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In 1944, a Columbia University doctoral student in genetics named Evelyn Witkin made a fortuitous mistake. During her first experiment in a laboratory at Cold Spring Harbor, in New York, she accidentally irradiated millions of E. coli with a lethal dose of ultraviolet light. When she returned the following day to check on the samples, they were all deadexcept for one, in which four bacterial cells had survived and continued to grow. Somehow, those cells were resistant to UV radiation. To Witkin, it seemed like a remarkably lucky coincidence that any cells in the culture had emerged with precisely the mutation they needed to surviveso much so that she questioned whether it was a coincidence at all.

Original story reprinted with permission from Quanta Magazine, an editorially independent publication of the Simons Foundation whose mission is to enhance public understanding of science by covering research developments and trends in mathematics and the physical and life sciences.

For the next two decades, Witkin sought to understand how and why these mutants had emerged. Her research led her to what is now known as the SOS response, a DNA repair mechanism that bacteria employ when their genomes are damaged, during which dozens of genes become active and the rate of mutation goes up. Those extra mutations are more often detrimental than beneficial, but they enable adaptations, such as the development of resistance to UV or antibiotics.

The question that has tormented some evolutionary biologists ever since is whether nature favored this arrangement. Is the upsurge in mutations merely a secondary consequence of a repair process inherently prone to error? Or, as some researchers claim, is the increase in the mutation rate itself an evolved adaptation, one that helps bacteria evolve advantageous traits more quickly in stressful environments?

The scientific challenge has not just been to demonstrate convincingly that harsh environments cause nonrandom mutations. It has also been to find a plausible mechanism consistent with the rest of molecular biology that could make lucky mutations more likely. Waves of studies in bacteria and more complex organisms have sought those answers for decades.

The latest and perhaps best answerfor explaining some kinds of mutations, anywayhas emerged from studies of yeast, as reported in June in PLOS Biology . A team led by Jonathan Houseley, a specialist in molecular biology and genetics at the Babraham Institute in Cambridge, proposed a mechanism that drives more mutation specifically in regions of the yeast genome where it could be most adaptive.

Its a totally new way that the environment can have an impact on the genome to allow adaptation in response to need. It is one of the most directed processes weve seen yet, said Philip Hastings, professor of molecular and human genetics at Baylor College of Medicine, who was not involved in the Houseley groups experiments. Other scientists contacted for this story also praised the work, though most cautioned that much about the controversial idea was still speculative and needed more support.

Rather than asking very broad questions like are mutations always random? I wanted to take a more mechanistic approach, Houseley said. He and his colleagues directed their attention to a specific kind of mutation called copy number variation. DNA often contains multiple copies of extended sequences of base pairs or even whole genes. The exact number can vary among individuals because, when cells are duplicating their DNA before cell division, certain mistakes can insert or delete copies of gene sequences. In humans, for instance, 5 to 10 percent of the genome shows copy number variation from person to personand some of these variations have been linked to cancer, diabetes, autism and a host of genetic disorders. Houseley suspected that in at least some cases, this variation in the number of gene copies might be a response to stresses or hazards in the environment.

Jonathan Houseley leads a team that studies genome change at the Babraham Institute in Cambridge. Based on their studies of yeast, they recently proposed a mechanism that would increase the odds for adaptive mutations in genes that are actively responding to environmental challenges.

Jon Houseley/QUANTA MAGAZINE

In 2015, Houseley and his colleagues described a mechanism by which yeast cells seemed to be driving extra copy number variation in genes associated with ribosomes, the parts of a cell that synthesize proteins. However, they did not prove that this increase was a purposefully adaptive response to a change or constraint in the cellular environment. Nevertheless, to them it seemed that the yeast was making more copies of the ribosomal genes when nutrients were abundant and the demand for making protein might be higher.

Houseley therefore decided to test whether similar mechanisms might act on genes more directly activated by hazardous changes in the environment. In their 2017 paper, he and his team focused on CUP1 , a gene that helps yeast resist the toxic effects of environmental copper. They found that when yeast was exposed to copper, the variation in the number of copies of CUP1 in the cells increased. On average, most cells had fewer copies of the gene, but the yeast cells that gained more copiesabout 10 percent of the total population became more resistant to copper and flourished. The small number of cells that did the right thing, Houseley said, were at such an advantage that they were able to outcompete everything else.

But that change did not in itself mean much: If the environmental copper was causing mutations, then the change in CUP1 copy number variation might have been no more than a meaningless consequence of the higher mutation rate. To rule out that possibility, the researchers cleverly re-engineered the CUP1 gene so that it would respond to a harmless, nonmutagenic sugar, galactose, instead of copper. When these altered yeast cells were exposed to galactose, the variation in their number of copies of the gene changed, too.

The cells seemed to be directing greater variation to the exact place in their genome where it would be useful. After more work, the researchers identified elements of the biological mechanism behind this phenomenon. It was already known that when cells replicate their DNA, the replication mechanism sometimes stalls. Usually the mechanism can restart and pick up where it left off. When it cant, the cell can go back to the beginning of the replication process, but in doing so, it sometimes accidentally deletes a gene sequence or makes extra copies of it. That is what causes normal copy number variation. But Houseley and his team made the case that a combination of factors makes these copying errors especially likely to hit genes that are actively responding to environmental stresses, which means that they are more likely to show copy number variation.

The key point is that these effects center on genes responding to the environment, and that they could give natural selection extra opportunities to fine-tune which levels of gene expression might be optimal against certain challenges. The results seem to present experimental evidence that a challenging environment could galvanize cells into controlling those genetic changes that would best improve their fitness. They may also seem reminiscent of the outmoded, pre-Darwinian ideas of the French naturalist Jean-Baptiste Lamarck, who believed that organisms evolved by passing their environmentally acquired characteristics along to their offspring. Houseley maintains, however, that this similarity is only superficial.

What we have defined is a mechanism that has arisen entirely through Darwinian selection of random mutations to give a process that stimulates nonrandom mutations at useful sites, Houseley said. It is not Lamarckian adaptation. It just achieves some of the same ends without the problems involved with Lamarckian adaptation.

Ever since 1943, when the microbiologist Salvador Luria and the biophysicist Max Delbrck showed with Nobel prize-winning experiments that mutations in E. coli occur randomly, observations like the bacterial SOS response have made some biologists wonder whether there might be important loopholes to that rule. For example, in a controversial paper published in Nature in 1988, John Cairns of Harvard and his team found that when they placed bacteria that could not digest the milk sugar lactose in an environment where that sugar was the sole food source, the cells soon evolved the ability to convert the lactose into energy. Cairns argued that this result showed that cells had mechanisms to make certain mutations preferentially when they would be beneficial.

Budding yeast (S. cerevisiae) grow as colonies on this agar plate. If certain recent research is correct, a mechanism that helps to repair DNA damage in these cells may also promote more adaptive mutations, which could help the cells to evolve more quickly under harsh circumstances.

Jon Houseley/QUANTA MAGAZINE

Experimental support for that specific idea eventually proved lacking, but some biologists were inspired to become proponents of a broader theory that has come to be known as adaptive mutation. They believe that even if cells cant direct the precise mutation needed in a certain environment, they can adapt by elevating their mutation rate to promote genetic change.

The work of the Houseley team seems to bolster the case for that position. In the yeast mechanism theres not selection for a mechanism that actually says, This is the gene I should mutate to solve the problem, said Patricia Foster, a biologist at Indiana University. It shows that evolution can get speeded up.

Hastings at Baylor agreed, and praised the fact that Houseleys mechanism explains why the extra mutations dont happen throughout the genome. You need to be transcribing a gene for it to happen, he said.

Adaptive mutation theory, however, finds little acceptance among most biologists, and many of them view the original experiments by Cairns and the new ones by Houseley skeptically. They argue that even if higher mutation rates yield adaptations to environmental stress, proving that the higher mutation rates are themselves an adaptation to stress remains difficult to demonstrate convincingly. The interpretation is intuitively attractive, said John Roth, a geneticist and microbiologist at the University of California, Davis, but I dont think its right. I dont believe any of these examples of stress-induced mutagenesis are correct. There may be some other non-obvious explanation for the phenomenon.

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I think [Houseleys work] is beautiful and relevant to the adaptive mutation debate, said Paul Sniegowski, a biologist at the University of Pennsylvania. But in the end, it still represents a hypothesis. To validate it more certainly, he added, theyd have to test it in the way an evolutionary biologist wouldby creating a theoretical model and determining whether this adaptive mutability could evolve within a reasonable period, and then by challenging populations of organisms in the lab to evolve a mechanism like this.

Notwithstanding the doubters, Houseley and his team are persevering with their research to understand its relevance to cancer and other biomedical problems. The emergence of chemotherapy-resistant cancers is commonplace and forms a major barrier to curing the disease, Houseley said. He thinks that chemotherapy drugs and other stresses on tumors may encourage malignant cells to mutate further, including mutations for resistance to the drugs. If that resistance is facilitated by the kind of mechanism he explored in his work on yeast, it could very well present a new drug target. Cancer patients might be treated both with normal courses of chemotherapy and with agents that would inhibit the biochemical modifications that make resistance mutations possible.

We are actively working on that, Houseley said, but its still in the early days.

Original story reprinted with permission from Quanta Magazine , an editorially independent publication of the Simons Foundation whose mission is to enhance public understanding of science by covering research developments and trends in mathematics and the physical and life sciences.

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August 17, 2017

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What makes humans different from chimpanzees? Evolutionary biologists from Howard University and the Yale School of Public Health have developed a unique genetic analysis technique that may provide important answers.

Michael C. Campbell, Ph.D., the papers first author and assistant professor in the Howard University Department of Biology, and co-author Jeffrey Townsend, Ph.D., the Elihu Associate Professor in Biostatistics at Yale, published their findings in the journal Molecular Biology and Evolution.

Their methodModel Averaged Site Selection via Poisson Random Field (MASS-PRF)looks at protein-coding genes to identify genetic signatures of positive selection. These signatures are actually DNA changes that contribute to the development of beneficial traits, or human adaptations, that emerged during human evolutionary history and that are shared across the human species.

It's a quantum leap in our statistical power to detect selection in recently diverged species.

Other approaches have examined this question but analyses have focused on whole genes, typically missing focused evolution that often occurs in small regions of genes. The method Campbell and Townsend created identifies selection within genes, pinpointing sets of mutations that have undergone positive selection.

Our method is a new way of looking for beneficial mutations that have become fixed or occur at 100 percent frequency in the human species, Campbell said. What we are concerned with are mutations within genes and traits that are specific to humans compared to closely related species, such as the chimpanzee. Essentially, we want to know is what are the mutations and traits that make us human and that unite us as a biological species.

Townsend said the technique has far-reaching implications. It helped the research team discover several genes whose evolution appears to have been critical to the divergence of humans from their common ancestor with chimpanzees. The genes play roles in neurological processing, immunity, and reproduction, and the method could eventually help scientists identify many more. It's a quantum leap in our statistical power to detect selection in recently diverged species, Townsend said.

Campbell began the research project with Drs. Zhao and Townsend while they were associate research scientists in the Department of Biostatistics at the Yale School of Public Health, before he arrived at Howard University in 2015. Dr. Zhao, currently a research scientist at The Jackson Laboratory for Genomic Medicine, co-authored the paper.

This article was submitted by Elisabeth Ann Reitman on August 17, 2017.

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Evolutionary Biologists Probe Long-standing Genetics Mystery - Yale News

Scientists recently used a gene-editing tool to fix a mutation in a human embryo. Around the world, researchers are chasing cures for other genetic diseases.

Now that the gene-editing genie is out of the bottle, what would you wish for first?

Babies with perfect eyes, over-the-top intelligence, and a touch of movie star charisma?

Or a world free of disease not just for your family, but for every family in the world?

Based on recent events, many scientists are working toward the latter.

Earlier this month, scientists from the Oregon Health & Science University used a gene editing tool to correct a disease-causing mutation in an embryo.

The technique, known as CRISPR-Cas9, fixed the mutation in the embryos nuclear DNA that causes hypertrophic cardiomyopathy, a common heart condition that can lead to heart failure or cardiac death.

This is the first time that this gene-editing tool has been tested on clinical-quality human eggs.

Had one of these embryos been implanted into a womans uterus and allowed to fully develop, the baby would have been free of the disease-causing variation of the gene.

This type of beneficial change would also have been passed down to future generations.

None of the embryos in this study were implanted or allowed to develop. But the success of the experiment offers a glimpse at the potential of CRISPR-Cas9.

Still, will we ever be able to gene-edit our world free of disease?

According to the Genetic Disease Foundation, there are more than 6,000 human genetic disorders.

Scientists could theoretically use CRISPR-Cas9 to correct any of these diseases in an embryo.

To do this, they would need an appropriate piece of RNA to target corresponding stretches of genetic material.

The Cas9 enzyme cuts DNA at that spot, which allows scientists to delete, repair, or replace a specific gene.

Some genetic diseases, though, may be easier to treat with this method than others.

Most people are focusing, at least initially, on diseases where there really is only one gene involved or a limited number of genes and theyre really well understood, Megan Hochstrasser, PhD, science communications manager at the Innovative Genomics Institute in California, told Healthline.

Diseases caused by a mutation in a single gene include sickle cell disease, cystic fibrosis, and Tay-Sachs disease. These affect millions of people worldwide.

These types of diseases, though, are far outnumbered by diseases like cardiovascular disease, diabetes, and cancer, which kill millions of people across the globe each year.

Genetics along with environmental factors also contribute to obesity, mental illness, and Alzheimers disease, although scientists are still working on understanding exactly how.

Right now, most CRISPR-Cas9 research focuses on simpler diseases.

There are a lot of things that have to be worked out with the technology for it to get to the place where we could ever apply it to one of those polygenic diseases, where multiple genes contribute or one gene has multiple effects, said Hochstrasser.

Although designer babies gain a lot of media attention, much CRISPR-Cas9 research is focused elsewhere.

Most people who are working on this are not working in human embryos, said Hochstrasser. Theyre trying to figure out how we can develop treatments for people that already have diseases.

These types of treatments would benefit children and adults who are already living with a genetic disease, as well as people who develop cancer.

This approach may also help the 25 million to 30 million Americans who have one of the more than 6,800 rare diseases.

Gene editing is a really powerful option for people with rare disease, said Hochstrasser. You could theoretically do a phase I clinical trial with all the people in the world that have a certain [rare] condition and cure them all if it worked.

Rare diseases affect fewer than 200,000 people in the United States at any given time, which means there is less incentive for pharmaceutical companies to develop treatments.

These less-common diseases include cystic fibrosis, Huntingtons disease, muscular dystrophies, and certain types of cancer.

Last year researchers at the University of California Berkeley made progress in developing an ex vivo therapy where you take cells out of a person, modify them, and put them back into the body.

This treatment was for sickle cell disease. In this condition, a genetic mutation causes hemoglobin molecules to stick together, which deforms red blood cells. This can lead to blockages in the blood vessels, anemia, pain, and organ failure.

Researchers used CRISPR-Cas9 to genetically engineer stem cells to fix the sickle cell disease mutation. They then injected these cells into mice.

The stem cells migrated to the bone marrow and developed into healthy red blood cells. Four months later, these cells could still be found in the mices blood.

This is not a cure for the disease, because the body would continue to make red blood cells that have the sickle cell disease mutation.

But researchers think that if enough healthy stem cells take root in the bone marrow, it could reduce the severity of disease symptoms.

More work is needed before researchers can test this treatment in people.

A group of Chinese researchers used a similar technique last year to treat people with an aggressive form of lung cancer the first clinical trial of its kind.

In this trial, researchers modified patients immune cells to disable a gene that is involved in stopping the cells immune response.

Researchers hope that, once injected into the body, the genetically edited immune cells will mount a stronger attack against the cancer cells.

These types of therapies might also work for other blood diseases, cancers, or immune problems.

But certain diseases will be more challenging to treat this way.

If you have a disorder of the brain, for example, you cant remove someones brain, do gene editing and then put it back in, said Hochstrasser. So we have to figure out how to get these reagents to the places they need to be in the body.

Not every human disease is caused by mutations in our genome.

Vector-borne diseases like malaria, yellow fever, dengue fever, and sleeping sickness kill more than 1 million people worldwide each year.

Many of these diseases are transmitted by mosquitoes, but also by ticks, flies, fleas, and freshwater snails.

Scientists are working on ways to use gene editing to reduce the toll of these diseases on the health of people around the world.

We could potentially get rid of malaria by engineering mosquitoes that cant transmit the parasite that causes malaria, said Hochstrasser. We could do this using the CRISPR-Cas9 technique to push this trait through the entire mosquito population very quickly.

Researchers are also using CRISPR-Cas9 to create designer foods.

DuPont recently used gene editing to produce a new variety of waxy corn that contains higher amounts of starch, which has uses in food and industry.

Modified crops may also help reduce deaths due to malnutrition, which is responsible for nearly half of all deaths worldwide in children under 5.

Scientists could potentially use CRISPR-Cas9 to create new varieties of food that are pest-resistant, drought-resistant, or contain more micronutrients.

One benefit of CRISPR-Cas9, compared to traditional plant breeding methods, is that it allows scientists to insert a single gene from a related wild plant into a domesticated variety, without other unwanted traits.

Gene editing in agriculture may also move more quickly than research in people because there is no need for years of lab, animal, and human clinical trials.

Even though plants grow pretty slowly, said Hochstrasser, it really is quicker to get [genetically engineered plants] out into the world than doing a clinical trial in people.

Safety and ethical concerns

CRISPR-Cas9 is a powerful tool, but it also raises several concerns.

Theres a lot of discussion right now about how best to detect so-called off-target effects, said Hochstrasser. This is what happens when the [Cas9] protein cuts somewhere similar to where you want it to cut.

Off-target cuts could lead to unexpected genetic problems that cause an embryo to die. An edit in the wrong gene could also create an entirely new genetic disease that would be passed onto future generations.

Even using CRISPR-Cas9 to modify mosquitoes and other insects raises safety concerns like what happens when you make large-scale changes to an ecosystem or a trait in a population that gets out of control.

There are also many ethical issues that come with modifying human embryos.

So will CRISPR-Cas9 help rid the world of disease?

Theres no doubt that it will make a sizeable dent in many diseases, but its unlikely to cure all of them any time soon.

We already have tools for avoiding genetic diseases like early genetic screening of fetuses and embryos but these are not universally used.

We still dont avoid tons of genetic diseases, because a lot of people dont know that they harbor mutations that can be inherited, said Hochstrasser.

Some genetic mutations also happen spontaneously. This is the case with many cancers that result from environmental factors such as UV rays, tobacco smoke, and certain chemicals.

People also make choices that increase their risk of heart disease, stroke, obesity, and diabetes.

So unless scientists can use CRISPR-Cas9 to find treatments for these lifestyle diseases or genetically engineer people to stop smoking and start biking to work these diseases will linger in human society.

Things like that are always going to need to be treated, said Hochstrasser. I dont think its realistic to think we would ever prevent every disease from happening in a human.

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Will Gene Editing Allow Us to Rid the World of Diseases? - Healthline - Healthline