A scan of all the mutations in the human gene map shows something surprising – people of European descent are evolving fast, and not for the better.

The study finds that in the past 5,000 years, European-Americans have developed a huge batch of potentially harmful genetic mutations – many more than African-Americans.

The study, published in the journal Nature, may help explain why so many people develop diseases even though they don’t have common genetic mutations. It can also help explain why different people have so many different reactions to the same drug, said Joshua Akey of the University of Washington in Seattle who led the study.

It likely has to do with population explosion, Akey said. European populations expanded after the Ice Age ended and prosperous agricultural societies emerged. “The number of mutations that exist is directly attributable to the population growth that happened in the last 5,000 years,” Akey told NBC News.

“The things that allowed us to go from millions to billions of has also been the same process that has been pumping in all these new mutations.”

Akey and colleagues at genetics institutions across the country examined the gene sequences of more than 6,500 people – more than 4,200 European-Americans and 2,200 African-Americans. They were looking for small changes in the genetic code called single nucleotide variants – one-letter differences in the genetic code of A,C, T and G.

They found “an enormous excess of rare variants” in the European-Americans. And 73 percent of these mutations only appeared in the human genome in the past 5,000 to 10,000 years. Most were mutations that are known to weaken proteins, Akey said, and most of these harmful mutations were also in the people of European descent.

Now researchers are working to see which of these mutations might be associated with diseases. But many are in known disease-causing genes, such as the LAMC1 gene associated with premature ovarian failure, LRP1, which is linked with both Alzheimer’s disease and obesity and the CPE gene linked to hardening of the arteries.

Most are rare mutations – meaning they only affect a few people. “Some genes might be more disease-causing than other genes,” Akey said.

It may explain why it’s been so hard to find clear genetic links to many diseases. “We have been looking for disease risk where it isn’t,’ he said. “The last five to 10 years have been dominated by looking for common genetic variations that dominate common diseases. There is a lot of disease risk that is unexplained. Maybe there are classes of mutations that haven’t been looked at.”

The findings could explain why some people can smoke for a lifetime and never get lung cancer or heart disease, while someone else might suffer a heart attack despite having healthy blood pressure and cholesterol levels.

It definitely shows evolution in action, Akey said. “It’s just the process of evolution playing out in real time,” he said. “The dramatic population expansions that occurred over the past couple thousand years had a profound consequence on our genetic variability.”

Genetic mutations usually occur by accident – they are just mistakes that get made when DNA gets copied. They become important to evolution when they affect a person’s ability to survive and have children. The expansion of civilization, and the ability of societies to care for people who are less fit, was probably a factor in allowing these mutations to spring up, Akey said. “I think that is undoubtedly true,” he said.

Some of the genes identified in the scan also affect peoples’ response to drugs. That could explain why some people are helped, for example, by a cholesterol-lowering drug while others may not be. There wouldn’t have been much “selective pressure” on these genes before the modern drug era, but that doesn’t mean the genes were not influenced by something else. “It turns out that genes involved in adverse drug responses also have different biological roles,” Akey said – for instance, detoxifying certain foods.

There may even be more evolution in the future, Akey predicted. One example – phenylketonuria or PKU. It’s caused by a mutation in a gene that breaks down an amino acid called phenylalanine. People with PKU mutations must eat a strict, low-protein diet or they can develop seizures and mental retardation.

Now newborns are routinely tested for PKU so they can start the diet immediately and avoid any brain damage. Akey said because these kids can now grow up and lead normal lives, they will likely start having children and the gene may become more common in the population.

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University of Washington

Dr. John A. Stamatoyannopolous, associate professor of genome sciences, in his lab. Stamatoyannopolous worked on the giant ENCODE project that is re-defining human biology.

In what many scientists say is a revolution in biology, a giant new project is rewriting our understanding not only of what causes diseases or what makes our eyes a certain color, but what makes us human. And it turns out scientists have been looking in the wrong place for a very long time.

The bounty of new discoveries, released in a batch of 40 research papers on Wednesday, shows the stretches of DNA that we call genes are only a very small piece of what makes the body work. Much more important is the stuff in between the genes – stuff once dismissed as “junk DNA”. It turns out that junk DNA is what is in control, they report in the series of papers in the journals Nature, Science and elsewhere.

“This has opened up whole new galaxies. It’s like having a bigger telescope,” says Dr. Bruce Stillman, president of Cold Spring Harbor Laboratory, which played a major role in the work. 

Scientists already knew in 2003, as they finished the giant Human Genome Project, that they did not have the understanding they had hoped for.  It turned out that humans had just a measly 22,000 genes – fewer than some animals and far fewer even than a plant such as rice. How could something as complex and advanced as a human be boiled down into something so simple?

“We understood precious little about the processes that turns genes on and off. In short we had more questions than answers about how the human genome works,” said Dr. Eric Green, director of the National Human Genome Research Institute, which conducted the study.

The next phase of work, called ENCODE for Encyclopedia of DNA Elements, shows there’s nothing simple about it. As many as 40 million different switches are controlling these genes, turning them on and off in complex and subtle ways.

“The genome is loaded with gene controlling switches. There are literally millions of these,” Dr. John Stamatoyannopoulos of the University of Washington, who worked on the studies, told reporters in a telephone briefing.

Dr. Francis Collins, director of the National Institutes of Health, calls the findings “awesome and elegant.”

“This is the first truly comprehensive view, of how the three billion letter instruction book for human biology actually carries out its work, across many tissues and over the course of development,” he told NBC News in an interview.

Stanford University genomic expert Michael Snyder says it looks like gene mutations -- the changes in DNA sequences that we associate with causing diseases -- may only affect rare diseases. Common diseases, like heart disease, cancer, and allergy, are probably controlled elsewhere. “We think that most of the changes that affect disease don’t lie in the genes themselves, but the switches,” Snyder says.

So treating these common diseases may lie in trying to affect the switches. “The pharmaceutical industry has largely given up on genomics and the genome in favor of older approaches,” said Stamatoyannopoulos. These new findings may reinvigorate new drug research, he said. “Now we have a huge amount of genetic data about human disease that we can actually put to work to find the right kind of genes and proteins to target,” he said.

This new data will also help doctors diagnose disease in the first place, predict which treatments will work best for patients, and monitor their progress. It  points the way to studies to determine the causes of hundreds of diseases including  all kinds of cancer, Alzheimer’s disease, schizophrenia, heart disease, type 1 and type 2 diabetes, lupus, rheumatoid arthritis and asthma.  It also may lead to a better understanding of how our genetics determine such non-disease factors as height, weight and expected life span.

Not only that, it also can help explain why humans and chimpanzees share 98 percent or more of our genes, yet are so different.

"Genes occupy only a tiny fraction of the genome, and most efforts to map the genetic causes of disease were frustrated by signals that pointed away from genes. Now we know that these efforts were not in vain, and that the signals were in fact pointing to the genome's 'operating system' -- the instructions for which are hidden in millions of locations around the genome," said Stamatoyannopoulos. "The findings provide a new lens through which to view the role of genetics and genome function in disease."

Another surprising finding was that the regulatory circuitry blueprints could be used to pinpoint cell types that play a role in specific diseases -- without requiring any prior knowledge about how the disease worked. For example, DNA changes associated with Crohn's disease (a common type of inflammatory bowel disease) are concentrated in the switches controlling two types of immune cells.

Researchers can use this same method to identify cell types not previously known to play a role in a particular disease, expanding our understanding of the disease process and potentially leading to new therapies.

"We now have a parts list of what makes us human," says Mark Gerstein of Yale university, who worked on the project. "What we are doing is figuring out the wiring diagram of how it all works."

The findings rewrite biology 101 for most of us.  Each gene, we were taught, provided the code for a single protein. The proteins were the building blocks of cells, and the products made by the cells, from compounds called growth factors to signal-carrying chemicals. An intermediary genetic structure called RNA carried this information. ENCODE shows this is not quite so straightforward, that RNA generates the 40 million switches that can affect how and when many things happen within the cells.

“This is another grand chapter in the ongoing and historic research story that is unraveling the details about how life works, and how disease occurs,” Collins said.

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