Women already had chromosome errors in their eggs before they were born

Breaking new ground 11. mar 2021 2 min Professor in Molecular Genetics, NNF Young Investigator Eva Ran Hoffmann Written by Kristian Sjøgren

Ten percent of the eggs in a woman’s ovaries have a chromosome error that already arose before the woman was born.

The eggs a woman can eventually use to become pregnant are already developing while she is a fetus. New Danish research shows that genetic errors arise at this stage. A generation later this can result in a woman giving birth to a child with Down’s syndrome.

The researchers examined eggs from the ovaries of fetuses from electively terminated pregnancies and found that 10% contained errors with a high risk of leading to chromosome errors.

The discovery may help to explain why 20% of all pregnancies are lost and can be used to construct better models for determining a woman’s risk of not being able to conceive at all.

“These research results have various perspectives. Evolution has determined that a woman’s eggs have an error rate of about 10%, so a woman giving birth to a child with a chromosome error does not result from anything the woman has done. We have improved understanding of this now,” explains a researcher behind the study, Eva Hoffmann, Professor at the Department of Cellular and Molecular Medicine, University of Copenhagen.

The research has been published in the American Journal of Human Genetics.

Examined eggs from aborted fetuses

The researchers examined more than 7,000 immature eggs (oocytes) from 160 fetal ovaries obtained from electively terminated pregnancies with gestational ages ranging from 15 to 24 weeks.

The researchers removed the oocytes from the fetal ovaries and examined them under a microscope, finding that many chromosomes had failed to recombine in pairs as they should.

Nearly 10% of the oocytes contained at least one exchangeless chromosome pair that, if the fetus had survived, would have resulted in a child with severe chromosome errors.

Chromosomes 21 and 22 frequently failed to recombine. Chromosome 21 is linked to the development of Down’s syndrome, in which a person has one extra chromosome 21 – most often from the mother.

“For some reason, human oocytes seem to be very inconsistent, and many contain chromosome errors. This does not happen with sperm,” says Eva Hoffmann.

Oocytes deteriorate over time

On average, women at the most fertile age have a 20% risk of chromosome errors in each oocyte.

Eva Hoffmann explains that the study shows that the chromosome error baseline is 10%, which then increases during childhood and early adulthood.

After a woman turns 40 years, 70% of her oocytes have chromosome errors, and this causes the increased risk of pregnancy loss and children born with chromosome errors and infertility later in life.

“One might ask why evolution has not selected for this and minimized the risk. But we seem to have to accept that this is just part of being a woman,” explains Eva Hoffmann.

Molecular glue cannot recombine the chromosomes

According to Eva Hoffmann, the high error rate in oocytes results from the fact that, at this very early stage in life, the chromosomes are not very good at joining together in pairs.

When chromosomes need to recombine, they must be paired together and attached with molecular glue.

When the process functions correctly, the eggs are ready to be fertilized and become healthy children between 20 and 50 years later. This happens when the eggs mature and half the chromosomes are discarded to enable the egg’s DNA to combine with the sperm’s DNA.

Things go wrong in the eggs that did not recombine correctly.

If the recombination did not succeed in assembling all the chromosomes in pairs and sticking them together with the molecular glue, complications can arise when the eggs have to mature and the chromosome pairs have to separate.

In this situation, the biological process goes haywire and instead of passing one chromosome 21 to the mature egg, both copies or neither copy of chromosome 21 may be transferred into the mature egg.

When this egg is fertilized, problems arise. If the fertilized egg ends up with three copies of chromosome 21 (two from the mother and one from the father), the baby will develop Down’s syndrome.

“When the eggs recombine properly and the molecular glue holds the chromosomes together, the cells then divide correctly. When the chromosomes are not connected in pairs, how many chromosomes move to the mature egg becomes completely arbitrary. The development of the egg at this very early stage in life causes many pregnancy losses and is the reason why some children are born with chromosomal errors,” says Eva Hoffmann.

Failure to recombine is a common feature of human oogenesis” has been published in the American Journal of Human Genetics. In 2015, the Novo Nordisk Foundation awarded a grant to Eva Hoffmann for the project Mapping the Genomic Landscape in the Human Germline. Eva Hoffmann was elected as a member of the European Molecular Biology Organization, a lifetime honour in recognition of her extraordinary results within the biological sciences.

Chromosomes are rearranged and organized into new sets to create diversity as they are passed from parent to offspring through the germline. The genet...

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