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Fetal genome deduced from parental DNA
Method could make noninvasive screening commonplace ― and problematic.
Alison Motluk
06 June 2012
No mystery: parental samples alone can yield the genome of a fetus with high accuracy.
EDELMANN/SCIENCE PHOTO LIBRARY
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Heralding a future in which a child’s entire genetic blueprint can be examined for traits and defects ― noninvasively ― long before birth, researchers have announced that they have reconstructed the whole genome of a fetus by using only a blood sample from its mother and a saliva sample from its father. The work was published today in Science Translational Medicine1.
The feat relies on the fact that when a woman is pregnant, her blood contains DNA fragments both from her own genome and that of her unborn child. Depending on the individual woman and the stage of her pregnancy, more than 10% of the free floating DNA ― called ‘cell-free DNA’ ― in her blood may come from the fetus. The challenge facing those wishing to glean information from this fetal DNA is to figure out how to distinguish it from the mother's genetic signal.
Jay Shendure, a geneticist at the University of Washington in Seattle, and his colleagues isolated 5 nanograms of cell-free DNA from a maternal blood sample taken after 18.5 weeks of gestation. They performed 'deep sequencing' on the DNA, which involves sampling fragments about 78 times.
The researchers also constructed the mother’s genome using her blood cells, and they worked out how her variants grouped together into blocks or haplotypes. The results from the deep sequencing were then compared to a computationally predicted ratio of haplotypes expected to come from the mother. Where the ratio of haplotypes diverged from the prediction, the researchers surmised they might be reading some of the genetic material from the fetus.
To work out the paternal contribution to the fetal genome, the researchers genotyped the father using DNA from his saliva. Sequences that never turned up in the maternal blood were presumed not to have been inherited. Sequences that did were presumed to belong to the fetus.
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A fetal genome can also have its own de novo mutations, which don’t come from either parent but rather arise spontaneously. The researchers also developed computational techniques to try to detect these.
To test the accuracy of the deduced genome, the child’s full genome was sequenced from cells collected from its cord blood after birth. The researchers were able to make predictions at most but not all variant sites. Where they were able to make predictions, they report a greater than 98% accuracy. They also managed to detect 39 of 44 de novo mutations in the fetus, but with limited specificity. Recognizing the importance of early detection, they also tested the technique on a second family with a fetus of 8.2 weeks of age, and obtained 95% accuracy.
At present, most fetal diagnosis is done either with a sample of placental tissue or amniotic fluid, both of which must be obtained using invasive methods that can trigger miscarriage. Some prenatal tests already sample maternal blood, but they target specific chromosomal disorders such as Down’s syndrome. Wide-ranging, noninvasive sequencing such as this could reach the clinic within a few years, says Shendure. But he warns that more needs to be done to refine the method and make the results meaningful to patients. “The technical piece is not the only challenge,” he says.
James Evans, a professor of genetics and medicine at the University of North Carolina at Chapel Hill, agrees that the idea is not yet ready for the clinic. “We don’t know how to interpret the vast majority of variations we find in the genome,” he says. He also warns that parents have very little time to make life-or-death decisions. “The stakes are high,” he says. “Many are testing to decide about termination.”
“Catching everything in the basket” may also hasten our intolerance for variation, says Francoise Baylis, a bioethicist at Dalhousie University in Halifax, Canada. “As technology moves, so does our willingness to think of difference as a defect,” she says.
Originally, prenatal testing was conducted only to detect life-threatening disorders. Then, conditions such as Down’s syndrome were added, she says. Recently, British parents were given the go-ahead to test for genes such as BRCA, which aren’t likely to cause disease until later in life. She wonders how long it will take before traits such as albinism are considered defects that need to be screened out.
Dennis Lo, a geneticist at the Chinese University of Hong Kong, who was the first to discover fetal DNA in maternal blood, argues that a better approach would be to target specific parts of the genome involved in significant genetic diseases. Sequencing everything, he says, will create serious ethical dilemmas.
“People always overestimate the certainty technology can provide us,” says Evans. “We’re never going to be able to guarantee a healthy child.”
Nature doi:10.1038/nature.2012.10797
References
Kitzman, J. O. et al. Sci. Transl. Med. 4, 137ra76 (2012).
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http://www.nature.com/news/fetal-genome-deduced-from-parental-dna-1.10797
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