Focus on function helps identify the changes that made us human

Date:
June 20, 2023
Source:
Whitehead Institute for Biomedical Research
Summary:
Research sheds light on human evolution, and demonstrates an
approach for identifying significant differences in how genes are
used between closely-related species.


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FULL STORY ========================================================================== Humans split away from our closest animal relatives, chimpanzees, and
formed our own branch on the evolutionary tree about seven million years
ago. In the time since -- brief, from an evolutionary perspective -- our ancestors evolved the traits that make us human, including a much bigger
brain than chimpanzees and bodies that are better suited to walking on
two feet. These physical differences are underpinned by subtle changes at
the level of our DNA. However, it can be hard to tell which of the many
small genetic differences between us and chimps have been significant
to our evolution.

New research from Whitehead Institute Member Jonathan Weissman; University
of California, San Francisco Assistant Professor Alex Pollen; Weissman
lab postdoc Richard She; Pollen lab graduate student Tyler Fair;
and colleagues uses cutting edge tools developed in the Weissman lab
to narrow in on the key differences in how humans and chimps rely on
certain genes. Their findings, published in the journal Cell on June
20th, may provide unique clues into how humans and chimps have evolved, including how humans became able to grow comparatively large brains.

Studying function rather than genetic code Only a handful of genes are fundamentally different between humans and chimps; the rest of the two
species' genes are typically nearly identical. Differences between the
species often come down to when and how cells use those nearly identical
genes. However, only some of the many differences in gene use between
the two species underlie big changes in physical traits. The researchers developed an approach to narrow in on these impactful differences.

Their approach, using stem cells derived from human and chimp skin
samples, relies on a tool called CRISPR interference (CRISPRi) that
Weissman's lab developed. CRISPRi uses a modified version of the
CRISPR/Cas9 gene editing system to effectively turn off individual
genes. The researchers used CRISPRi to turn off each gene one at a time
in a group of human stem cells and a group of chimp stem cells. Then
they looked to see whether or not the cells multiplied at their normal
rate. If the cells stopped multiplying as quickly or stopped altogether,
then the gene that had been turned off was considered essential: a gene
that the cells need to be active-producing a protein product- in order
to thrive. The researchers looked for instances in which a gene was
essential in one species but not the other as a way of exploring if and
how there were fundamental differences in the basic ways that human and
chimp cells function.

By looking for differences in how cells function with particular genes disabled, rather than looking at differences in the DNA sequence or
expression of genes, the approach ignores differences that do not appear
to impact cells.

If a difference in gene use between species has a large, measurable
effect at the level of the cell, this likely reflects a meaningful
difference between the species at a larger physical scale, and so
the genes identified in this way are likely to be relevant to the distinguishing features that have emerged over human and chimp evolution.

"The problem with looking at expression changes or changes in DNA
sequences is that there are many of them and their functional importance
is unclear," says Weissman, who is also a professor of biology at the Massachusetts Institute of Technology and an Investigator with the Howard Hughes Medical Institute. "This approach looks at changes in how genes
interact to perform key biological processes, and what we see by doing
that is that, even on the short timescale of human evolution, there has
been fundamental rewiring of cells." After the CRISPRi experiments were completed, She compiled a list of the genes that appeared to be essential
in one species but not the other. Then he looked for patterns. Many of
the 75 genes identified by the experiments clustered together in the
same pathways, meaning the clusters were involved in the same biological processes. This is what the researchers hoped to see. Individual small
changes in gene use may not have much of an effect, but when those changes accumulate in the same biological pathway or process, collectively they
can cause a substantive change in the species. When the researchers'
approach identified genes that cluster in the same processes, this
suggested to them that their approach had worked and that the genes were
likely involved in human and chimp evolution.

"Isolating the genetic changes that made us human has been compared
to searching for needles in a haystack because there are millions of
genetic differences, and most are likely to have negligible effects
on traits," Pollen says. "However, we know that there are lots of
small effect mutations that in aggregate may account for many species differences. This new approach allows us to study these aggregate effects, enabling us to weigh the impact of the haystack on cellular functions." Researchers think bigger brains may rely on genes regulating how quickly
cells divide One cluster on the list stood out to the researchers:
a group of genes essential to chimps, but not to humans, that help to
control the cell cycle, which regulates when and how cells decide to
divide. Cell cycle regulation has long been hypothesized to play a role
in the evolution of humans' large brains.

The hypothesis goes like this: Neural progenitors are the cells that
will become neurons and other brain cells. Before becoming mature
brain cells, neural progenitors divide multiple times to make more of themselves. The more divisions that the neural progenitors undergo, the
more cells the brain will ultimately contain -- and so, the bigger it
will be. Researchers think that something changed during human evolution
to allow neural progenitors to spend less time in a non-dividing phase
of the cell cycle and transition more quickly towards division. This
simple difference would lead to additional divisions, each of which
could essentially double the final number of brain cells.

Consistent with the popular hypothesis that human neural progenitors may undergo more divisions, resulting in a larger brain, the researchers found
that several genes that help cells to transition more quickly through
the cell cycle are essential in chimp neural progenitor cells but not
in human cells. When chimp neural progenitor cells lose these genes,
they linger in a non-dividing phase, but when human cells lose them,
they keep cycling and dividing. These findings suggest that human neural progenitors may be better able to withstand stresses -- such as the loss
of cell cycle genes -- that would limit the number of divisions the cells undergo, enabling humans to produce enough cells to build a larger brain.

"This hypothesis has been around for a long time, and I think our study
is among the first to show that there is in fact a species difference in
how the cell cycle is regulated in neural progenitors," She says. "We
had no idea going in which genes our approach would highlight, and
it was really exciting when we saw that one of our strongest findings
matched and expanded on this existing hypothesis." More subjects lead
to more robust results Research comparing chimps to humans often uses
samples from only one or two individuals from each species, but this
study used samples from six humans and six chimps. By making sure that
the patterns they observed were consistent across multiple individuals
of each species, the researchers could avoid mistaking the naturally
occurring genetic variation between individuals as representative of the
whole species. This allowed them to be confident that the differences
they identified were truly differences between species.

The researchers also compared their findings for chimps and humans to orangutans, which split from the other species earlier in our shared evolutionary history. This allowed them to figure out where on the
evolutionary tree a change in gene use most likely occurred. If a
gene is essential in both chimps and orangutans, then it was likely
essential in the shared ancestor of all three species; it's more likely
for a particular difference to have evolved once, in a common ancestor,
than to have evolved independently multiple times.

If the same gene is no longer essential in humans, then its role most
likely shifted after humans split from chimps. Using this system, the researchers showed that the changes in cell cycle regulation occurred
during human evolution, consistent with the proposal that they contributed
to the expansion of the brain in humans.

The researchers hope that their work not only improves our understanding
of human and chimp evolution, but also demonstrates the strength of
the CRISPRi approach for studying human evolution and other areas of
human biology.

Researchers in the Weissman and Pollen labs are now using the approach to better understand human diseases -- looking for the subtle differences
in gene use that may underlie important traits such as whether someone
is at risk of developing a disease, or how they will respond to a
medication. The researchers anticipate that their approach will enable
them to sort through many small genetic differences between people to
narrow in on impactful ones underlying traits in health and disease,
just as the approach enabled them to narrow in on the evolutionary
changes that helped make us human.

* RELATED_TOPICS
o Health_&_Medicine
# Stem_Cells # Human_Biology # Brain_Tumor # Genes
o Fossils_&_Ruins
# Evolution # Early_Humans # Human_Evolution #
Charles_Darwin
* RELATED_TERMS
o Human_evolution o Evolution o Evolutionary_psychology
o Convergent_evolution o Pupil o Gorilla o
Timeline_of_human_evolution o BRCA2

========================================================================== Story Source: Materials provided by Whitehead_Institute_for_Biomedical_Research. Original written by Greta
Friar. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Richard She, Tyler Fair, Nathan K. Schaefer, Reuben A. Saunders,
Bryan J.

Pavlovic, Jonathan S. Weissman, Alex A. Pollen. Comparative
landscape of genetic dependencies in human and chimpanzee stem
cells. Cell, 2023; DOI: 10.1016/j.cell.2023.05.043 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2023/06/230620113811.htm

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