by Alicia Chung
Single-cell genetic analysis on embryos generated by IVF finds suprisingly high rates of rearrangements
The gain or loss of chromosomal segments causes many problems in cell function, with malignant growth being the most worrying. Screening for such abnormalities is standard practice in fertility clinics for embryos generated by in vitro fertilization, and it has revealed that these embryos, sometimes donated for the generation of human embryonic stem cell lines, often possess chromosome imbalances. In a recent study published in Nature Medicine, Joris Vermeesch and colleagues at the Center for Human Genetics at the Catholic University Leuven, in Belgium, used high-resolution single-cell genetic analysis to show that such abnormalities are also found in embryos generated by in vitro fertilization from fertile young women (less than 35 years old) and are likely to be an inherent feature of early human development1.
Current screening for chromosome abnormalities on embryos generated by in vitro fertilization does not cover the entire genome. Using new array-based approaches, Vermeesch's group performed a genome-wide scan of chromosome copy number variation and single-nucleotide polymorphisms at 25,000 positions on a single-cell level. Their study of 23 pre-implantation embryos from 9 fertile couples found that chromosome instability was much higher than anticipated. Previous studies using fluorescence in situ hybridization on 10 chromosomes had shown aneuploidies occurring at a rate of around 50%, says Vermeesch, a rate considered the upper limit for embryos from fertile young women. "Since we have for the first time looked at all chromosomes, we find 90% of embryos with abnormal cells." Additionally, rearrangements such as segmental imbalances, thus far only observed in tumours, were observed in 70% of the 23 embryos tested by Vermeesch's group. "Because of the genome wideview," he says, "we see much more."
The reason why chromosomes are unstable during early human embryogenesis is unclear, but the findings have implications not only for fertility research but also for the derivation of embryonic stem cell (ESC) lines. Vermeesch believes chromosomal imbalances may be present before a line is derived. On the other hand, says Martin Pera, director for the Center for Regenerative Medicine and Stem Cell Research at the University of Southern California in Los Angeles, normal diploid cells do seem to have selective advantages over abnormal cells during both in vivo fertilization and human embryonic stem cell (hESC) line establishment, so genetically normal hESC lines could be established from embryos, even if some of their cells contain genetic abnormalities. However, he says, abnormalities in ESCs often arise during culture. According to Pera, these genetic changes tend to be recurrent, resembling those found in germ cell tumours of the testis, and can confer a growth advantage to pluripotent cells.
It's possible that hESC lines created from very early-stage embryos might be more inclined toward unstable karyotypes, says Steven Stice, director of the Regenerative Bioscience Center at the University of Georgia. But he thinks techniques to monitor ESC lines for abnormalities, inherent or acquired, will overcome such issues. The implications of Vermeesch's study are not likely to apply to the selection of embryos from which to derive cell lines but rather to better assessment of lines once they have been derived.
Source: Nature