Mating Molds Provide New Insights
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
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
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
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
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
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
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.
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