By: Freya Preimsberger
In a study conducted by researchers at the University of Leuven, populations of Escherichia coli bacteria were found to modulate their mutation rates to survive when placed in stressful environments, contrasting with previous observations that mutations are slow to occur and heavily regulated by cells. According to the study, the findings may help to explain why cells mutate rapidly in certain situations, such as in the development of antibiotic-resistant bacteria or in the recurrence of cancer after treatment with chemotherapy. The researchers published their findings in eLife on May 2, 2017.
Mutations, which are changes in DNA sequence, can be neutral, beneficial or harmful to a cell’s biological fitness. Some mutations are necessary for survival in new or stressful environments, but random mutations often have neutral or deleterious effects and require more energy from the cell during replication. Because of this, cells are careful to modulate how many mutations they develop and typically maintain low genomic mutation rates. In some instances, cellular repair mechanisms that usually correct alterations in DNA fail, causing some cells to mutate more rapidly in a process called hypermutation. Hypermutation is found in some species of bacteria and in pathogenic fungi and parasites, and is an important process for cancer proliferation and tumor progression. These observations suggest that for certain environments, particularly harsh ones, hypermutation is advantageous for some cells’ survival. Hypermutation can lead to cell death, but it can also enable cells to adapt to quickly changing environments, serving as a crucial survival mechanism for microbes exposed to nearly-lethal conditions. Previous studies on hypermutation only looked at how microbes react under mildly stressful conditions, prompting researchers in the study to examine how bacteria mutate in high-stress, nearly-lethal conditions.
Researchers subjected samples of E. coli, which are bacteria found in the intestines of warm-blooded animals, to environments containing high concentrations of ethanol, which is found in alcoholic beverages, solvents and types of fuel. They found that some of the bacterial populations mutated rapidly in a way that allowed them to become tolerant of the ethanol. Mutations developed and interacted epistatically in a way that allowed some of the bacteria to adapt to a high-ethanol environment, while bacteria that did not mutate quickly enough or at all failed to develop a tolerance for the ethanol and died. The bacteria that mutated showed unexpected flexibility in their mutation rates in response to stress from their environment; mutation rates rose sharply with increases in ethanol and then declined quickly once the cells had adapted. The study also identified defective methyl-directed mismatch repair pathways, which take part in DNA repair, as the primary cause of increased mutations.
The results of the study differ from previous observations, which had found that mutation rates were slow and mutations were strictly regulated by the cells. The study found that a population of bacteria can modify the rate at which mutations occur in the face of dynamic stress levels, and that periods of hypermutation alternate with periods of decreased mutation rate; mutation rates decrease sharply when concentrations of ethanol are kept constant. Interestingly, researchers found the primary driver of hypermutation in bacterial populations to be cell mortality. The study hypothesized that this was due to higher mutation rates and higher genetic loads increasing the likelihood of acquiring lethal mutations, and that this explains why bacteria with low mutation and mortality rates that are already adapted to the environment do well.
Although the study examined gut bacteria, which are prokaryotic, hypermutation is also found to occur in eukaryotic cells. A pathogenic yeast, the parasite responsible for malaria and relapsed brain tumor cells treated with chemotherapy all exhibit hypermutation under extreme environmental stress. However, eukaryotes hypermutate at lower rates than prokaryotes due to having multiple sets of chromosomes and different ways of coping with environmental stress. According to the study, the findings demonstrate how cells can balance evolvability and fitness.
This process also may contribute to the development of antibiotic-resistant bacteria and drug-resistant cancer cells. Certain species of bacteria have adapted to become untreatable with antibiotics and other antimicrobial agents, making treating these infections difficult and expensive. Approximately two million Americans are infected with antibiotic-resistant bacteria each year, and over 23,000 die as a result of these infections, according to statistics from the Centers for Disease Control and Prevention. In some cases, a patient’s cancer will recur after treatment with chemotherapy drugs. The hypermutation observed in the study may help to explain why antibiotic resistance and cancer relapse occur. The study also suggests targeting the mechanism behind hypermutation in creating new anti-cancer drugs and controlling the spread of antibiotic-resistant bacteria. An additional use of the mechanism is in industrial processes, such as in biofuel production. For instance, sugars derived from waste and plant products can be converted into ethanol, which can be used as fuel, by E. coli bacteria, which will then be killed by the ethanol they produced.
E. coli are a species of bacteria found in the environment and in the intestines of humans and animals. Although most strains are harmless and even an integral part of a healthy digestive system, some cause disease after infection, which occurs through ingestion of contaminated food or water or contact with infected people or animals. Symptoms include abdominal pain, diarrhea and vomiting and will usually subside after five to seven days. Vulnerable groups, such as pregnant women, children, the elderly and those with compromised immune systems, are at higher risk of complications and severe infections. To prevent food-contracted E. coli infection, it is recommended that you observe safe food practices. These include refrigerating food within two hours, washing kitchen surfaces and your hands often, cooking food thoroughly and with the use of a food thermometer, separating meat and eggs from other foods. It is also recommended that you don’t consume raw or undercooked animal products, unpasteurized juice or dairy products or unwashed raw produce. If you have questions on food safety or E. coli contamination, contact the Centers for Disease Control and Prevention for information at 1-800-CDC-INFO.