DNA double take

 Not long ago, researchers had thought it was rare for the cells in a single healthy person to differ genetically in a significant way. But scientists are now finding that it’s quite common for an individual to have multiple genomes, writes Carl Zimmer.

From biology class to “CSI”, we are told again and again that our genome is at the heart of our identity. Read the sequences in the chromosomes of a single cell, and learn everything about a person’s genetic information — or, as 23andme, a prominent genetic testing company, says on its website, “The more you know about your DNA, the more you know about yourself.”

But scientists are discovering that — to a surprising degree — we contain genetic multitudes. Not long ago, researchers had thought it was rare for the cells in a single healthy person to differ genetically in a significant way. But scientists are finding that it’s quite common for an individual to have multiple genomes. Some people, for example, have groups of cells with mutations that are not found in the rest of the body. Some have genomes that came from other people.

“There have been whispers in the matrix about this for years, even decades, but only in a very hypothetical sense,” said Alexander Urban, a geneticist at Stanford University. Even three years ago, suggesting that there was widespread genetic variation in a single body would have been met with skepticism, he said. “You would have just run against the wall.” But a series of recent papers by Urban and others has demonstrated that those whispers were not just hypothetical.

The variation in the genomes found in a single person is too large to be ignored. “We now know it’s there,” Urban said. “Now we’re mapping this new continent.”

Dr James R Lupski, a leading expert on the human genome at Baylor College of Medicine, wrote in a recent review in the journal Science that the existence of multiple genomes in an individual could have a tremendous impact on the practice of medicine. Scientists are finding links from multiple genomes to certain rare diseases, and now they’re beginning to investigate genetic variations to shed light on more common disorders.

Science’s changing view is also raising questions about how forensic scientists should use DNA evidence to identify people. It’s also posing challenges for genetic counselors, who can’t assume that the genetic information from one cell can tell them about the DNA throughout a person’s body. When an egg and sperm combine their DNA, the genome they produce contains all the necessary information for building a new human. As the egg divides to form an embryo, it produces new copies of that original genome.

For decades, geneticists have explored how an embryo can use the instructions in a single genome to develop muscles, nerves and the many other parts of the human body. They also use sequencing to understand genetic variations that can raise the risk of certain diseases.

Genetic counselors can look at the results of genetic screenings to help patients and their families cope with these diseases — altering their diet, for example, if they lack a gene for a crucial enzyme. The cost of sequencing an entire genome has fallen so drastically in the past 20 years — now a few thousand dollars, down from an estimated $3 billion for the public-private partnership that sequenced the first human genome — that doctors are beginning to sequence the entire genomes of some patients. And they’re identifying links between mutations and diseases that have never been seen before. Yet, all these powerful tests are based on the assumption that, inside our body, a genome is a genome is a genome.

Scientists believed that they could look at the genome from cells taken in a cheek swab and be able to learn about the genomes of cells in the brain or the liver or anywhere else in the body. In the mid-1900s, scientists began to get clues that this was not always true. In 1953, for example, a British woman donated a pint of blood. It turned out that some of her blood was Type O and some was Type A. The scientists who studied her concluded that she had acquired some of her blood from her twin brother in the womb, including his genomes in his blood cells.

Chimerism, as such conditions came to be known, seemed for many years to be a rarity. But “it can be commoner than we realised,” said Dr Linda Randolph, a pediatrician at Children’s Hospital in Los Angeles who is an author of a review of chimerism published in The American Journal of Medical Genetics recently. Twins can end up with a mixed supply of blood when they get nutrients in the womb through the same set of blood vessels.

In other cases, two fertilised eggs may fuse together. These so-called embryonic chimeras may go through life blissfully unaware of their origins. One woman discovered she was a chimera as late as age 52. In need of a kidney transplant, she was tested so that she might find a match. The results indicated that she was not the mother of two of her three biological children.

It turned out that she had originated from two genomes. One genome gave rise to her blood and some of her eggs; other eggs carried a separate genome. Women can also gain genomes from their children. After a baby is born, it may leave some fetal cells behind in its mother’s body, where they can travel to other organs and be absorbed into those tissues. “It’s pretty likely that any woman who has been pregnant is a chimera,” Randolph said.

A century ago, geneticists discovered one way in which people might acquire new genomes. They were studying “mosaic animals,” rare creatures with oddly coloured patches of fur. The animals didn’t inherit the genes for these patches from their parents. Instead, while embryos, they acquired a mutation in a skin cell that divided to produce a coloured patch. Mosaicism, as this condition came to be known, was difficult to study in humans before the age of DNA sequencing.

Scientists could only discover instances in which the mutations and the effects were big. In 1960, researchers found that a form of leukemia is a result of mosaicism. A blood cell spontaneously mutates as it divides, moving a big chunk of one chromosome to another. Later studies added support to the idea that cancer is a result of mutations in specific cells.

But scientists had little idea of how common cases of mosaicism were beyond cancer. “We didn’t have the technology to systematically think about them,” said Dr Christopher Walsh, a geneticist at Children’s Hospital in Boston who recently published a review on mosaicism and disease in Science. “Now we’re in the midst of a revolution.”