The Human TKTL1 Mutation, the Evolution of Intellect, and a Spectacular Risk of Misinterpretation.

[NNadir]

The paper I'll discuss in this post is this one: Anneline Pinson, Lei Xing, Takashi Namba, Nereo Kalebic, Jula Peters, Christina Eugster Oegema, Sofia Traikov, Katrin Reppe, Stephan Riesenberg, Tomislav Maricic, Razvan Derihaci, Pauline Wimberger, Svante Pääbo, Wieland B. Huttner, Human TKTL1 implies greater neurogenesis in frontal neocortex of modern humans than Neanderthals, Science 377, 6611, eabl6422

The paper itself is behind a firewall apparently, I will briefly excerpt it using my access. If one wishes to escape my bullshitting commentary, one can simply go to a news item in another publication Nature which may be open sourced: Did this gene give modern human brains their edge?

Subtitle:

A mutation present in modern humans seems to drive greater neuron growth than does an ancient hominin version.

Another perspective, slightly more technical, on this work that may be open sourced is this one in the same journal where the full paper has been published: Scaling brain neurogenesis across evolution

Subtitle:

A genetic change could explain increased cortical neurogenesis in modern humans

Brigette Malgrange and Laurent Nguyen Science 8 Sep 2022 Vol 377, Issue 6611 pp. 1155-1156

Another possibly open sourced account of this work:

‘Breakthrough’ finding shows how modern humans grow more brain cells than Neanderthals

8 SEP 2022 By Rodrigo Pérez Ortega Science

Subtitle:

Lab experiments pinpoint extra brain growth orchestrated by a single gene change in modern humans

(Man, do I hate that word, "Breakthrough." More than once it's led to vast public stupidity.)

This paper has generated huge excitement, possibly even in the mainstream media, although I haven't looked.

I'm not a fan of genetic determinism, particularly the idea that what some people call "intelligence," is entirely or even primarily hereditary.

Of course, this idea of heritability has led to all kinds of morally and socially atrocious outcomes, from the historical (and regrettably modern) abyss of human slavery and other forms of racism, from the institution of monarchy, to the assignment of vast resources to intellectually deficient, morally depraved psychopaths like Donald Trump, and events like explosion of the worst war ever seen up to its time - the "First" World War, a dispute largely driven at it's outset by poor family relationships between highly inbred cousins, uncles and aunts, chiefly uncle Edward VII, his deformed nephew Wilhelm II, cousin Nicolas II, and niece czarina Alexandria. (cf. Tuchman, The Guns of August, one of the most beautifully written histories, ever) This war reignited 21 years after it ended as the "Second" World War, where the belief in heritability led to the murder of many millions of beautiful human beings based on who their forebears were, based on a bit of pseudoscientific mysticism barely removed from phrenology purported to "prove" the existence of a "master race."

The reality is that scientific results have been abused and perverted to support determinations originally codified by religious castes and notions of "divine rights", from "Social Darwinism," to the worse once (and possibly still) fashionable ideas about eugenics, to silly evocations about the absurd reductionist notion of their being something called "IQ," and its distribution among "races."

Of course, one could argue that this objection of mine to genetic determinism is sour grapes on my part, as I'm rather on the short end of the genetic, and in fact, intellectual stick. I have always enjoyed (in one translation at least) Dostoevsky's description of one his characters in The Idiot , Gavril Ardalionovich Ivolgin, described as a man who is merely intelligent enough to know how unintelligent he is. I read that novel for the first and last time more than 40 years ago and somehow that evocation still stings. I find it rather easy to go to places where I am the dumbest person in the room and have, in fact, made a habit of it. I grew up in a town where I was from the poor side of the tracks, and it did in fact leave me with the lifelong feeling of being ill prepared for, well, everything, somewhat deficient, certainly less urbane, a feeling I somewhat neurotically addressed with sometimes obsessive work.

Perhaps I only have had the illusion of rising out of my family background:

In Dostoevsky's time decades into pre-revolutionary Russia, my parents would have been serfs, in the antebellum American south, poor "yeoman farmers" or laborers - the class of poorly educated people who made up the bulk of the traitor Confederate Army and who supported slavery only because they wanted to feel superior to somebody, in this case, the slaves. Today these people make up the bulk of the MAGA slime, ironically people stupid enough to desire an autocracy in which they will be further and eternally debased.

Now we hear about a single mutation with the same modification (K317R in the long isoform cf. the supplemental information, figure S1) is a single gene that it is implied gives rise to human intelligence, specifically, a substitution of the basic amino acid lysine with the more basic residue arginine in the sequence of a metabolic protein, TKTL1, which is conserved in primate species including Neanderthals, but which features a single nucleotide polymorphism in humans.

(cf. Reference 27 in the full paper: K. Prüfer et al., The complete genome sequence of a Neanderthal from the Altai Mountains. Nature 505, 43–49 (2014). )

I'm not one to discount the power of single nucleotide polymorphisms (SNP). The social development - but happily not his intellectual development (although it might have been) - of my oldest son was determined by a somatic SNP in utero: Sturge–Weber Syndrome and Port-Wine Stains Caused by Somatic Mutation in GNAQ (Shirley, Matthew D. and Tang, Hao and Gallione, Carol J. and Baugher, Joseph D. and Frelin, Laurence P. and Cohen, Bernard and North, Paula E. and Marchuk, Douglas A. and Comi, Anne M. and Pevsner, Jonathan, N Engl J Med 2013; 368:1971-1979).

Nor am I competent to criticize the science in this paper, and even were I so, I do not expect that I would find any legitimate reason to do so. Even a superficial objection, that the number of fully sequenced genomes of Neanderthals (of which, to my knowledge there is one) may be entirely unrepresentative can be set aside by noting that a large number of primates have been fully sequenced for this gene and its transcribed product: The Uniprot listing for fully sequenced TKTL1 gives 10 fully curated protein sequences, two of which are human, and 167 unreviewed protein sequences including Sumatran Orangutans and Gorillas and Chimpanzees to hedgehogs, to narwhals, to Tasmanian devils to polar bears, koalas and lamas and more. From my perspective, this is a beautiful paper, written by hardworking brilliant scientists, the culmination of years of careful work. This gene is well known and well understood.

It is also self evident that insight to what it is to be human does have a genetic component, but how genes act to make a human being is hardly clear, my own feeling is that it will inexorably clear. The paper makes clear, as do the experiments therein both on human and murine fetal tissue that the effect of this gene is generally morphological and has no meaning on how these morphological structures will interact both with environmental and nutritional insults or access, nor does it predict how they may ultimately interact intellectually.

All this said, there is a social risk of this fine science in interpretation, particularly when presented by nominally educated people, charismatic people, and even malevolent people to take leaps of the type that often cause tragedy. To often in our culture we accept, without a whit of critical thinking, people are prone to accept appeal to authority arguments. Note that the authority may or may not be competent or even remotely competent. Consider a person who declares himself or herself a "very stable genius" who somehow stumbles into considerable power even absolute power. Suppose such a person infected with unnatural and patently absurd narcissism were to declare his or her genome some kind of standard, alleging it to be a high standard, might not this result in a new kind of racism based on an idiotic misinterpretation of molecular biology? This is not entirely a feature of paranoid inducing science fiction: In effect, for a long time in this country, leading up to the present day, people - even though they lacked a shred of insight to the molecular biology of inheritance - assumed that expression of TYRP1 gene in dermal tissue had some kind of bearing on human intelligence, although there is no evidence to my knowledge - and I looked to see if I could find any - that this gene has any importance in neural tissues. Nevertheless, the self-serving morons who advanced this wrong association devoid of any scientific credibility (not that they seriously looked for any), holding people who "labor for my happiness," - how's that for a euphemism from an arbiter of 'the rights of man' - under appalling conditions, all because of active dermal TRYP1. Might not some future capable but pernicious dictator declare that genes leading to dysfunction in the cingulate cortex - and clearly there are people with this dysfunction, some of whom are quite proud of it. These people are known as pyschopaths.

From the introductory text of the full paper:

Whether and how cognitive abilities of modern humans might differ from those of extinct archaic humans such as Neanderthals remains a matter of debate (1). Discovery of artifacts and art of presumably Neanderthal derivation (2, 3) fuels the debate. Cognitive abilities reside primarily in the neocortex, the largest and most recently evolved part of the brain, which is present only in mammals. The evolutionary expansion of the neocortex and the concomitant increase in neuron production are considered to be a basis for the increase in cognitive abilities that occurred during human evolution (4). Analyses of endocasts indicate that the endocranial volume of modern humans and Neanderthals was similar, suggesting similar brain and neocortex size (5). But whether similar neocortex size implies similar neocortical neuron production has remained unclear.

One approach to address this question would be to compare key features of neocortex development between modern humans and Neanderthals, using appropriate model systems and focusing on the actions of modern human versus Neanderthal variants of key genes that govern neocortex development. Of particular interest here are genes that influence the behavior of neural progenitor cells (neuroprogenitors) in the fetal neocortex, as their abundance and proliferative capacity determine the number of cortical neurons generated during development (6, 7).

Two principal classes of neuroprogenitors are present in the developing neocortex, referred to as apical progenitors (APs) and basal progenitors (BPs). APs, the primary class, reside in the ventricular zone (VZ). After the onset of neurogenesis, the major AP type is the apical (or ventricular) radial glia (aRG). Rather than producing neurons, aRG generate mostly BPs, the secondary class of neuroprogenitors. Newborn BPs migrate to the subventricular zone (SVZ), from where they generate most of the cortical neurons (7).
Two types of BPs have been characterized, referred to as basal intermediate progenitors (bIPs) and basal (or outer) radial glia (bRG). In mammals with a small and lissencephalic neocortex, such as mice, ~90% of the BPs are neurogenic bIPs that typically divide once to give rise to two neurons [(7) and references therein]. bRG constitute only ~10% of the BPs in embryonic mouse neocortex (8–10). In contrast, in ferrets (a gyrencephalic carnivore) and in primates such as marmosets, macaques, and humans, bRG constitute ~50% of the BP pool (8, 11–13)...

... In contrast to bIPs, neurogenic divisions of bRG are typically asymmetric, generating a bRG (self-renewal) and a neuron (7, 12, 13). This mode of cell division reflects the presence of cell polarity of bRG, evident as a basal process, which is lacking in bIPs (7, 12, 13). bRG generate more cortical neurons over time than bIPs (12).

A gene that could influence the behavior of neuroprogenitors in fetal human neocortex is transketolase-like 1 (TKTL1) (16). TKTL1 belongs to the transketolase family of enzymes. It operates in the pentose phosphate pathway (PPP), a metabolic pathway linked to glycolysis (17–19). We focused on TKTL1 because: (i) TKTL1 is preferentially expressed in neuroprogenitors, including bRG, of fetal human neocortex (20–23). (ii) TKTL1, implicated in human tumors (24, 25) and tumor cell proliferation (19, 26), may also increase neuroprogenitor numbers. (iii) TKTL1 is one of the few proteins with an amino acid substitution found in essentially all present-day humans and absent from extinct archaic humans, Neanderthals and Denisovans, and other primates (27)...

The authors found that insertion of the human TKTL1 gene into mouse and ferret embryonic cells increases the number and viability of the basal radial glial (bRG) cells which can generate vastly more neurons (see the text above) and that inserting the non-human TKTL1 gene into human fetal neurological tissue decreased this number.

This figure from the paper indicates how this metabolic protein acts on the pentose phosphate pathway:

Fig. 5. Inhibition of the pentose phosphate pathway abolishes the hTKTL1-induced increase in bRG in embryonic mouse neocortex and reduces bRG abundance in fetal human neocortex.
(A) Schematic representation of the glycolysis and pentose phosphate pathways. Known TKT, and proposed TKTL1 (19), sites of action are indicated. 6-Aminonicotinamide (6-AN) and S3: 6-phosphogluconate dehydrogenase (6PGDH) inhibitors. (B and C) Mouse lateral neocortex (lat. ncx.) E13.5 IUE with GFP plasmid, together with empty (control, CTL) or hTKTL1 plasmid. E14.5: Hemisphere rotation culture (HERO, 24 hours) in the absence or presence of 10, 50, or 100 μM 6-AN. Quantifications of pVim+/GFP+/BPs without pVim+ process (mitotic bIPs) (B) and with pVim+ process (mitotic bRG) (C) in 200-μm-wide fields. Means of 3 to 9 embryos. Error bars, SD. (B) Two-way ANOVA; (C) two-way ANOVA with Bonferroni post hoc test, ****P < 0.0001, **P < 0.01. (D to F) Free-floating tissue culture (FFT, 48 hours) of human neocortical tissue (PCW 10 to 14) for 48 hours, without or with 10, 50, or 100 μM 6-AN. (D) pVim (magenta) immunofluorescence plus DAPI staining (gray). Right sides: white boxed areas at higher magnification; pVim+/BP without pVim+ process (mitotic bIP, dashed lines), and with pVim+ process (mitotic bRG, solid lines). Scale bar, 40 μm. [(E) and (F)] Quantification of pVim+/BPs without pVim+ process (mitotic bIPs) (E) and with pVim+ process (mitotic bRG) (F) in 200-μm-wide field. Means of 3 to 5 fetal samples, each a different color. (E) One-way ANOVA; (F) one-way ANOVA with Tukey post hoc test, *P < 0.05.

It is notable that an environmental insult, the chemical 6-aminonicotinamide, a powerful rodenticide, 6-aminonictotinamide, causes human fetal tissue to become "mouse-like," suppressing the growth of bRG cells.

It should be clear therefore that genes alone are not responsible for development, either in neurological morphological and cell type development, but that environment also plays a role.

It is also notable that the hTKLT1, as a metabolic protein involved in cell division is also a potential target in cancer, as are mutations in the isocitrate dehydrogenase protein, also a metabolic protein.

I'm not sure that the pulse of paranoia I feel whenever neurophysiology and the nebulous concept of "intellect" are combined, if only because of the long and sordid history of the misappropriation of science to racism exists, but I very much doubt that the molecular biology of what and how I feel will ever be entirely understood.

Although I very much admire the science this paper represents, I'm glad that knowing some things is a long way off. I cling to the idea that a human being is far more than a polymer of phosphate linked purinylated and pyridmidylated riboses.

Too much reduction is, I think, dangerous.

Have a nice Sunday.

[eppur_se_muova]

1. Evolution is the realization of statistical effects on a massive scale.

I tend to think of genes not so much as cause-and-effect mechanisms as devices that 'tend to' steer things one way or another, with the final outcome determined by the net operation of such tendencies across many genes within the same organism, and many organisms within a population. Simple cause and effect gets rather washed out in such an enormous space of possibilities.

Not something that makes for sexy headlines, unfortunately.

[Layzeebeaver]

2. And once again, man's progress devolves into another plot device for a Planet of the Apes movie.

with Werner Hertzog directing.

NNadir - always love your posts!