Meiosis: the elusive process of dividing chromosomes — and genetic traits — during the formation of eggs and sperm; the harbinger of skin color, personality, ability and disability…

PULLMAN – Geneticist Terry Hassold is on the leading edge of the quest to understand meiosis. For more than 30 years he has been on a mission to discover exactly what happens as the genetic cards are shuffled and dealt in cells destined to become eggs and sperm.
With a passion as pragmatic as it is academic, he is investigating the causes behind chromosome abnormality — a leading cause of reproductive failure. In fact, he says more than 50 percent of all human pregnancy losses can be attributed to chromosome imbalance in the fetus.
Recently, Hassold and his colleagues have made significant headway with a number of new discoveries. They have not only shown that the process of meiosis differs in men and women, but that some eggs — counter to conventional wisdom — are predisposed before a woman’s birth to have an error in meiotic division.
“At least one out of five human eggs have the wrong number of chromosomes — as compared to yeast or flies which have rates of 1:1,000 to 1:10,000,” said Hassold, director of the Center for Reproductive Biology and Eastlick Distinguished Professor in the School of Molecular Biosciences.
Although no one yet knows why humans are at such high risk, it is known that the risk increases dramatically as women age.
“What may be a 2 or 3 percent risk of error in meiotic division at age 25 becomes a 40 percent risk by age 40,” said Hassold. “We are trying to understand the molecular basis for these abnormalities with the hope of someday developing therapies to decrease the likelihood of it happening.”
 
Predisposed before birth

While men produce new sperm on a regular basis, women form all of their eggs when they are still tiny embryos in the womb. And while sperm speed through meiosis all at once, eggs are required to complete a two-step process.
The first step occurs in the embryonic eggs when chromosomes divide and find their match, glue themselves together and then exchange DNA in a process called recombination (or crossing over). At this point, the eggs “hibernate” until the female reaches puberty.
Then, in the second stage of meiosis, one or more eggs mature during monthly ovulation until a woman reaches menopause around age 45 or 50.  In effect, some eggs must wait more than 40 years to complete meiosis, “and that’s asking an awful lot of a single cell,” said Hassold.
While many people assume chromosome abnormalities are more prevalent in older women, Hassold’s studies suggest the egg is predisposed to errors even before birth.
“Clearly there is evidence of things going on at the end of the egg’s life cycle,” he said. “But there are also things happening at the beginning of the egg’s development … that set the chromosomes up to misdivide decades later.”
Hassold believes some of those things are glitches that occur during the DNA recombination phase in the first stage of meiosis.
 
Live action studies

To help prove his hypothesis, he joined forces with Edith Cheng from the University of Washington in one of the first studies using immunofluorescent antibodies to observe human female recombination as it is actually occurring. Results showed that during meiosis women’s chromosomes often behave in untidy and unpredictable ways that can lead to an exceptionally high rate of abnormalities, such as the one that causes Down syndrome.
In contrast, male chromosome pairs line up and divide precisely. If an aberration does occur, meiosis stops. In women, the process continues even with anomalies — chromosomes may not match up correctly or may have fewer points of recombination than expected, or none at all.
 
Proteins in process

Such errors in recombination can result in chromosomes that fail to divide and separate normally. If this happens, a human cell may end up with more or less than the standard 46 chromosomes — a condition called aneuploidy.
Just one extra chromosome (a total of three in the cell) can result in trisomies such as trisomy 21 which causes Down syndrome. One less chromosome leads to monosomies such as monosomy X, the cause of Turner syndrome.
But Hassold said the $64,000 question remains — what is the actual culprit behind this failure of recombination, or DNA exchange? With the immunofluorescence studies, he and his team hope to more closely pinpoint the problem by studying the specific proteins that control the meiotic process.
“We are looking at proteins that control crossover, proteins that control pairing between chromosomes, proteins that glue chromosomes together or that glue parts of the chromosomes together,” he said.
“Once we understand what the problem is, we may be able to replace the missing proteins and thereby prevent the error from ever occurring.”