Humans vs. Chimps: How Are We Different?
Around seven million years ago, humanity took a divergent path from its closest kin, the chimpanzees, carving its own unique lineage on the evolutionary tree. Since then, humans have developed defining traits such as larger brains and a physique better adapted for bipedal locomotion. Although these phenotypic alterations are subtly embedded within our genetic code, discerning the key genetic variations that spurred human evolution can be a complex task due to the myriad of subtle differences between us and our primate relatives.
In an innovative study led by Jonathan Weissman from Whitehead Institute, Assistant Professor Alex Pollen from the University of California, San Francisco, and their team, state-of-the-art techniques were employed to focus on the crucial differences in gene reliance between humans and chimps. Their results, published in Cell on June 20th, offer potential insights into the evolutionary divergence of humans and chimps, particularly highlighting the genetic basis for humans’ larger brain size.
Shifting Focus to Function over Genetic Code
Interestingly, a large proportion of genes are almost identical between humans and chimpanzees. What sets the two species apart often boils down to the timing and manner in which these virtually identical genes are utilized by cells. However, only a subset of these numerous gene usage variations lead to significant physical traits. The team devised a strategy to zero in on these consequential differences.
Leveraging stem cells extracted from human and chimp skin samples, the researchers used a tool called CRISPR interference (CRISPRi), pioneered in Weissman’s lab. This technique, a variant of the CRISPR/Cas9 gene editing system, allows for individual genes to be effectively silenced. The team applied CRISPRi to sequentially disable each gene in both human and chimp stem cells, subsequently assessing whether the cells proliferated at their usual rate. If the cells’ multiplication rate slowed down or halted, the silenced gene was considered indispensable for the cell to thrive, suggesting that it is required for protein production. Instances where a gene was indispensable in one species but not in the other indicated possible foundational differences in how human and chimp cells operate.
The researchers’ methodology focused on differences in cell function with specific genes deactivated, rather than differences in DNA sequence or gene expression. This perspective excludes differences that don’t seem to impact cell performance. If a variation in gene usage between species results in a notable cellular impact, it likely signifies a meaningful interspecies divergence on a larger physical scale. Thus, the genes identified through this method are probably key players in the distinct evolutionary paths of humans and chimps.
“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,” explains Weissman. “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.”
Once the CRISPRi trials concluded, they assembled a roster of genes that showed up as vital in one species but not the other. Subsequently, the team examined these genes for any discernible trends. A significant portion of the 75 genes highlighted by the experiments congregated within identical biological pathways, implying that these groups of genes partook in the same life processes. This observation aligned perfectly with the researchers’ expectations. While individual minute shifts in gene utilization might not have a substantial impact, when these shifts accumulate within the same biological pathway or process, their collective influence can incite a significant transformation in the species. As the researchers’ methodology unearthed genes that congregated within the same processes, it indicated to them that their approach was successful and the identified genes likely had a role to play in the divergent evolution of humans and chimps.
“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 adds. “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.”
Scientists believe the size of the brain may be linked to the genes governing cell division rates
Among the clusters of genes that the researchers identified, one particular group caught their attention: a set of genes that were crucial to chimps but not to humans, playing a pivotal role in managing the cell cycle—the process determining when and how cells decide to split. For a long time, it has been suggested that the regulation of the cell cycle had a key role in the evolution of larger human brains. The reasoning is as follows: Neural progenitors—cells destined to evolve into neurons and other brain cells—undergo numerous divisions to replicate themselves before they mature into full-fledged brain cells. The more these neural progenitors divide, the more cells they generate, thereby enlarging the brain. It is believed that during human evolution, a shift occurred that allowed neural progenitors to shorten their non-dividing phase in the cell cycle and transition faster toward division. This simple modification would result in additional cell divisions, potentially doubling the final count of brain cells.
In alignment with the hypothesis suggesting that more divisions of human neural progenitors could lead to larger brains, the team discovered that several genes, which aid in faster transitioning through the cell cycle, were crucial in chimp neural progenitors but not in human ones. When these genes were removed in chimp neural progenitors, these cells stalled in the non-dividing phase, whereas human cells continued to cycle and divide. This evidence implies that human neural progenitors might have a superior capacity to cope with stresses—such as the loss of cell cycle genes—which would ordinarily limit the cells’ division rate, thereby enabling humans to generate sufficient cells to construct 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,” the authors add. “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.”
Increased sample sizes yield stronger findings
Usually, studies comparing humans and chimps use samples from just one or two individuals from each species. However, this research utilized samples from six humans and six chimps. This allowed researchers to ensure the observed patterns were consistent across multiple individuals per species, thereby eliminating the risk of mistaking individual genetic variation for species-wide differences. This provided a higher degree of confidence that the differences identified were indeed between species.
In addition, the researchers juxtaposed their findings for chimps and humans with orangutans, who diverged earlier from the shared evolutionary path. This helped pinpoint the timing of gene use changes on the evolutionary tree. If a gene is vital in both chimps and orangutans, it’s likely that the shared ancestor of all three species also found it essential. It’s more plausible that a specific difference evolved once in a common ancestor, rather than independently on multiple occasions. If the same gene is no longer vital in humans, its role likely changed after humans diverged from chimps. Using this methodology, the researchers indicated that changes in cell cycle regulation happened during human evolution, supporting the theory that these changes contributed to the brain’s expansion in humans.
The researchers believe their work not only enhances our understanding of human and chimp evolution but also showcases the power of the CRISPRi technique for studying human evolution and other areas of human biology. Weissman and Pollen’s labs are now using this methodology to gain better insights into human diseases—identifying the slight differences in gene use that might determine significant traits such as disease susceptibility, or response to medication. They foresee that their approach will help sift through numerous small genetic differences between individuals to zero in on the impactful ones that underpin traits in health and disease, in a similar way as it helped narrow down the evolutionary changes that contributed to our humanness.
Source:10.1016/j.cell.2023.05.043
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