Researchers have reconstructed the whole genome sequence of a human fetus, using DNA samples obtained from a pregnant woman and the father-to-be. The findings, reported in the 6 June issue of Science Translational Medicine, open up the possibility of evaluating a fetus noninvasively for all single-gene disorders.
Huntington’s disease, cystic fibrosis, and Tay-Sachs disease are among the “Mendelian” disorders that are caused by a defect in a single gene, which collectively affect about 1% of new births.
Jay Shendure of the University of Washington and colleagues said their new technique could someday help screen for these types of genetic mutations in the fetus without procedures that breach the fetus’ protective amniotic sac and raise the risk of miscarriage.
“This work opens up the possibility that we will be able to scan the whole genome of the fetus for more than 3000 single-gene disorders through a single, non-invasive test,” Shendure said.”
The research team was able to map the whole genome of a fetus at 18.5 weeks gestation, about midway through the second trimester. They reconstructed the fetal genome using DNA in a saliva sample from the father, and DNA from the mother’s blood plasma.
Fetal DNA is found in maternal plasma, but it can be difficult to separate which genetic signature belongs to the mother and which belongs to the fetus, the researchers explained. To identify the fetal DNA, Shendure and colleagues first used a new technique to identify blocks of genetic variation, called haplotypes, that could be traced back to the mother’s genome.
This information, along with data from the father’s DNA sample, allowed the researchers to determine which parts of the maternal and paternal genomes were inherited by the fetus. A second, more intensive analysis of the mother’s blood plasma then helped the team pinpoint new genetic mutations that appeared only in the fetal genome.
The researchers were able to check the accuracy of their genome reconstruction by sequencing DNA from umbilical cord blood collected at birth. They had discovered 39 of the baby’s 44 new mutations during the genome reconstruction.
Jacob Kitzman, a graduate student in Shendure’s lab and lead author of the Science paper, explained that the researchers’ methods were distinguished by the ability to assess many and more subtle variations in the fetus’ genome, down to tiny, “one-letter” changes in the DNA code.
“The improved resolution is like going from being able to see that two books are stuck together,” Kitzman said, “to being able to notice one word misspelled on a page.”
Read the abstract for “Noninvasive Whole-Genome Sequencing of a Human Fetus,” by Jacob Kitzman and colleagues.