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In a special issue of the journal Science covering processes
in reproduction, Patricia Hunt, Ph.D., associate professor of
genetics, and Terry Hassold, professor of genetics, at the CWRU
School of Medicine, published papers on the phenomenon of aneuploidy.
Aneuploid gametes are eggs or sperm that
have an abnormal number of chromosomes. The normal human gamete
has 23 chromosomes, but an aneuploid cell may have 22 or 24. A
fertilized aneuploid egg almost always aborts itself, accounting
for 10 to 20 percent of all miscarriages in humans. The fetuses
that do survive may have mental or physical changes, such as those
seen in people with Downs syndrome.
Hunt reviewed numerous papers on meiotic
errors for Science. In "Sex Matters in Meiosis," Hunt shows that
there are major differences in the production of eggs and sperm.
"There are some quite astonishing differences
between the sexes," Hunt said.
Meiosis is the process by which a germ cell
is divided twice to produce gametes. Along the way from a regular
cell with two copies of each chromosome to a gamete cell with
just one copy of each, the cycle stops at several "checkpoints,"
where the cell determines if its division is proceeding properly
before it goes on to the next step. According to Hunt, both male
and female meiosis have the same checkpoints, but the mechanism
is much more sensitive to defects in males.
"When there is a disruption, male meiosis
screeches to a halt, but female meiosis keeps going," Hunt said.
In the paper she wrote, "In mammals, fertilization
typically involves the ovulation of one or a few eggs at one end
of the female reproductive tract and the entry of millions of
sperm at the other. Given this disparity in numbers, it might
be expected that the more precious commodity—eggs—would
be subject to more stringent quality-control mechanisms. However,
information from engineered mutations of meiotic genes suggests
just the opposite."
Hunt's survey as well as her own research
on age-related aneuploidy gives the scientific community a glimpse
at points of focus for possible treatments. Hunt speculated on
hormones that could produce a better quality egg with more sensitive
checkpoints.
"I think if we can understand what happens
with age, there's always a chance we can treat it," Hunt said.
"We'll have one foot in the door, at least."
Hassold's paper, "Covariation of Synaptonemal
Complex Length and Mammalian Meitoic Exchange Rates," looks at
another side of aneuploidy, the mechanism in males.
"We're defining effectively the normal
pattern of meiotic recombination in males," Hassold said.
In the early stages of meiosis, pairs of
chromosomes in germ cells come together in such close contact
that they can switch parts between them in a process called recombination.
The result in the long run is genetic diversity. That is, rather
than passing down an exact copy of mom's chromosome 16 to all
subsequent offspring, each egg or sperm produced will contain
a chromosome 16 that has parts of both parents' genes. But chromosomes
themselves are not concerned with making sure that no two people
are exactly the same.
"Chromosomes only care about tethering together,
and then separating from one another, during meiosis," Hassold
said. Hassold used fluorescent antibodies that bind to certain
proteins in the cell to look at how chromosomes tether to each
other. Hassold looked at a specific protein complex, the synaptonemal
complex, that binds homologous chromosomes so recombination can
occur.
"This step is extraordinarily important
to fertility in males," Hassold said.
Hassold found that the presence or absence
of the tethering determined to a large extent whether the chromosome
would go through meiosis or arrest partway through the process.
Further, if the chromosomes bind to one another at the very ends
of the strands or at the centromere (the crux of the X shape),
they are likely to go into the same daughter cell during division,
causing aneuploidy.
Hassold also found that the rate of recombination
is not the same in everyone.
"We identified significant variation of
recombination in different men," Hassold said. According to Hassold,
this variation is correlated to the length of the synaptonemal
complex. The reason all males don't produce synaptonemal complexes
of similar length is the next reproductive mystery to be tackled.
Hassold's study involved researchers from
the departments of Genetics and Urology at the CWRU School of
Medicine, University Hospitals of Cleveland and the Louis Stokes
Cleveland VA Medical Center. The paper was co-first authored by
two post-doctoral fellows in genetics, Kara Koehler and Audrey
Lynn. It was funded by the National Institute of Child Health
and Human Development, one of the National Institutes of Health.
The papers appeared in the June 21 issue
of Science.
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