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   PID: hpt/lnx 1.9.0-cur 2019-01-08   
   TID: hpt/lnx 1.9.0-cur 2019-01-08   
    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   
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   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   
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   Link to news story:   
   https://www.sciencedaily.com/releases/2023/06/230620113811.htm   
      
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