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Fertility doctors in Beijing have begun testing a new method for genome analysis of human eggs before using them for in vitro fertilization, or IVF. The tests, using technology developed by a Harvard chemist, allow doctors to know the genome of a woman’s egg before it is used in IVF, which could provide a safer way to help their patients avoid genetic disorders in children.

The test is part of a larger effort by researchers to develop techniques to sequence the genomes of single cells. In some medical situations, such as when examining the scarce cancer cells that can be found in some patients’ blood (see “Finding Cancer Cells in the Blood”), doctors have only a tiny amount of genetic material to work with and so must use specialized techniques to prepare samples for DNA sequencing.  

Researchers are also exploring single-cell-genomic techniques as part of screening tests in fertility clinics. Genetic analyses that are more limited than whole-genome sequencing are already widely performed on IVF embryos by plucking a single cell to determine the number of chromosomes or screen for specific mutations. But there is some concern among reproductive researchers that taking a cell from a developing embryo could damage it, says Jie Qiao, director of the fertility center at the Third Hospital of Peking University.

Qiao is leading a new patient trial to determine whether another genetic analysis technique, which avoids harming the egg, is as successful at catching genetic problems as methods that depend on taking a cell from a growing embryo. During human egg formation, two segregated structures containing copies of the genome are relegated to the large cell’s outer edge. These two structures can be harmlessly removed from the egg before it undergoes IVF, and their DNA contents can then be sequenced.

But whether they’re analyzing these egg structures or a single embryonic cell, doctors and researchers face a challenge in getting enough DNA from their samples to perform genetic tests. For the genome of a single cell to be read, its genetic material must be copied or “amplified.” This process isn’t perfect: it can create more copies of some regions of the genome than others and introduce changes to the original sequence. Both errors are worrisome when considering the technology as a potential screening or diagnostic tool in medicine.

“There’s no room for mistakes,” says Sunney Xie, a chemist at Harvard University who developed a method of genome amplification that more uniformly copies genetic material. However, the method can introduce single-nucleotide changes during the amplification process. No amplification process is perfect, but researchers hope Xie’s method and other progress in the field will drive improvements.

The patient trial in Beijing, done in collaboration with Fuchou Tang of Peking University, will ask how Xie’s amplification method performs when medical decisions are at stake. The results of the egg analysis will be compared to results from the more common embryo biopsy method.

In the trial, genetic testing will tell a prospective mother who is using IVF and who knows she has a genetic disorder in her family whether each of her eggs is free of that known disorder. Mothers who have failed IVF treatments three or more times for unknown reasons can also participate in the trial, says Qiao. The trial will test how well DNA sequencing following the genome amplification method can detect single-nucleotide changes as well as larger changes in chromosomal structure or number, which can cause disease and fertility problems.

The limitation, says Qiao, is that this inspection only works if the genetic disease is in the mother’s family, because it depends on unique by-products of egg development that aren’t available for sperm.

“We get many difficult cases each year,” says Qiao, whose fertility center performs some 11,000 IVF cycles each year. “We believe we can increase the pregnancy rate.”

Qiao’s team is preparing to implant two embryos developed from eggs screened using the amplification process, which means the first baby from a mother participating in the test could be born next year. Qiao wants to test around 30 patients in the pilot study. 

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Tagged: Biomedicine, DNA sequencing, IVF, reproductive medicine

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