Some problems that are difficult to explain in biology will only be recognized after more healthy people have sequenced their genomes. For example, despite carrying some catastrophic mutations that can lead to chronic failure diseases such as cystic fibrosis and Fanconi anemia, there are still a few extremely lucky people who can avoid being shot to stay healthy and show good resilience to diseases. How did this happen?
The research team led by professors Brenda Andrews, Charles Boone and Frederick Roth of Donnelly Research Center and Department of Molecular Genetics of the University of Toronto, in cooperation with Professor Chad Myers of the University of Minnesota Twin Cities, compiled the first comprehensive intracellular inhibitory mutation spectrum so far, and related research was published in the recent journal Science. Four professors are also members of the genetic network research project group of the Canadian Institute of Advanced Studies (CIFAR). Their findings are helpful to explain how the inhibitory gene mutation can combine with the pathogenic mutation to neutralize the attack of the disease and even protect the individual from the disease damage completely.
Harm.
What is gene suppression?
Chad Myers and others published this research in Science, entitled "Exploring genetic suppression interactions on a global scale". It is generally believed that when an organism has a genetic mutation, it is a genetic error. But not all mutations are harmful. At this time, another gene mutation can be used to save the phenotypic defect caused by this mutation. This process is called "gene suppression" (or "genetic repression") by scientists.
"In fact, we don’t know why some people with destructive mutations are sick and others are not. Part of the reason can be attributed to environmental factors, but it is more likely that other mutations have inhibited the previous mutations, "said Roth, a senior researcher from Lunenfeld-Tanenbaum Institute of Sinai Health System.
Imagine that you are locked in a room with a broken thermostat, and the room begins to get very hot. To cool down, you can choose to fix the thermostat-or you can just break a window. This is how gene suppression keeps cells healthy in the presence of destructive mutations. This provides a new way of thinking for understanding and even treating hereditary diseases.
Yeast substitution experiment
"If we know which genes have inhibitory mutations, then we can figure out the relationship between them and the pathogenic genes, which will help guide the development of drugs in the future," said Dr. Jolanda van Leeuwen, a postdoctoral researcher in Boone Laboratory and one of the leading scientists in this research.
But finding these mutations is not easy. In the human body, this job is like looking for a needle in a haystack. Theoretically, an inhibitory mutation may be any one of thousands of DNA coding errors, scattered among about 20,000 human genes and making each genome unique. Therefore, it is unrealistic to detect all the inhibitory mutations.
"Similar research has not been carried out at the genome-wide level. Considering that it is difficult to carry out such a laboratory with human cells, we use yeast as a model organism, in which we can clearly know how mutations affect the health of cells, "said Van Leeuwen. With only 6,000 genes, yeast cells can be regarded as "simplified versions" of human cells, but both of them follow some similar basic genetic laws. Moreover, it is much easier to remove any gene from yeast cells when studying serious mutation cases in which all gene functions are missing.
Narrow the search scope of mutant genes
The research team adopted a two-pronged strategy. On the one hand, they analyzed the known mutual inhibition relationship in published yeast genes. Despite the huge amount of information, these results are inevitably biased towards some of the most common genes, which have been fully studied by scientists. Therefore, Van Leeuwen and his colleagues conducted an unbiased analysis by evaluating the growth state of yeast cells with destructive mutations and their combination with other mutations. Because harmful mutations will slow down the growth rate of cells, any increase in cell growth rate can be attributed to an inhibitory mutation in another gene. These experiments revealed hundreds of inhibitory mutations corresponding to some known harmful mutations.
Importantly, the experimental data of different methods all point to the same conclusion. In the process of searching for suppressor genes, we usually don’t need to stay away from harmful gene mutations-these genes tend to play a similar role in cells, or because their coding proteins are located in the same position, or because they play a role in the same molecular pathway.
"We revealed the basic principle of gene suppression and found that harmful mutations and their inhibitory mutations are often located in genes with similar functions. When searching for the inhibitory mutation corresponding to human hereditary diseases, we can now narrow the scope of attention instead of looking for a needle in a haystack. We narrowed the search range of genes from 20,000 to hundreds, or even dozens. That’s a great progress. " Boone said.
The Paper (www.thepaper.cn) interviewed Jolanda van Leeuwen, the first author of this research email. She is a postdoctoral researcher in the laboratory of Professor Charlie Boone and Brenda Andrews at Donnelly Center for Cell and Molecular Biology, University of Toronto, Canada. At present, the main work is to use functional genomics tools to study how the interaction of mutations leads to the occurrence of unexpected phenotypes and how this determines the severity of genetic traits, including human diseases.
The Paper:People who carry harmful mutations can still stay healthy and not get sick. How to understand the significance of sequencing and analyzing the genome of such people? How to accurately correlate huge amounts of data with rare genetic diseases?
Jolanda：At present, we can sequence the genome of healthy people with disease-related mutations. Through this genome sequencing, we can find thousands of gene mutations, but we still don’t know how to identify which mutations are involved in the suppression of disease phenotype from these mutations. To make the situation more complicated, only a few individuals showing the "resilience" of the disease have been sequenced, and these data are obviously not enough for the identification of inhibitory mutations.
The Paper:At present, the experimental research is based on yeast. How can similar research guide the research in human cells? Considering that there are many genes in the human body, and the functions of most genes are unknown.
Jolanda：Theoretically, similar research can be carried out in human cells, and we are currently engaged in this research. This kind of research is indeed more complicated, because the number of inhibitory mutations is rare, and researchers need more cells to be able to identify them. Compared with yeast, human cells have more genes and the proliferation rate is much slower, so it will be difficult to screen out spontaneous inhibitory mutations. At present, we are increasing the incidence of inhibitory mutation events by inducing mutation, and we hope to reveal the mechanism of human cell inhibitory genes based on these data.
The Paper:What reference does it have for screening, diagnosis, pathogenesis research or treatment of genetic diseases? Can you give an example?
Jolanda：We have identified and quantified the mechanism of gene suppression. We found that inhibitory mutations often occur in genes that have significant functional correlation with their suppressed genes. Understanding how the inhibitory effect occurs will hopefully narrow the scope of research and help us identify the inhibitory mutations related to diseases from thousands of variations in the genomes of these resilient people. Knowing which genes the inhibitory mutation occurs in is helpful to the development of disease treatment methods.
The PaperWhat do you think is the most important significance of this research?
Jolanda：The identification and quantification of the inhibition mechanism described above is the most important discovery, because it has a significant potential correlation with human diseases. In addition, I am currently expanding the "inhibition network" in yeast and developing a screening method for this inhibition in human cell lines.
(Zhang Jiaojiao, Ph.D. student in food science of Zhejiang University, and Zhang Zhenyu, Ph.D. in gastrointestinal anorectal surgery of Dongfang Hospital affiliated to Tongji University also contributed to this article. News source: Science Daily, original title "Why bad genes are not necessarily bad news")
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