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Failed fishing leads to faulty human eggs

Mouse oocyte

Once chromosomes (blue) have lined up across the centre of the oocyte, microtubules (green) fish them out by their kinetochores (red)(Source: T.Kitajima/EMBL)

Trial and Error Although women are born with all their eggs, it is not understood why many of these contain the incorrect number of chromosomes, which is a leading cause of miscarriage.

But now scientists in Germany and Japan have discovered a mechanism that could explain this phenomenon, known as aneuploidy.

The findings are published online in the journal Cell.

According to Dr Jan Ellenberg of the European Molecular Biology Laboratory (EMBL) who led the study, aneuploid embryos do not usually survive to term.

"The rate of aneuploid foetuses averaged over all stages of prenatal development and all ages of the mothers is around 5 per cent. So it is very high," he says.

"Current data suggest aneuploidies are found in around 35 per cent of clinically recognised spontaneous abortions or miscarriages."

Aneuploid embryos are mostly monosomic or trisomic; that is one chromosome too few or too many in each cell. Those that survive have congenital diseases such as Down's syndrome.

"The reason for aneuploid embryos are mostly aneuploid oocytes [immature egg cells], as aneuploid sperm are relatively rare with an estimated frequency of about 2 per cent, while aneuploid oocytes are quite common with an estimated frequency of more than 20 per cent," he says.

Fishing for chromosomes

Each of our cells has two copies of each chromosome. Humans have 23 pairs, or 46, chromosomes. But our germ cells (sperm and eggs) only have one copy of each chromosome; 23 in total.

This is because when they form they discard half of their chromosomes in a process called meiosis.

To find out what happens to individual chromosomes during meiosis, the researchers tracked their movement during egg development. They used live mouse oocytes, which are very similar to human oocytes.

Ellenberg and team used a special fluorescence microscope to capture 3D time-lapse videos of oocytes for eight hours.

The resulting footage revealed that the cell machinery that separates the chromosomes takes a 'trial and error' approach.

During meiosis, fibres called microtubules attach themselves to the centre (kinetochore) of the chromosomes. The microtubules act like fishing lines and once a chromosome is 'caught' it is pulled to the opposite side of the cell from its partner.

But, before the microtubules hook the chromosomes, the researchers noticed that they herd them together into the centre of the cell. Despite this repositioning, almost 90 per cent of chromosomes were let off the hook only to be re-caught.

"We saw that they [the microtubules] have to go through several tries before getting the connection right," says Ellenberg.

Third time lucky

In fact, some chromosomes were released up to six times, though most averaged three. Ellenberg says this means that the pathway that corrects the errors by uncoupling the chromosome and the microtubule is therefore heavily used and thus more prone to making mistakes - resulting in too few or too many chromosomes in the egg.

"Our findings provide a plausible explanation for the high rate of errors during egg formation."

Ellenberg adds that their observations make error correction proteins good candidates for age-related infertility.

"They form the basis to focus our future work on age-related female infertility, as it seems very likely that a component of the pathway that corrects these errors will be involved. The individual proteins that make up the machinery to correct the errors may simply not have a sufficiently long life-span to function well in very old oocytes," he says.

Dr Paul Kalitsis of the Murdoch Children's Research Institute in Melbourne says that oocytes, especially in humans, sit around ready to go for decades.

"As an oocyte ages the liklihood of errors increases. There is more to learn about the relationship between age and the increase in the number of errors, because it is only partly explained by this study. There are other checkpoints during oocyte development."

Tags: health, reproduction-and-contraception, fertility-and-infertility, science-and-technology, research, genetics