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Body and mind

Girls and young women have surprisingly many chromosome errors in their eggs

Women older than 40 years are not the only women who have chromosome errors in their eggs. Teenagers have chromosome errors in 4 of 5 eggs.

A new study led by Danish researchers shows for the first time that teenagers have a surprising number of chromosome errors – one more or one less chromosome – in their unfertilized eggs.

Chromosome errors increase the risk of miscarriage and congenital disorders.

The research also shows that some unclear mechanism presumably repairs the eggs so they are ready to become viable as teenage girls get older and reach the optimal age for giving birth.

The chromosome errors emerge again with advancing age, and women older than 40 years are therefore more likely to give birth to children with chromosome errors such as those in Down’s syndrome.

“Our research is the most comprehensive study of human eggs so far. These results show that assuming that women’s eggs are optimal very early in life and then deteriorate with age is incorrect. This is not true at all,” explains the researcher behind the new report, Eva Hoffmann, Professor, Center for Chromosome Stability, University of Copenhagen.

The research has been published in Science.

20,000 miscarriages per year in Denmark

Chromosome errors in women’s eggs are the main cause of miscarriages.

About one quarter of all pregnancies end in miscarriage, and 90% of these occur in the first 12 weeks of pregnancy.

Chromosome errors cause most of this loss, with few eggs with chromosome errors – chromosome 13 (Pateau syndrome), chromosome 18 (Edwards syndrome), chromosome 21 (Down’s syndrome), chromosome X (Turner syndrome) and XXY chromosome (Klinefelter syndrome) – resulting in a viable fetus.

Researchers and doctors have long known that women older than 40 years have a higher risk of giving birth to a baby with a chromosome error and that this risk is linked to the higher incidence of chromosome errors in their eggs that limits fertility as they age.

“Women experience 20,000 miscarriages per year in Denmark. This is a very high number of fetuses that are not viable. We have long known that chromosome errors account for half these miscarriages and that this occurs more frequently as women age. However, no one had previously investigated chromosome errors in eggs from teenagers,” explains Eva Hoffmann.

Examined 3000 eggs from Danish girls and women

The researchers from the University of Copenhagen examined 3000 eggs from 300 Danish girls and women 9–43 years old.

The eggs were obtained from the large freezers at Rigshospitalet in Copenhagen. For example, women who are to be treated with chemotherapy are offered the opportunity to have their ovarian tissue frozen because chemotherapy can destroy this tissue so that they cannot become pregnant later.

Frozen eggs can later be thawed to enable a woman to get pregnant with her own eggs.

Considerable tissue is wasted during the freezing process, and Eva Hoffmann has examined this for chromosome errors.

“This is the largest study of human eggs ever, and we examined 3000. We have a unique ability to do this in Denmark, but only because Claus Yding Andersen has built our nationwide ovarian tissue freezing programme from Aarhus University Hospital, Odense University Hospital and Rigshospitalet,” says Eva Hoffmann.

25- to 27-year-olds have surprisingly many eggs with errors

Eva Hoffmann says that the results show surprisingly many chromosome errors in eggs, even among women 25–27 years old, who are considered to be at the optimal time in their lives for giving birth.

Women 25–27 years old had chromosome errors in 20–30% of their eggs.

That figure rose to 80% for women 42–43 years old.

“This is a very high percentage, and then the increase in the percentage of chromosome errors is not linear. The increase accelerates after women reach 35 years,” says Eva Hoffmann.

Shockingly many errors in eggs among girls

The research also shows that girls as young as 9 years old have many chromosome errors in their eggs.

Girls 10–11 years old had errors in 80% of their eggs, the same as for women 42–43 years old, and this is shockingly high.

“We had always thought that women’s eggs are optimal early in life and then deteriorate over time, but we found for the first time that the proportion of eggs with chromosome errors follows a U-shaped curve, with many chromosome errors early and later in life, with the fewest chromosome errors at about 25 years,” explains Eva Hoffmann.

The body can repair errors in eggs

According to Eva Hoffmann, the explanation for this very surprising result can presumably be that the body has several mechanisms for repairing chromosome errors in the eggs, and these mechanisms are activated as a woman approaches the optimal age to give birth.

Eva Hoffmann also thinks that the signal to repair the eggs arises both inside the eggs and in a signal pathway that is linked to the maturation of the eggs, which occurs every month when the woman is about to ovulate.

“We are now examining this more closely to understand how the process works so that we can hopefully gain enough insight to enable us to help older women who want to become pregnant but have difficulty because of many chromosome errors in their eggs,” says Eva Hoffmann.

Evolutionary explanation for errors in eggs among teenagers

Why does nature cause many initial chromosome errors in the eggs and then reduces the number but then ends up with many errors again?

According to Eva Hoffmann, evolution probably provides the answer.

In evolutionary terms, girls 12–13 years old are not physically mature enough to give birth, mainly because their hips are not developed enough to push out the fetus.

It therefore makes sense that nature ensures that girls’ eggs have many chromosome errors so that they are likely to miscarry if they become pregnant.

Later, when their hips are mature enough to give birth, their bodies begin to repair the eggs to reduce the percentage with chromosome errors and they can more easily become pregnant with a viable fetus.

“Evolution is certainly linked with this, and this is a good way to ensure that girls seldom get pregnant and risk dying during childbirth because their hips are not fully formed,” says Eva Hoffmann.

Chromosome errors in human eggs shape natural fertility over reproductive life span” has been published in Science. In 2015, the Novo Nordisk Foundation awarded a grant to Eva Hoffmann for the project Mapping the Genomic Landscape in the Human Germline.

Eva Ran Hoffmann
Professor in Molecular Genetics, NNF Young Investigator
Chromosomes are rearranged and organized into new sets to create diversity as they are passed from parent to offspring through the germline. The genetic changes can be followed in populations, however this represents only a small proportion of the diversity that is generated in our germline. Men produce 500 billion sperm in their lifetime and women are born with two million eggs. Human reproduction is particularly error-prone. 50% of pre-implantation embryos have defects in their development and 20%-85% of human eggs have extra or missing chromosomes (aneuploidy). Maternal age is the strongest risk factor known for aneuploidy and our interests in reproductive aging also includes understanding the decreased quality as well as the decline in the number of eggs as women age. Our laboratory investigates the role of the DNA damage response and cell cycle proteins in governing the genetic changes that occur in the germline to generate diversity and maintain genome stability. In particular, we focus on those genes that when defective give to reproductive disease or cancer. We use a powerful combination of model organisms (mouse and yeast) as well as human eggs and embryos to explore this poorly understood area of human biology.