Scientists Study How A Single Gene Alteration May Have Separated

CURIOUS FEBURARY 2021
Scientists study how a single gene alteration may have separated

As a professor of pediatrics and cellular and molecular medicine at University of California San Diego School of
Medicine, Alysson R. Muotri, PhD, has long studied how the brain develops and what goes wrong in neurological
disorders. For almost as long, he has also been curious about the evolution of the human brain -; what changed that
makes us so different from preceding Neanderthals and Denisovans, our closest evolutionary relatives, now extinct?
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 cataloged 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.
It's fascinating to see that a single base-pair alteration in human DNA can change how the brain is wired. 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."
Alysson R. Muotri, Study Senior Author, Director, UC San Diego Stem Cell Program and Member, Sanford
Consortium for Regenerative Medicine
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.
Brain organoids are little clusters of brain cells formed by stem cells, but they aren't exactly brains (for one, they
lack connections to other organ systems, such as blood vessels). Yet organoids are useful models for studying
genetics, disease development and responses to infections and therapeutic drugs. Muotri's team has even optimized
the brain organoid-building process to achieve organized electrical oscillatory waves similar to those produced by
the human brain.
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.
According to Muotri, the neural network changes in Neanderthal-ized brain organoids parallel the way newborn non-
human primates acquire new abilities more rapidly than human newborns.
"This study focused on only one gene that differed between modern humans and our extinct relatives. Next we want
to take a look at the other 60 genes, and what happens when each, or a combination of two or more, are altered,”
Muotri said
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"We're looking forward to this new combination of stem cell biology, neuroscience and paleogenomics. The ability
to apply the comparative approach of modern humans to other extinct hominins, such as Neanderthals and
Denisovans, using brain organoids carrying ancestral genetic variants is an entirely new field of study."
To continue this work, Muotri has teamed up with Katerina Semendeferi, professor of anthropology at UC San
Diego and study co-author, to co-direct the new UC San Diego Archealization Center, or ArchC.
"We will merge and integrate this amazing stem cell work with anatomic comparisons from several species and
neurological conditions to create downstream hypotheses about brain function of our extinct relatives,”
Semendeferi said. "This neuro-archealization approach will complement efforts to understand the mind of our
ancestors and close relatives, like the Neanderthals."
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A body burned inside a hut 20,000 years ago signaled shifting views of
death
Linking the dead with human-built structures may have brought the dead and living
closer
Middle Eastern hunter-gatherers changed their relationship with the dead nearly 20,000 years ago. Clues to that
spiritual shift come from the discovery of an ancient woman’s fiery burial in a hut at a seasonal campsite.
Burials of people in houses or other structures, as well as cremations, are thought to have originated in Neolithic
period farming villages in and around the Middle East no earlier than about 10,000 years ago. But those treatments of
the dead appear to have had roots in long-standing practices of hunter-gatherers, says a team led by archaeologists Lisa
Maher of the University of California, Berkeley and Danielle Macdonald of the University of Tulsa in Oklahoma.
The new find suggests that people started to associate the dead with particular structures at a time when groups of
hunter-gatherers were camping for part of each year at a hunting and trading site in eastern Jordan. A budding desire
to link the dead with human-built structures possibly reflected a belief that by doing so the dead would remain close to
the living, the scientists report in the March Journal of Anthropological Archaeology.
Excavations at the ancient site, now called Kharaneh IV, in 2016 revealed a woman’s partial, charred skeleton on
the floor of a hut that had been lit on fire. Her body had been placed on its side with knees flexed. Analyses of
charring patterns on her bones and burned sediment surrounding her remains suggest the woman’s body was placed
inside the hut just before the brushwood structure was intentionally burned. Charcoal- and ash-rich sediment
borders where the hut once stood, a sign that the fire was confined to the structure. The hut’s walls apparently fell
inward after being set ablaze.
Radiocarbon-dated samples from the earthen floor near the woman’s remains date her interment to around 19,200
years ago.
Several Neolithic sites contain examples of the dead having been placed in or under burned houses, as well as
instances of bodies that were intentionally burned after death, says archaeologist Peter Akkermans of Leiden
University, who did not participate in the new research. “The work at Kharaneh IV now dates these practices to more
than 10,000 years earlier, in wholly different cultural settings of hunter-gatherer communities versus Neolithic farming
villages.”
Other social developments traditionally attributed to Neolithic farmers, including year-round settlements (SN: 8/30/10)
and pottery making (SN: 6/28/12), first appeared among hunter-gatherers.
Remains of at least three other huts have been found at Kharaneh IV, including one with graves beneath the floor that
contained two human skeletons (SN: 2/22/12). That roughly 19,400-year-old hut was also burned down, possibly
when the site’s occupants stopped using it but not as part of a human burial event.
The new discovery at Kharaneh IV “links the death of a person and the destruction or death of a building as part of a
funerary rite,” Maher says. Perhaps the hut was where the woman or her family lived, or perhaps she died there and the
structure was deemed off-limits, she suggests. Either way, Kharaneh IV was occupied for several generations after the
woman’s death, until roughly 18,600 years ago, so establishing a permanent place for her may have been considered
important.
Meanings and beliefs that Kharaneh IV residents attributed to burning a hut in which a dead woman’s body had been
placed are still a mystery, Maher says. The use of fire in that event might have signified some type of transformation,
rebirth, cleansing or life-and-death cycle, she suggests.
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Humanlike thumb dexterity may date back as far as 2 million years

ago
Improved grip gave tool-wielding ancestors an advantage over related hominids
Thumb dexterity similar to that of people today already existed around 2 million years ago, possibly in some of the
earliest members of our own genus Homo, a new study indicates. The finding is the oldest evidence to date of an
evolutionary transition to hands with powerful grips comparable to those of human toolmakers, who didn’t appear for
roughly another 1.7 million years.
Thumbs that enabled a forceful grip and improved the ability to manipulate objects gave ancient Homo or a closely
related hominid line an evolutionary advantage over hominid contemporaries, says a team led by Fotios Alexandros
Karakostis and Katerina Harvati. Now-extinct Australopithecus made and used stone tools but lacked humanlike thumb
dexterity, thus limiting its toolmaking capacity, the paleoanthropologists, from Eberhard Karls University of Tübingen in
Germany, found.
The researchers digitally simulated how a key muscle influenced thumb movement in 12 previously found fossil
hominids, five 19th century humans and five chimpanzees. Surprisingly, Harvati says, a pair of roughly 2-million-year
old thumb fossils from South Africa display agility and power on a par with modern human thumbs.
Scientists disagree about whether the South African finds come from early Homo or Paranthropus robustus, a species
on a dead-end branch of hominid evolution (SN: 4/2/20). But the thumb dexterity in those ancient fossils is
comparable to that found in members of Homo species that appeared after around 335,000 years ago, the researchers
report January 28 in Current Biology. That includes Neandertals from Europe and the Middle East, and a South
African hominid dubbed Homo naledi, which possessed an unusual mix of skeletal traits (SN: 5/9/17).
By comparison, they conclude, Homo or P. robustus possessed thumbs that were more forceful than those of three
several-million-year-old Australopithecus species, two of which have previously been proposed to have humanlike
hands (SN: 1/22/15).
“Australopithecus would probably be able to perform most [tool-related] hand movements, but not as efficiently as
humans or other Homo species we studied,” Harvati says. The tool-wielding repertoire of Australopithecus species
fell closer to that of modern chimpanzees, who use twigs to collect termites and rocks to crack nuts, she suggests (SN:
11/6/09).
Harvati’s team went beyond past efforts that focused only on the size and shape of ancient hominids’ hand bones.
Using data from humans and chimpanzees on how hand muscles and bones interact while moving, the researchers
constructed a digital, 3-D model to re-create how a key thumb muscle — musculus opponens pollicis — attached to a
bone at the base of the thumb and operated to bend the digit’s joint toward the palm and fingers.
These new models of how ancient thumbs worked underscore the slowness of hominid hand evolution, says
paleoanthropologist Matthew Tocheri of Lakehead University in Thunder Bay, Canada. Australopithecus made and
used stone tools as early as around 3.3 million years ago (SN: 5/20/15). “But we don’t see major changes to the
thumb until around 2 million years ago, soon after which stone artifacts become far more common across the African
landscape,” he says.
Karakostis and Harvati’s 3-D models of ancient thumb dexterity represent a promising advance, says
paleoanthropologist Carol Ward of the University of Missouri in Columbia. But further work needs to examine how
other thumb muscles interacted with musculus opponens pollicis to influence how that digit worked in different
hominid species, she adds.
In a related finding, Ward and her colleagues — including Tocheri — reported in 2014 that a roughly 1.42-million
year-old hominid finger fossil from East Africa pointed to an early emergence of humanlike manipulation skills.
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Scientists Study How A Single Gene Alteration May Have Separated

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CURIOUS FEBURARY 2021