Genes in complex organisms (including humans)
activities are likely to be interrelated
Compilation: Jizhi Translation Group
Source: www.quantamagazine.org
原题：How Many Genes Do Cells Need? Maybe Almost All of Them
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A study of yeast showed that the health of cells relies on highly complex interactions of multiple genes, with few genes that can be recklessly deleted.
By knocking out three genes at a time, the scientists painstakingly derived a network of gene interactions that keep cells active. Researchers have long identified genes that are indispensable for yeast cells to remain active, but the new findings,[1] published in Science[1] suggest that focusing only on these genes can be misleading: many genes are not necessary when they exist alone, but become critical when others disappear. This suggests that the minimum number of genes that yeast cells — and perhaps can be generalized to other, more complex organisms — can be quite large in the smallest number of genes used to sustain and reproduce.
1. "Crazy" experiments to knock out genes
Image source: chem17.com
About twenty years ago, Charles Boone and Brenda Andrews decided to do something crazy. They are all biologists at the University of Toronto who study yeast, and they want to systematically destroy genes in yeast cells in pairs, and want to know how genes interact with each other. In the yeast genome, there are about 6,000 genes, and nearly 1,000 are necessary for life, accounting for about 17%, and even if one of the necessary genes is missing, the entire body will die. It seems that the loss of other genes alone will not lead to such an outcome, and only if these genes are destroyed one after another will the yeast cells become sick or die. Biologists have concluded that those genes are likely to do the same job in cells, or at least participate in the same life process, and that if a gene doesn't fit either of these, its deletion can cause yeast to die because it can't metabolize properly.
Scientifically, we may still know nothing about what's going on in yeast cells, let alone anything more completely about our own cells.
Boone and Andrews realized they could use this conclusion to figure out what was really going on between multiple genes. Together with their collaborators, they deliberately bred 20 million strains of yeast missing two genes, covering all combinations of knocking out two genes in 6,000 genes. The researchers then began documenting the health of these double-mutant strains and began investigating how the rejected genes interacted. The researchers used the results to map the interaction of genes. Two years ago, they published the details of this atlas, revealing the role of genes that were previously unknown.
However, during the experiment, they realized that there were indeed quite a few genes in the experiment that did not interact significantly with other genes. "It's possible that in some cases, deleting two genes isn't enough," Andrews reflects. Elena Kuzmin, an undergraduate student in the lab at the time and now a postdoc at McGill University, decided to go a step further and knock out three genes at once.
Charles Boone and Brenda Andrews, genomics researchers at the University of Toronto, who oversee knocking out gene pairs and trigenes in yeast cells in order to observe the function of genes. They found that even seemingly unrelated genes have crucial interactions.
In a paper now published in Science, Kuzmin, Boone, Andrews, and their collaborators at the University of Toronto, the University of Minnesota, and elsewhere published their more in-depth and nuanced map of the inner activity of cells. Unlike the double-mutation experiment, the researchers didn't exhaust every possible type of mutation, because there are about 36 billion possibilities for knocking out three genes in yeast cells.
However, they looked at the gene pairs that had previously been knocked out and sorted by severity of the effects. These genes have a large and small impact, from making cells grow more slowly, to seriously damaging the cells, and then pairing these gene pairs with other genes, resulting in about 200,000 three-mutant strains. They monitored the growth of these mutant strains, and once they found which variant was having difficulty growing, they went to the database to find out which genes were at work.
2. Interactions between genomes
As scientists began to build and map, something gradually became clear. First, about two-thirds of the three-mutant strains exhibit additional gene interactions, and knocking out the third gene tends to exacerbate the problem with the double-mutant strain. Andrews said that the pairs of genes are already interacting with each other. "But when we delete the third gene, it gets even worse." The situation, Boone says, is like losing a third gene, dealing a fatal blow to an already unstable system.
However, a third of the interactions are completely new discoveries. And that includes some completely different processes than before. In two mutants, the functional connections between genes tend to be tighter: one gene associated with DNA repair tends to be associated with another GENE repair-related gene, and the interacting genome often interacts with other similar genomes. In the three-mutation experiment, more numerous and wider-ranging activities began to form relationships in living organisms. This series of interrelated cellular activities undergoes subtle shifts and changes.
Image source: nature
"The sampling we're taking here may have some functional connections that we've never seen before in a cell." Andrews said.
For example, a new set of connections involves genes that transport proteins and DNA repair genes. On the face of it, it's hard to figure out exactly what makes the two connected. In fact, researchers still can't make a reasonable explanation for this. But they're pretty sure something must have worked. "Our immediate reaction was, well, it's random." Andrews said, "But we already knew in the process of doing this project that it wasn't random. It's just that we don't know yet how the cells are wired. ”
While their research team is just beginning to explore the link between protein transport and DNA repair, according to Andrews, if you look closely at these yeast cells, they do have a large degree of DNA damage. The interaction map helps them focus on this: "This certainly wouldn't have been studied before. She said.
3. Design a minimal genome
The main obstacles faced
Yeast geneticists never felt that only the necessary genes were important. But the new study reinforces this view: a simple explanation of what is important in yeast cells is flawed. According to Andrews and Boone, the reality is more complicated. They believe that when the interaction between dual and triple genes is taken into account, the number of genes that yeast actually needs will skyrocket. As they write in the paper, the minimum number of genes required for yeast cells to avoid major damage "may be close to encoding all the genes in the genome."
Note: This atlas shows the interactions between genes (expressed as dots) in the yeast genome, with genes with interactions represented by wires; genes with stronger correlated effects closer together on the map. The color of the dot indicates the biological process in which the gene is involved and the corresponding organelle.
In fact, many experiments want to determine the minimum genome that microarchites need, to find the minimum number of genes needed for a cell to survive, and to use this as the first step in artificially creating genomes. Experimental studies like this have found that it is very difficult for you to knock out genes while keeping an individual's life alive.
In 2006, researchers at the J. Craig Venter Institute (JCVI) published a report[2] in which they artificially created genomes for mycoplasma bacteria, knocking out some of its 525 genes, leaving only 473. But knocking out seemingly unimportant genes still had serious negative consequences, and according to Clyde A. Hutchison III, a biochemist at JCVI who participated in the experiment and a distinguished professor, "Choosing the right genes is indeed the main obstacle to designing the smallest genome." ”
Image source: guardian.ng
Joel Bader, a systems biologist at Johns Hopkins University, says the study now suggests that one conjecture in human genetics has an interesting correlation with current research: The arrangement of a series of genes may subtly affect features that we wouldn't normally associate at all. "The more carefully we studied, the more we could see the consequences of interfering with one of these genes, which could affect the entire system." "These effects have become weaker, but they can still be measured," he said. ”
Scientifically, we may still know nothing about what's going on in yeast cells, let alone anything more completely about our own cells. Part of the reason the experiment, conducted at the University of Toronto, is that yeast has been studied extensively, and its genes have been studied and carefully labeled by generations of biologists. The study of the human genome is not up to this level, and the human genome is relatively large, intricate and full of mysteries. Still, the researchers hope that as gene-editing techniques in human cells evolve, such experiments could reveal how more cells work and how genes in the genome relate to each other. "I think there are still a lot of fundamentals in gene biology that we haven't discovered yet." Andrews said.
annotations
[1] Science:Systematic analysis of complex genetic interactions.
Source:http://science.sciencemag.org/content/360/6386/eaao1729
[2] Science:Design and synthesis of a minimal bacterial genome.
Source:http://science.sciencemag.org/content/351/6280/aad6253
Translated by Frank Xu
Reviewers: T.R.Y, Yang Xujiang
Edit: Jizhi Luna
Original URL:
https://www.quantamagazine.org/how-many-genes-do-cells-need-maybe-almost-all-of-them-20180419/