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Rethinking text-book genetics in human IVF embryos

In all organisms more complex than bacteria (animal, plants, fungi), our basic understanding of genetics is that one gamete (e.g. sperm) with half a genome (we call it haploid) meets another (e.g. egg), also with a corresponding half. There are exceptions (bees for instance) but, basically, the idea is that fertilization occurs and the normal (diploid) state is restored. In humans, sperm have 23 chromosomes (coiled coils of DNA and protein in which the genome is packaged), eggs usually also have 23 and the first cell from which all we arise (the zygote) has 46. Textbooks would have us believe that cell division (cytogeneticists call it mitosis, embryologists call it cleavage) faithfully takes over, and every single subsequent daughter cell has 46 chromosomes.

Not so in human embryos according to a recent study by the Griffin lab.

The human embryo starts as a ball of cells (on day-three to -four after fertilization) but then starts to differentiate on the fifth day as follows: The inner cell mass will eventually become the baby, there is a surrounding hollow ball of cells called the trophectoderm which eventually forms the placenta. The trophectoderm encases both the inner cell mass and a fluid-filled cavity called the blastocoel. There also appear to be a few non-descript cells on the periphery of the embryo.

We’ve known for a while that day-three embryos seem to have an unreasonably high number of chromosome abnormalities, but these seems to be far lower at day-five, as the embryo starts to differentiate. How, and why, this happens is the question.

This study aimed to answer whether chromosomal abnormalities detected in a developing embryo day-three remained in the inner cell mass, or if they were sequestered towards other structures that are not involved in foetal development (trophectoderm, blastocoel, peripheral cells).

The research found that chromosomally normal cells seem to remain in the inner cell mass, but the abnormal ones are more likely to be seen in the other structures. The trophectoderm is a little more abnormal, but still quite similar, to the inner cell mass and most abnormalities seem to be found in the blastocoel and the peripheral cells.

This study sampled one cell from 964 day-three embryos, to determine chromosome constitution – about half were normal and half abnormal. Pregnancy rate was assessed only for those determined as chromosomally normal and had undergone blastulation (this is the first stage of differentiation of the embryo, when, the embryo forms the inner cell mass, trophectoderm etc) and was 59%. Blastulation rate was assessed for all embryos and was much higher when the single cell had previously been determined as chromosomally normal (65%) than if determined chromosomally abnormal (35%).

For those 174 embryos that were chromosomally abnormal (aneuploid) but still blastulated, the inner cell mass, trophectoderm, blastocoel, and peripheral cells were analysed for chromosome constitution. The study specifically looked for differences in chromosomal constitution that correlated to the original day-three diagnosis, more specifically, did any embryos normalise to euploid in either the inner cell mass, blastocoel cavity, trophectoderm or peripheral cells?

The study suggests that in, human embryos, frequently detected chromosomally abnormal (aneuploid) cells tend to segregate away from the inner cell mass, partly in the trophectoderm but mostly in the blastocoel fluid and peripheral cells during the progression of the embryo from day-three to day-five. These results suggest that it is possible for human embryos showing aneuploidy to differentiate into a normal inner cell mass (and subsequently, baby) where euploid cell populations predominate.

This study has profound implications for preimplantation genetic testing for aneuploidy (PGT-A). That is, the trophectoderm biopsy used to determine whether the inner cell mass is normal (or aneuploid) is usually accurate. We do however need to re-think our idea of basic genetics, when we assume a single diploid cell gives rise to all cells in the body (and placenta) with the same number of chromosomes.

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