Mating Molds Provide New Insights Into Speciation And Human Reproduction
A new study on the sex life of molds is raising startling
new questions about gene silencing, speciation and perhaps some facets of
human reproduction.
The study, featured in the journal Cell, focuses on the mating habits of
Neurospora crassa, commonly called pink bread mold - a fungus that has been
a useful genetic model organism for more than half a century. Neurospora
became famous when George Beadle and Edward Tatum used it at Stanford in
1941 for the first experiments in biochemical genetics - an achievement that
won them the Nobel Prize.
"Fungus is very easy to manipulate," said Patrick K. T. Shiu, a
postdoctoral fellow in the Stanford Department of Biological Sciences and
lead author of the Cell paper. "It only takes two weeks for a genetic cross
to mature, and you can insert or delete any gene you want."
When it comes to sex, molds and humans share at least
one fundamental principle: In both species, the parents must donate a copy
of their DNA to the offspring in order to successfully reproduce.
In most human cells, DNA resides in 23 pairs of chromosomes. One
chromosome is inherited from the father, one from the mother.
Neurospora, on the other hand, contains only seven different chromosomes,
and - during most of its life cycle - only one copy of each. During the
sexual phase, one set from each parent briefly forms a cell with 14
chromosomes, each chromosome containing a grab bag of genetic information
from one parent or the other. The corresponding chromosomes from each parent
pair up and then separate to form progeny, which again have only seven
chromosomes.
Silence of the genes
This complex cellular process - in which parental chromosomes pair up and
split apart to form offspring or sex cells (sperm and eggs) - is called
meiosis and occurs in all organisms that reproduce sexually, from people to
plants to fungi.
In their recent Cell study, Shiu and his colleagues took a closer look at
meiosis in mold and made a surprising discovery: Each cell with 14
chromosomes has some kind of internal mechanism that scans the paired
chromosomes before they split apart. The researchers determined that, if one
chromosome in a pair carries an extra copy of a gene not found in its
partner chromosome, the fungus will turn off all copies of that gene in the
cell.
Because the genes are turned off in the early stages of meiosis before
the two parental chromosomes separate and still have the chance to check for
mismatched (unpaired) genes, Shiu and his co-workers have dubbed the process
MSUD - "meiotic silencing by unpaired DNA."
The results of MSUD are devastating. Instead of turning out healthy black
spores capable of reproduction, silencing of essential genes by MSUD
produces white spores that are dead - or no spores at all.
"In meiosis, normal chromosomes pair with one another perfectly," noted
Stanford Research Professor Robert L. Metzenberg, co-author of the Cell
study. "We discovered that, when chromosomes pair, there`s a built-in
checking system we didn`t expect to find that checks if the pairing is
correct. It does not detect tiny differences in the two DNA sequences, but
any deviation the size of a gene or larger triggers the checking system."
Three copies distributed between two parents is sure to make trouble,
Metzenberg said, because one copy is likely to be unpaired, but four genes
are not necessarily bad because they can pair normally and do not trigger
the MSUD checking mechanism.
"If there`s a gene missing or appears in one chromosome but not in its
mating partner, the cell says, `Something is wrong. There`s something from
one of the parents that doesn`t belong there," he added.
The extra gene may be from a virus that jumped into the chromosome or
from an insertion sequence - a mobile segment of DNA that can interfere with
normal genetic function.
"Organisms are constantly under siege by viruses and insertion
sequences," Metzenberg observed. "Most of them are bad. They make you carry
something you shouldn`t, or they may disrupt a gene you need. They would
like to hitch a ride into the future by jumping into the progeny - the
children, grandchildren and great-grandchildren."
With MSUD, organisms can prevent unwanted viral genes and insertion
sequences from spreading.
"It`s as if the organism says, `No thanks, I don`t want that. I`m going
to activate my cellular machinery to turn off genes that are not paired
properly at the 14-chromosome stage," Metzenberg explained.
"It`s a meiotic defense system that defends the fungus against invasion
at a time when chromosomes are especially vulnerable to the spread of
viruses and insertion sequences," Shiu added.
Humans and speciation
In addition to eliminating deleterious genes in mold, Metzenberg
suggested that MSUD could be involved in screening out genetic parasites in
other organisms that reproduce sexually - plants, insects and even people.
One example is oogenesis in women - a biological process in the ovary that
results in the formation of eggs.
"Human oogenesis is, at first glance, a bizarre process," Metzenberg
wrote in Cell, noting that, at birth, a girl already will have developed
some seven million egg cells that are "frozen" in an early stage of meiosis
during which all 23 chromosomes sets are paired. Remarkably, the chromosomes
remain in this frozen state until menstruation begins some 12 years later.
Of the original seven million cells, only 400 or 500 will be made available
for reproduction during a woman`s lifetime.
"We speculate that this is not a random process," Metzenberg observed. "It`s
a perfect situation for weeding out extra genes or seeing if there`s a bad
match or too many bad matches in the chromosomes. We suspect that there is a
system in humans that causes gene silencing, but we don`t know the mechanism
yet."
The researchers made another surprising discovery with evolutionary
implications. Animals, plants and fungi are divided into species based, in
part, on their ability or inability to interbreed. Redwoods and Douglas firs
have some physical similarities, but it`s unlikely that they will be able to
mate to give hybrids, especially fertile ones. Clearly, they are different
species of trees.
Likewise several species of Neurospora - N. crassa, N. sitophila and N.
tetrasperma - are normally infertile when crossed in the laboratory. Yet, by
including a dominant mutant gene called Sad-1 in the DNA of the three mold
species, Shiu and his colleagues were able to produce viable spores through
cross-breeding of species that normally are sterile with one another.
The ability of Sad-1 to breach interspecies sexual barriers apparently
works by preventing meiotic silencing from occurring, according to
Metzenberg.
"To our knowledge, this is the first case where the barrier between
interspecies crosses has been observed to break down as a result of mutation
in a single gene," Shiu added, "but since gene silencing is universal, it
could occur in other kingdoms, including plants and animals."
Commercial interest
The Cell study is the latest in a series of discoveries in gene silencing
- one of the most explosive fields in biology in the past decade.
According to Metzenberg, MSUD silences genes by destroying messenger RNA
(mRNA) - molecules that carry specific instructions ("transcripts") from DNA
telling the cell which proteins to build. In gene silencing, mRNA molecules
are destroyed after they are transcribed - a method known as
"post-transcriptional gene silencing" (PTGS).
Researchers in a number of industries - including pharmaceuticals and
agriculture - are particularly interested in using PTGS to screen for
disease resistance, flavor enhancement and other commercially valuable
traits by turning off several genes simultaneously.
"MSUD could provide a quick and dirty way of testing how genes function
in meiosis," Shiu concluded. "We can silence a gene simply by inserting an
extra copy, without interfering with the growth of the fungus before
meiosis. We`re still not clear whether extra copies of a gene can trigger
meiotic silencing in plants and animals - or other fungi, such as
penicillium. That would be interesting for scientists to study in the
future."
Other co-authors of the Cell study are Stanford senior research scientist
Namboori B. Raju and Professor Denise Zickler of the Institut de Genetique
et Microbiologie at the Universite Paris-Sud. The research was supported by
grants from the U.S. Public Health Service and the National Science
Foundation.
This story has been adapted from a news release issued by Stanford
University.
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