Mine eyes have seen the scupting of the brain

With apologies to the Battle Hymn of the Republic

Mine eyes have seen the sculpting of the brain

He is trampling out the variants where the memes of thought are stored

He hath loosed the fateful errors of his terrible swift sword

Our genes are marching on

Well not quite but we know quite a bit more about the genetic changes that have given us our much larger and much more complex brain than the chimpanzee.

Many thanks to Pierre Vanderhaeghen one of the authors of [ Neuron vol. 111 pp. 65 – 80 ’23 ] discussed in a recent post — https://luysii.wordpress.com/2023/02/01/the-evolutionary-construction-and-magnification-of-the-human-brain/ for sending me the PDF of his review “Cellular and Molecular Mechanisms Linking Cortical Development and Evolution” in Annu. Rev. Genet. vol. 55 pp. 24.1 – 24.27 ’21 in response to my request for more information about the genetic changes which make our brains what they are today.

It will be very difficult to separate the significant changes in our genomes which are specific to humans and not found in the chimp and gorilla.  Some 20,000,000 to be exact.  (This figure comes from the notes I took on Cell vol. 149 pp. 737 –  739, 912 – 922, 923 – 935 ’12** or Nature vol. 486 pp. 481 – 482 ’12** years ago.  Unfortunately when I tried to pull up these papers on the net to check the figure, I couldn’t do it — there will be more of this in this post, and when I can’t I’ll put a ** after the year).

The previous paper talked about CROCCP2, a duplicated gene unique to man which is expressed only in the human developing cerebral cortex.   Our genome contains 10 families of protein coding genes the duplications of which are only found in man.  Our genome contains over 50 families of duplicated protein coding genes (obviously not all unique to man), but 30 duplicated genes are expressed in the fetal developing brain.  The CROCCP2 variant leads a larger brain — for details please see https://luysii.wordpress.com/2023/02/01/the-evolutionary-construction-and-magnification-of-the-human-brain/.

Well 30 duplicated genes isn’t much.  What about where the real action is — the control of when and where these genes are expressed.

The following is from a post of 2015

”

It ain’t the bricks, it’s the plan

Nothing better shows the utility (and the futility) of chemistry in biology than using it to explain the difference between man and chimpanzee. 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.”

One of the things  determining when and where proteins are expressed are the enhancers.  These are stretches of DNA which enhance the transcription of a protein coding gene into mRNA which is translated by the ribosome into protein.  They consist of hundreds of basepairs of DNA and are bound by transcription factors. Each cell type is estimated to contain 70,000 -100,000 enhancers [ Cell vol. 183 p. 40 ’20 ]**

Here’s where the evolutionary rubber hits the road.  Human Gained Enhancers (HGEs) are enhancers active only in man and thousands of them are active in cerebral cortex formation [ Annu. Rev. Genet. vol. 55 pp. 24.1 – 24.27 ’21 ].

Human Accelerated Regions (HARs) are regions of our genome which are thought to show accelerated mutation changes in an otherwise evolutionarily ultraconserved sequence.  These sequences are unique to the human genome and there are 2,772 of them [ Neuron vol. 109 pp. 3231 – 3233, 3239 – 3251 ’21 ]**.  As you might expect, they are in the 98% of our genomes which are not coding for the amino acids of proteins.  They are enriched for transcription binding motifs.  So some might be in enhancers, some might be in promoters, but they’re all about ‘the plan’ and not the bricks.

Control elements can also be lost, and some 510 locations are known where DNA sequences have been lost in the human genome.  These sequences are highly conserved between chimp and other mammals, and most of them are in enhancers [ Nature vol. 471 pp. 216 – 219 ‘ 11 ]**.

And then there is repurposing of an existing gene.  Osteocrinin (aka Musclin) is an exercise induced protein which acts in muscle to increase exercise capcity.  It is turned on by MEF2 (Myocyte Enhancer Factor 2) a transcription factor. t of  But only in man, is osteocrinin found in the brain why.  Because another MEF binding site has been put in front of the gene, so that (in some unspecified manner, neural activity turns it on). [ Nature vol. 539 pp. 171 – 172, 242 – 247 ’16 ]**

So we have myriads of genome changes involved in building our brains (enhancer gain and loss), human accelerated regions, duplicated genes with new functions and repurposed genes.

Mine eyes have seen the sculpting of the brain (but only dimly presently). Stay tuned.