Human cells normally have 46 chromosomes. But egg and sperm cells have 23. This is because their precursors divide twice to produce four cells, each with half the normal number of chromosomes. This process, known as meiosis, is designed to ensure that each parent donates only one copy of each chromosome to their child.
In practice, however, this equable allocation of chromosomes sometimes breaks down. The best known example is Down's syndrome, caused by an embryo inheriting an extra copy of chromosome 21. "Until now we haven't had a clue what causes these chromosome segregation errors," says Terry Hassold of Case Western Reserve University in Cleveland, Ohio.
Hassold's group joined forces with a team led by Stephanie Sherman of Emory University in Atlanta, Georgia, to study chromosome 16. Although less well-known than Down's syndrome, faulty chromosome 16 segregation is even more common. More than one in 100 embryos have an extra copy of chromosome 16, and this inevitably results in spontaneous abortion.
The researchers examined 62 miscarried embryos for some hint of what went wrong. They knew that in the early part of meiosis, chromosomes line up like pairs of shoes set instep to instep at the centre of the cell. The outer edge of each chromosome then attaches to protein cables that pull it towards one end of the cell, so that each chromosome ends up in the correct daughter cell when cell division is completed.
Hassold, Sherman and their colleagues suspected that the problem might lie in a feature of meiosis called crossing over. In this process, which occurs many times in each chromosome pair, the two chromosomes break and reattach to each other, thus swapping portions of their genetic material. This introduces extra genetic variability and also serves two other functions. First, the crossovers weave the two chromosomes together and prevent them from moving away from one another before the cell is ready to divide. And secondly, by holding the "instep" sides of the paired chromosomes closely together, the crossovers ensure that each chromosome can only attach to a protein cable on one side.
The researchers compared the genetic sequence of parts of chromosome 16 from the miscarried embryos and their mothers. This revealed that the rate of crossing over for the eggs that gave rise to these embryos had been normal near the ends of the chromosomes, but reduced by about one-third near the middle (American Journal of Human Genetics, vol 57, p 867).
This dearth of crossing over could explain the problem, says Hassold, as it would mean that the two copies of chromosome 16 were not properly anchored together at the start of meiosis. The chromosomes would have flopped around, he says, exposing their inner edges. Hassold speculates that the exposed inner edge of one copy of chromosome 16 became attached to a protein cable. Because the same chromosome was also attached on its other side, a tug of war began between the two daughter cells. If the wrong cell won the battle, the loser would be left without chromosome 16 and would soon die. The other would end up with two copies, and after dividing again would give two abnormal eggs.
But what could cause the lack of crossing over? Hassold believes the culprit could lie among the proteins that help bring paired chromosomes together, or which cut and splice DNA to form the crossovers. In simpler organisms such as yeast, similar abnormalities can result if one of these meiosis proteins is missing or mutated.
From issue 2000 of New Scientist magazine, 21 October 1995, page 20
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