Friday, 12 February 2021

Evolution News - How a Single Gene Alteration May Have Separated Modern Humans From Cousin Species

Modern Human skull (L) compared to Neanderthal skull (R)
How a Single Gene Alteration May Have Separated Modern Humans from Predecessors | UC San Diego News Center

Researchers at UC San Diego, led by Alysson R. Muotri, PhD, believe they have shown that a mutation in a single gene could have altered the way our ancestors' brains were wired, enabling them to develop complex social structures, language, adaptability, creativity and use of technology, all of which appear to have arisen over a very short period of time, by evolutionary standards.

The mutation involved a single base-pair substitution - the simplest of all mutations!

They did this by growing brain 'organoids' in Petri dishes from modified stem cells. The UC San Diego news release explains:
Evolutionary studies rely heavily on two tools — genetics and fossil analysis — to explore how a species changes over time. But neither approach can reveal much about brain development and function because brains do not fossilize, Muotri said. There is no physical record to study.

So Muotri decided to try stem cells, a tool not often applied in evolutionary reconstructions. Stem cells, the self-renewing precursors of other cell types, can be used to build brain organoids — “mini brains” in a laboratory dish. Muotri and colleagues have pioneered the use of stem cells to compare humans to other primates, such as chimpanzees and bonobos, but until now a comparison with extinct species was not thought possible.

In a study published February 11, 2021 in Science, Muotri’s team catalogued the differences between the genomes of diverse modern human populations and the Neanderthals and Denisovans, who lived during the Pleistocene Epoch, approximately 2.6 million to 11,700 years ago. Mimicking an alteration they found in one gene, the researchers used stem cells to engineer “Neanderthal-ized” brain organoids.

Neanderthal-ized brain organoids (left) look very different than modern human brain organoids (right) — they have a distinctly different shape, and differ in the way their cells proliferate and how their synapses form.
“It’s fascinating to see that a single base-pair alteration in human DNA can change how the brain is wired,” said Muotri, senior author of the study and director of the UC San Diego Stem Cell Program and a member of the Sanford Consortium for Regenerative Medicine. “We don’t know exactly how and when in our evolutionary history that change occurred. But it seems to be significant, and could help explain some of our modern capabilities in social behavior, language, adaptation, creativity and use of technology.”

The team initially found 61 genes that differed between modern humans and our extinct relatives. One of these altered genes — NOVA1 — caught Muotri’s attention because it’s a master gene regulator, influencing many other genes during early brain development. The researchers used CRISPR gene editing to engineer modern human stem cells with the Neanderthal-like mutation in NOVA1. Then they coaxed the stem cells into forming brain cells and ultimately Neanderthal-ized brain organoids.

[...]

The Neanderthal-ized brain organoids looked very different than modern human brain organoids, even to the naked eye. They had a distinctly different shape. Peering deeper, the team found that modern and Neanderthal-ized brain organoids also differ in the way their cells proliferate and how their synapses — the connections between neurons — form. Even the proteins involved in synapses differed. And electrical impulses displayed higher activity at earlier stages, but didn’t synchronize in networks in Neanderthal-ized brain organoids.
In other words, under the influence of the gene with the minimal mutation, human brain cells develop differently to those of our closest evolutionary cousins, the Neanderthals.

Such was the advantage of this change that the mutation appears to have spread very rapidly through the human population, probably giving us a major competitive edge over our then contemporaneous cousin species, the Neanderthals and the Denisovans, when we migrated out of Africa and came into close contact with them.

As mentioned above the team's findings are published today in Science:

Structured Abstract



INTRODUCTION


Current views of human evolution, as supported by the fossil record, indicate that many hominin lineage branches arose, but only one survived to the present. Neanderthals and Denisovans, two of these extinct lineages, are our closest evolutionary relatives and therefore provide the most subtle genetic and phenotypic contrast to our species. Comparison of Neanderthal, Denisovan, and extant human genomes has shown that many humans today carry genes introduced through past admixture events and has allowed enumeration of human-specific genetic differences that may have been important for recent human evolution. Neuro-oncological ventral antigen 1 (NOVA1) includes one of the few protein-coding differences between modern human and archaic hominin genomes that could affect human neurodevelopment.

RATIONALE


NOVA1 regulates alternative splicing in the developing nervous system and is a master regulator of splicing genes responsible for synapse formation. Altered NOVA1 splicing activity in humans is associated with neurological disorders, underscoring the role of NOVA1 in neural function. Using CRISPR-Cas9 genome-editing technology in human induced pluripotent stem cells (iPSCs), we replaced the modern human allele of the NOVA1 gene with the ancestral allele found in Neanderthals and Denisovans, which contains a single-nucleotide substitution at position 200 that causes an isoleucine-to-valine change. To investigate the functional importance of this amino acid change in humans, we followed iPSC neural development through functional cortical organoids.

RESULTS


The reintroduction of the archaic version of NOVA1 into a human genetic background causes changes in alternative splicing in genes involved in neurodevelopment, proliferation, and synaptic connectivity. These changes co-occur with differences in organoid morphology and neural network function, suggesting a functional role for the derived human-specific substitution in NOVA1. Furthermore, cortical organoids carrying the archaic NOVA1 displayed distinct excitatory synaptic changes, which may have led to the observed alterations in neural network development. Collectively, our data suggest that expression of the archaic NOVA1 leads to modified synaptic protein interactions, affects glutamatergic signaling, underlies differences in neuronal connectivity, and promotes higher heterogeneity of neurons regarding their electrophysiological profiles.

CONCLUSION


A subset of genetic changes may underly the phenotypic traits that separate our species from these extinct relatives. We developed a platform to test the impact of human-specific genetic variants by reintroducing the archaic form found in Neanderthals and Denisovans and measuring its effects during neurodevelopment using human brain organoids. Our results suggest that the human-specific substitution in NOVA1, which became fixed in modern humans after divergence from Neanderthals, may have had functional consequences for our species’ evolution.

NOVA1 archaic variant in cortical organoids affects cellular, molecular, and neural network activity profiles.


During human evolution, modern humans acquired a specific nucleotide substitution in the RNA binding domain of NOVA1. Using genome editing technology, the archaic version of NOVA1 was introduced in human iPSCs and differentiated into cortical organoids. The changes could be observed in different levels, from altered proliferation, different gene expression, and splicing profiles to modified glutamatergic synapsis and neuronal network connectivity. NOVA1I200, NOVA1 gene containing isoleucine archaic variant. NOVA1V200, NOVA1 gene containing valine human variant; NOVA1Ar/Ar, human cell line with homozygous reintroduction of the NOVA1 archaic variant; NOVA1Hu/Hu, human cell line with NOVA1 human variant. Figure created with BioRender.com.


Abstract


The evolutionarily conserved splicing regulator neuro-oncological ventral antigen 1 (NOVA1) plays a key role in neural development and function. NOVA1 also includes a protein-coding difference between the modern human genome and Neanderthal and Denisovan genomes. To investigate the functional importance of an amino acid change in humans, we reintroduced the archaic allele into human induced pluripotent cells using genome editing and then followed their neural development through cortical organoids. This modification promoted slower development and higher surface complexity in cortical organoids with the archaic version of NOVA1. Moreover, levels of synaptic markers and synaptic protein coassociations correlated with altered electrophysiological properties in organoids expressing the archaic variant. Our results suggest that the human-specific substitution in NOVA1, which is exclusive to modern humans since divergence from Neanderthals, may have had functional consequences for our species’ evolution.

Trujillo, Cleber A.; Rice, Edward S.; Schaefer, Nathan K.; Chaim, Isaac A.; Wheeler, Emily C.; Madrigal, Assael A.; Buchanan, Justin; Preissl, Sebastian; Wang, Allen; Negraes, Priscilla D.; Szeto, Ryan A.; Herai, Roberto H.; Huseynov, Alik; Ferraz, Mariana S. A.; Borges, Fernando S.; Kihara, Alexandre H.; Byrne, Ashley; Marin, Maximillian; Vollmers, Christopher; Brooks, Angela N.; Lautz, Jonathan D.; Semendeferi, Katerina; Shapiro, Beth; Yeo, Gene W.; Smith, Stephen E. P.; Green, Richard E.; Muotri, Alysson R.
Reintroduction of the archaic variant of <em>NOVA1</em> in cortical organoids alters neurodevelopment
Science 12 Feb 2021: Vol. 371, Issue 6530, eaax2537 DOI: 10.1126/science.aax2537

Copyright: © 2021 The authors.
Published by American Association for the Advancement of Science
Reprinted by kind permission under licence #5006181488980
This research shows how even the smallest possible mutation can have a profound effect on the evolution of a species. In our case it enabled us to progress from hunter-gatherers to take advantage of the larger brain we had been evolving and the lengthening pharynx that was making speech possible, to becoming the highly intelligent, technologically and culturally advanced species that we are today, although the continued existence of Creationism calls into question the extent to which we are 'highly intelligent'.

Incidentally, did anyone else spot the casual refutation of the Creationist lie that all mutations are harmful and 'devolutionary' [sic] (© Michael J. Behe)? That's the problem with trying to foist a half-baked, counter-factual notion, onto your dupes - the facts keep refuting it. The basic problem is that it was not very intelligently designed to make it look like there is a grain of truth in the Abrahamic creation myth.








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