Fetal Genome Mapped Through Maternal-Paternal DNA
June 7, 2012

Fetal Genome Mapped Through Maternal-Paternal DNA

Scientists have successfully sequenced the genome of a fetus after taking a blood sample from a woman who was 18 weeks pregnant, and a swab of saliva from the father -- a move that could play a significant role in the screening of rare disorders before the child is even born.

The research, published in the journal Science Translational Medicine, is not the first study to have shown a fetal genome can be glimpsed with a sample of the mother´s blood, but does offer a more accurate picture of the fetal composition by combining DNA from both mother and father.

Scientists have long known that a pregnant woman´s blood plasma contains cell-free DNA from her developing fetus. While concentration varies among individuals, about 10 percent of the cell-free DNA in their blood plasma come from the fetus. This phenomenon has prompted other research labs to design blood tests to look for flaws in the genetic makeup. These types of tests are considered to be a safer substitute for the more invasive sampling of fluid from the uterus, which is a common procedure in obstetrics.

The latest study, led by Dr. Jay Shendure, associate professor of genome sciences at the University of Washington, and research assistants Jacob Kitzman and Matthew Snyder, shows promise for a screening method that could enable doctors to screen for as many as 3,500 genetic disorders before the birth of the child. Currently, the only genetic disorder routinely tested for is Down´s Syndrome.

However, Shendure and colleagues warned that being able to test for literally thousands of genetic disorders raises “many ethical questions” because unwanted results may lead to abortion.

Josephine Quintavalle, founder of the Pro-Life Alliance told the Telegraph: “One always hopes, vainly, that in utero testing will be for the benefit of the unborn child. But, whilst this new test may not itself be invasive, given our past track record, it is difficult to imagine that this new test will not lead to more abortions.”

Shendure cautioned that more study is needed to fully harness the capability of the science before it can be offered to the general public. “Although the non-invasive prediction of a fetal genome is now technically feasible, its interpretation -- even for single-gene Mendelian disorders -- will remain an enormous challenge.”

Yet, the study results remain significant.

The team, with the aid of new technical advances and models, overcame several obstacles that had hindered previous attempts to produce fetal genomes. With a dominant amount of maternal rather than fetal DNA in plasma samples, a major problem was trying to decipher which genetic variants had passed from mother to child.

However, a child can have genetic variations not shared with either parent. These brand new or de novo mutations can occur during egg or sperm formation or at or near conception. Because de novo mutations underpin a substantial proportion of dominant genetic disorders, searching for them is critical to comprehensive prenatal genetic diagnosis.

The researchers showed that ultra-deep sequencing, computational biology and statistics could locate de novo mutations genome-wide in the growing fetus. They discovered 39 of the baby´s 44 de novo mutations while it was still a fetus.

They were also able to resolve the mother´s haplotypes, which are groups of genetic variations residing on the same chromosome. From these groupings, the researchers could pick out the parts of the fetus´s genetic material inherited from each parent with over 98 percent accuracy.

“It was rewarding to apply biostatistics to help solve this problem,” said Snyder. Although, he noted, there is still more work to be done to improve the technique, including the need for a more robust, scalable, overarching protocol, as well as ways to lower costs and automate and standardize parts of the process.