Jigsaw genetics

DNA fragments in mother's blood allow scientists to piece together fetal genome, check for disease

Doctors may soon be able to diagnose a baby’s genetic health by taking a blood sample from the mother.

Researchers in Hong Kong have pieced together the entire genetic blueprint of an unborn baby from snippets of DNA in the mother’s blood, the team reports in the Dec. 8 Science Translational Medicine. The scientists were able to determine the baby’s genetic makeup well enough to test for a genetic disease.

The accomplishment “is a relative tour de force,” says Laird Jackson, a medical geneticist at Drexel University in Philadelphia. “It’s opened the door on something that people have dreamed about for a while.”

Determining a baby’s genetic makeup from a mother’s blood sample could circumvent the need for invasive procedures such as amniocentesis or chorionic villus sampling, says Sinuhe Hahn, a molecular biologist at the University of Basel in Switzerland. Those procedures, now used for prenatal genetic testing, result in miscarriages in about 1 percent of cases, Hahn says. A new test based on the mother’s blood would be much safer and could provide an unprecedented wealth of genetic information about the fetus, he says.

“This technology is so revolutionary that we’re going to have to involve regulatory agencies and have ethical discussions” about how such genetic information should be used, Hahn predicts.

Prior to this work, the Hong Kong group, led by Y.M. Dennis Lo, a chemical pathologist at the Chinese University of Hong Kong, had shown that bits of fetal DNA can be found in the mother’s blood. About 10 percent of DNA found in a pregnant woman’s blood plasma actually comes from the fetus, the researchers found.

Some groups have used that DNA to detect traits inherited from the father or to determine whether the fetus carries extra chromosomes. But no one knew whether the entire fetal genome was floating around in its mother.

The new study shows that every bit of a fetus’s genome can be found in its mother’s blood, mostly in pieces 143 DNA letters long. The mother’s DNA is found in slightly longer pieces, most of them 162 letters long. The difference could help researchers separate mom’s DNA from baby’s, making the task of piecing together the baby’s DNA easier.

The researchers drew blood from a mother during the 12th week of pregnancy and began the task of putting together the fetus’s DNA. It took a couple of months for the researchers to determine the sequence of DNA letters in about 4 billion pieces of DNA isolated from the mother’s blood, Lo says.

Then the team had to determine which bits belonged to the fetus and which to the mother. “It’s like trying to put together a million-piece jigsaw puzzle in which the one you want is mixed in with another one with 10 times more pieces,” Lo says. It was relatively easy to figure out which genes the baby had inherited from its father. But the researchers had to devise new statistical procedures to deduce what was inherited from the mother.

Both of the parents were carriers for mutations in the hemoglobin gene that cause beta-thalassemia, a type of anemia. If the baby inherited both defective copies it would have the condition. Once the researchers had compiled the fetus’s genome, they examined the gene and found that the child had inherited the father’s mutation, but had a healthy copy of the gene from mom.

Assembling another fetus’s DNA could be done much more quickly in the future since scientists now know how to do it. But the technology requires expensive, specialized equipment not available in most clinical laboratories. Lo estimates the cost at about $200,000 per test, although Jackson says the expense of compiling a genome is dropping rapidly and it probably won’t be long before such a test is widely available.

“It’s coming,” says Jackson. “This stuff is going to work.”

Tina Hesman Saey

Tina Hesman Saey is the senior staff writer and reports on molecular biology. She has a Ph.D. in molecular genetics from Washington University in St. Louis and a master’s degree in science journalism from Boston University.

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