, leaving you nothing to build new tumor cells with.  All 6 carbons remain present after glycolysis

The last stage of mitosis is called anaphase, where the mitotic spindle (made of microtubules) is broken down, among other things such as reformation of the nuclear membrane, and separation of the two daughter cells.

Well protein breakdown immediately brings ubiquitin to mind which, when added to most proteins, targets them to the proteasome, a huge molecular complex which breaks proteins down completely to their constituent amino acids.

APC/C is another huge multiprotein complex (at least 13 different protein subunits with a molecular mass of 1.2 megaDaltons) which acts to add ubiquitin to components of the mitotic  spindle (made mostly of microtubules).  So APC/C is a ubiquitin ligase, a dangerous thing to have around most of the time, which it is why it is usually inhibited so the cell doesn’t destroy itself.

One APC/C subunit is APC4, which has ubiquitinLike molecules (SUMO) attached to two of its lysines (#722 and #798) to activate the ubiquitin ligase activity of APC/C.    APC4 is held in check by yet another enzyme, SENP1, which removes the SUMOs.

Where does lactic acid fit in to all this?  It binds to the active site of SENP1 when coordinated with zinc ions, inhibiting SENP1’s ability to remove SUMO.

Byzantine enough for you?  Lactic acid inhibits SENP1 which inhibits APC4 allowing uninhibited APC4 to activate APC/C which breaks down the mitotic spindle.

Lactic acid, if thought of at all, was regarded as an important part of cellular metabolism, not an enzyme inhibitor.   This is an example of moonlighting, a lot of which goes on in the cell. https://luysii.wordpress.com/2021/05/04/is-there-anything-in-the-cell-that-has-just-one-function-more-moonlighting-this-time-mrna/  with its links will get you started.

Here is one of the larger issues the paper raises — how events in the cell at all levels of structure are linked to each other.  Phillip Anderson famously said “More is Different”.  The paper shows how something very small (lactic acid fits into a 5 Angstrom (.5 nanoMeters) sphere) and yet  is responsible for breaking down something 40,000 – 100,000 times larger  (the length of a microtubule in the mitotic spindle).

Here is the other (even larger) issue — Lactic acid was found as a player in cell metabolism, e.g., it is a member of the metabolome.  I was amazed to find out how large it is — some 42,000 for in the Human Metabolome DataBase http://www.hmdb.ca/metabolites?c=hmdb_id&d=up&page=1676 — for details please see https://luysii.wordpress.com/2015/06/03/how-little-we-know-2/.  Not only do we not know what they are doing, we don’t even know the structure of most of them. State of the art untargeted metabolomics studies still report ‘up to’ 40% unidentified, but potentially important metabolitcs which can be detected reproducibly. The unknown metabolites are only rarely characterized because of the extensive work required for de novo structure determination..

85 tomorrow

Time to wax philosophical and even somewhat theological as I’ll  turn 85 tomorrow.  Only a  neurologist with decades of hands on clinical experience can know how fortunate an 85 year old with good health and a (semi)intact brain really is.   Add to that 60+ years in the company of a very intelligent and very beautiful woman, and I’m even more fortunate.

A lot of this has absolutely nothing to do with anything I did.  My father lived to 100 in good health, and when asked what his secret was, always said “I chose my parents very carefully.”

You’ve got to play the hand you’re dealt, but a fair amount of my time was spent with people who spindled and mutilated their cards (alcohol, smoking, harder drugs, obesity etc.).

But many of my patients (and friends and relatives) didn’t do any of those things, yet suffered terribly and died far too soon.   So I was face to face with theodicy, even as far back as in college reading Camus’ “The Plague” with the scene of a child suffering and dying as the protagonist and a priest looked on.

Certainly, clinical experience in those early years did nothing to resolve the problems of disease and suffering. Gradually, as we learned more and more molecular biology and physiology the question of illness and suffering disappeared, and was replaced by the much larger question of why we’re as healthy as we are for so long.  See the copy of an older post at the end.

A two year detour into graduate work in Chemistry right after college in the early 60s gave me the background to understand and follow molecular biology as we both grew up.

So how do you spend your time when you’re 85?  For me it’s continuing to read the scientific literature (Science, Nature, Cell, Neuron, PNAS) on molecular biology, neurology and a variety of other things as the over 1,000 posts on this blog will show.  Fortunately I have the background and the brain left to understand it.

That’s not all of course, there’s playing chamber music with friends and family.  Unfortunately our family breeds like sequoias, and although my wife and I have 4 grandchildren, their ages range from 5 to 9, and it’s unlikely that I’ll see them all at 16 when they think they’re the smartest people in the world as I did at that age when I told my grandmother (who crossed the Atlantic alone at age 13) that she was the dumbest woman in the world.

One son told me that there are only 5 (or 6 or 7) basic plots of the novel.  How  incredibly dull !  Reading the five journals always shows something new and totally unexpected.  It’s like opening presents not knowing what you’ll find.

The technological progress is immense.  We’ve gone from the decade it took to map out the first human genome, to the fact that we’ve now done it a million times and in single cells to boot.

So I’ll keep on doing what I’m doing and taking Satchel Paige’s (https://en.wikipedia.org/wiki/Satchel_Paige) advice “Don’t look back, something might be gaining on you.”

The Solace of Molecular Biology

Neurology is fascinating because it deals with illnesses affecting what makes us human. Unfortunately for nearly all of my medical career in neurology ’62 – ’00 neurologic therapy was lousy and death was no stranger. In a coverage group with 4 other neurologists taking weekend call (we covered our own practices during the week) about 1/4 of the patients seen on call weekend #1 had died by on call weekend #2 five weeks later.

Most of the deaths were in the elderly with strokes, tumors, cancer etc, but not all. I also ran a muscular dystrophy clinic and one of the hardest cases I saw was an infant with Werdnig Hoffman disease — similar to what Steven Hawking has, but much, much faster — she died at 1 year. Initially, I found the suffering of such patients and their families impossible to accept or understand, particularly when they affected the young, or even young adults in the graduate student age.

As noted earlier, I started med school in ’62, a time when the genetic code was first being cracked, and with the background then that many of you have presently understanding molecular biology as it was being unravelled wasn’t difficult. Usually when you know something you tend to regard it as simple or unimpressive. Not so the cell and life. The more you know, the more impressive it becomes.

Think of the 3.2 gigaBases of DNA in each cell. At 3 or so Angstroms aromatic ring thickness — this comes out to a meter or so stretched out — but it isn’t, rather compressed so it fits into a nucleus 5 – 10 millionths of a meter in diameter. Then since DNA is a helix with one complete turn every 10 bases, the genome in each cell contains 320,000,000 twists which must be unwound to copy it into RNA. The machinery which copies it into messenger RNA (RNA polymerase II) is huge — but the fun doesn’t stop there — in the eukaryotic cell to turn on a gene at the right time something called the mediator complex must bind to another site in the DNA and the RNA polymerase — the whole mess contains over 100 proteins and has a molecular mass of over 2 megaDaltons (with our friend carbon containing only 12 Daltons). This monster must somehow find and unwind just the right stretch of DNA in the extremely cramped confines of the nucleus. That’s just transcription of DNA into RNA. Translation of the messenger RNA (mRNA) into protein involves another monster — the ribosome. Most of our mRNA must be processed lopping out irrelevant pieces before it gets out to the cytoplasm — this calls for the spliceosome — a complex of over 100 proteins plus some RNAs — a completely different molecular machine with a mass in the megaDaltons. There’s tons more that we know now, equally complex.

So what.

Gradually I came to realize that what needs explaining is not the poor child dying of Werdnig Hoffman disease but that we exist at all and for fairly prolonged periods of time and in relatively good shape (like my father who was actively engaged in the law and a mortgage operation until 6 months before his death at age100). Such is the solace of molecular biology. It ain’t much, but it’s all I’ve got (the religious have a lot more).

How herpes viruses use the cell’s machinery to shut themselves off

Herpes viruses (simplex — for fever blisters, Kaposi’s sarcoma, herpes zoster — shingles) persist in the body in a latent state where they don’t don’t reproduce, don’t make many of their proteins and don’t make trouble.   Every now and then they reproduce and cause disease, as anyone with recurrent fever blisters will tell you.  Staying quiet allows them to avoid the immune system and essentially act as selfish DNA.

A recent paper [ PNAS vol. 120 e2212864120 ’23 ] shows that Kaposi’s Sarcoma Herpes Virus (KSHV) uses a circular RNA (circRNA) derived from a human oncogene called RELL1.  The circular RNA they induce is called hsa_circ-0001400.  In general circular RNAs are formed by back splicing of a 5′ splice to an upstream 3′ splice site.   One of their functions is to act as sponges for microRNAs as some contain multiple binding sites for them.  Some cells contain 25,000 of them.

Viruses are known to hijack cellular proteins to use for their own ends.  It isn’t clear how the herpes viruses stimulate formation of hsa_circ_0001400, but use it they do, as it promotes viral latency,  cell cycle genes and inhibits apoptosis.

This another example of the RNA world which supposedly existed before the DNA world, like DOS under the Windows operating system (forgotten but not gone)

Clinical reality comes to animal models of genetic disease

“So you’re going to be experimenting on me, doc?”  I heard that a fair amount practicing neurology in Montana.  There is no guarantee that any drug we use will always work, particularly drugs for epilepsy (anticonvulsants).  When one of them didn’t, it was always obvious.

Being honest with patients, I’d always say we’ll try drug X, it has a high chance of working.  And that was the (actually quite intelligent) response I sometimes got.

I’d then launch into some sort of explanation, saying that people aren’t cars and not all the same so they don’t respond the medications the same way (cue up rare side effects).  Of course in the 70’s and 80’s we had no idea just how different each of us actually is.

Now we do and this is even true for children in which the copies of their parents genomes is far from exact– https://luysii.wordpress.com/wp-admin/post.php?post=3442&action=edit&classic-editor —

From the ENCODE study.  Some 2,976 parent child trios had their whole genomes sequenced.  There were 200,435 de novo mutations in the group (an average of 67 mutations/child).  The number of de novo mutations increases by 1.39% for each year of paternal age and .38% for each year of maternal age at the time of the birth of the child.  Earlier work with far less data implied that maternal age at conception was irrelevant to the mutation rate — this is clearly incorrect.

The same variation in genomes is another pitfall in understanding what effects a protein mutation has when studied in animals.  Up to now research has been done in very inbred animal strains which all have exactly the same genome, to cancel out the variability in response. Usually just one inbred strain is studied.  This is good.

No it’s bad !! [ Neuron vol. 111 pp. 539 – 556 ’23 ] studied one particular mutation in a protein called CHD8 which is associated with autism in man.  They put the mutated protein into 1,000 mice from 33 different strains and measured a variety of phenotypes (brain and body weights, cognition, activity, social behavior, exploratory activity in an open field, etc. etc.).

Guess what?  The same mutant in the same protein had a wide variety of phenotypes which depended on the strain and sex.  Some strains showed no phenotypic effects at all, while others showed many large effects.

So a lot of animal work on disease should be repeated (or at least taken with several grains of salt) on multiple strains.

So experimental animals are just like people responding to drugs that docs experiment with on them

Location bias

Location bias:  no this isn’t about real estate or red lining.  It’s about how drugs act differently depending on where they’re able to get.  If this sounds too abstract, location bias may explain why dimethyl tryptamine (DMT) is a hallucinogen (it is the main psychoactive component of ayahuasca) and why serotonin (5 hydroxy tryptamine) is not.

The psychoactive effects of many drugs (LSD, DMT) are explained by their binding to one of the many (> 13) subtypes of serotonin receptors, namely 5HT2AR.

Well serotonin certainly binds to 5HT2AR, so why doesn’t it produce hallucinations?  This is where [ Science vol. 379 pp. 700 – 706 ’23 ] (and local bias) comes in.

We tend to think of receptors for neurotransmitters (like serotonin) as being on the outer membrane of the cell (the plasma membrane).  This makes sense as neurotransmitters are released from neurons into the extracellular space.  However it is now known that some neurotransmitter receptors (such as 5HT2AR) are found inside the cell where they are found on endosomes and the Golgi apparatus.

The article claims that the hallucinogenic effects of DMT, LSD etc. etc. are due to their binding to 5HT2ARs found inside the cell, not those on the plasma membrane. Serotonin with its free OH and NH2 groups is simply too water soluble (hydrophilic) to pass through the lipids of the plasma membrane.   DMT and LSD are not.   Unfortunately we are a long way from understanding how activation of 5HT2ARs inside the cell leads to hallucinations, but if the authors are right, it’s time to look.

We don’t know if animals hallucinate, and use things like head twitch and effects on dendritic branching and size in tissue culture as markers for hallucinations as LSD, DMT produce these things,.

The authors do show that putting a serotonin transporter into neuronal cultures so serotonin gets inside, produces similar effects on dendritic branching and size.  While fascinating, these effects are  pretty far removed from clinical reality.

The authors do raise a fascinating point at the end of their paper.  Perhaps there are endogenous intracellular ligands for intracellular 5HT2AR which differ from serotonin.   Perhaps the hallucinations and mental distortions of schizophrenia and other psychiatric disease are due to too much of them.

When does a description of something become an explanation ?

“It’s just evolution”. I found this explanation of the molecular biology underlying our brain’s threefold expansion relative to the chimp extremely unsatisfying.  The molecular biology of part of the expansion is fascinating and beautifully worked out. For details see a copy of the previous post below the ***.

To say that these effects are ‘just evolution’ is using the name we’ve put on the process to explain the process itself, e.g.  being satisfied with the description of something as an explanation  of it.

Newton certainly wanted more than that for his description of gravity (the inverse square law, action at a distance etc. etc.) brilliant and transformative though it was.  Here he is in a letter to Richard Bentley

“That gravity should be innate inherent & {essential} to matter so that one body may act upon another at a distance through a vacuum without the mediation of any thing else by & through which their action or force {may} be conveyed from one to another is to me so great an absurdity that I believe no man who has in philosophical matters any competent faculty of thinking can ever fall into it. ”

But the form of the force law for gravity combined with Newton’s three laws of motion (1687) became something much more powerful, a set of predictions of phenomena as yet unseen.

The Lagrange points are one example.  They are points of equilibrium for small-mass objects under the influence of two massive bodies orbiting their common center of gravity.  The first Lagrange points were found by Euler in 1750, Lagrange coming in 10 years later.  One of the Lagrange points of the Earth Sun  system is where the James Webb telescope sits today remaining stable without expending much energy to keep it there.  In a rather satisfying sense the gravitational force law explains their existence (along with Newton’s laws of motion and a lot of math).  So here is where a description (the force law) is actually an explanation of something else.

But Newton wanted more, much more than his description of the gravitational force (the inverse square law).  It took Einstein centuries later to come up with General Relativity — the theory of the gravitational force.  Just as a ball rolls down an incline here under the force of gravity, planets roll down the shape of Einstein’s spacetime, which is put there by the massive bodies it contains.  By shaping space everywhere, masses give the illusion of force, no action at a distance is needed at all.

It is exactly in that sense that I find the explanation for the 8 million year scuplting of our brain as evolution unsatisfying.  It is essential a description trying to pass itself off as an explanation.  Perhaps there is no deeper explanation of what we’re finding out.  Supernatural explanations have been with us in every culture.

Hopefully if such an explanation exists, we won’t have to wait over two centuries for it as did Newton.

*****

The evolutionary construction and magnification of the human brain

Our brains are 3 times the size of the chimp and more complex.  Now that we have the complete genome sequences of both (and other monkeys) it is possible to look for the protein coding genes which separate us.

First some terminology.  Not every species found since the divergence of man and chimp is our direct ancestor.  Many banches are extinct.  The whole group of species are called hominins [Nature vol. 422 pp. 849 – 857 ‘ 03 ].  Hominids are species in the path between us and the chimp — sort of a direct line of descent.  However the terminology is in flux and confusing and I’m not sure this is right.   But we do need some terminology to proceed.

Hominid Specific genes (HS genes) result which result from recent gene duplications in hominid/human genomes.  Gene duplication is a great way for evolution to work quickly.  Even if one gene is essential, messing with the other copy won’t be fatal.  HS genes include >20 gene families that are dynamically expressed during the formation of the human brain.  It was hard for me to find out just how many HS genes there are.

Here are some examples. The human-specific NOTCH2NL genes increase the self-renewal potential of human cortical progenitors (meaning more brain cell can result from them).  TBC1D3and ARGHAP11B, are involved in basal progenitor amplification (ditto).

A recent paper [ Neuron vol. 111 pp. 65 – 80 ’23 ] discusses CROCCP2 (you don’t want to know what the acronym stands for) which is one of several genes in this family with at least 6 copies in various hominid genomes.  However, CROCCP2 is a duplicate unique to man.   It is highly expressed during brain development and enhances outer Radial Glial Cell progenitor proliferation.

The mechanism by which this happens is detailed in the paper and involves the cilium found on every neuron, mTOR, IFT20 and others.

But that’s not the point here, fascinating although these mechanisms are.   We’re watching a series of at least 20 gene duplications with subsequent modifications build the brain that is unique to us over relatively rapid evolutionary times.  The split between man and chimp is thought to have happened only 8 million years ago.

What should we call this process?  Evolution?  The Creator in action? The Blind Watchmaker?   It is certainly is eerie to think about.  There are 17 more HS genes to go involving in building our brains remaining to be worked out.  Stay tuned

 

The evolutionary construction and magnification of the human brain

Our brains are 3 times the size of the chimp and more complex.  Now that we have the complete genome sequences of both (and other monkeys) it is possible to look for the protein coding genes which separate us.

First some terminology.  Not every species found since the divergence of man and chimp is our direct ancestor.  Many banches are extinct.  The whole group of species are called hominins [Nature vol. 422 pp. 849 – 857 ‘ 03 ].  Hominids are species in the path between us and the chimp — sort of a direct line of descent.  However the terminology is in flux and confusing and I’m not sure this is right.   But we do need some terminology to proceed.

Hominid Specific genes (HS genes) result which result from recent gene duplications in hominid/human genomes.  Gene duplication is a great way for evolution to work quickly.  Even if one gene is essential, messing with the other copy won’t be fatal.  HS genes include >20 gene families that are dynamically expressed during the formation of the human brain.  It was hard for me to find out just how many HS genes there are.

Here are some examples. The human-specific NOTCH2NL genes increase the self-renewal potential of human cortical progenitors (meaning more brain cell can result from them).  TBC1D3and ARGHAP11B, are involved in basal progenitor amplification (ditto).

A recent paper [ Neuron vol. 111 pp. 65 – 80 ’23 ] discusses CROCCP2 (you don’t want to know what the acronym stands for) which is one of several genes in this family with at least 6 copies in various hominid genomes.  However, CROCCP2 is a duplicate unique to man.   It is highly expressed during brain development and enhances outer Radial Glial Cell progenitor proliferation.

The mechanism by which this happens is detailed in the paper and involves the cilium found on every neuron, mTOR, IFT20 and others.

But that’s not the point here, fascinating although these mechanisms are.   We’re watching a series of at least 20 gene duplications with subsequent modifications build the brain that is unique to us over relatively rapid evolutionary times.  The split between man and chimp is thought to have happened only 8 million years ago.

What should we call this process?  Evolution?  The Creator in action? The Blind Watchmaker?   It is certainly is eerie to think about.  There are 17 more HS genes to go involving in building our brains remaining to be worked out.  Stay tuned