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Chronice of Higher Education From the
issue dated February 25, 2000
Biologists Track a 'Genetic Arms Race' Between Mothers and Fathers
By LILA GUTERMAN As textbooks tell it, genetic inheritance is simple.
A child gets a set of genes from mom and another from dad to make a matched
pair. Both sets are active and together help determine such characteristics
as the child's eye color, susceptibility to disease, and aggressiveness.
But it doesn't always happen that way. Scientists have discovered that
a few genes -- perhaps a tenth of 1 percent of all human genes -- break
the textbook laws. Some genes are active only if they come from the mother's
side, and others are turned on only if the father contributed them. Many
scientists think that mammals have evolved this odd pattern of inheritance
because of a long-standing conflict between parents over what's best for
their kids. To ensure the perpetuation of their line, the theory goes,
male mammals tend to pass down genes that make their children large --
or, alternatively, the genome they pass to their children shuts down certain
genes that slow growth. But a mother stands a greater chance of passing
on her genes if she divides attention equally among her offspring. If
one takes more nutrients and energy from her, others may suffer or die.
Worse, she could die if an embryo grew too large. So female mammals' genomes
tend to turn off genes for growth in their offspring. That conflict has
led to escalating moves and countermoves in what Shirley M. Tilghman calls
"a genetic arms race" between mothers and fathers. In a public lecture
in December at the Carnegie Institution in Washington, Ms. Tilghman, a
professor of biology at Princeton University, warned: "You are going to
think about your parents slightly differently after tonight's lecture."
This unusual inheritance pattern, called imprinting, was dreamed up around
1980, when scientists discovered that mammalian embryos manipulated to
have two sets of male or two sets of female chromosomes died early in
development. The chromosomes from the mother, the scientists reasoned,
must be different from those of the father, and having both must be vital
for offspring. It turned out they were right. In 1990, researchers at
Columbia University identified the first imprinted gene, called insulin-like
growth factor 2, or Igf2. When the researchers mutated that gene in male
mice so that it did not function, they saw just what they expected: The
mutant fathers' offspring were runts. But if the mutated gene was passed
down from a mother, the mice were of perfectly normal size. The mother
was silencing Igf2 in her offspring; therefore, mutating her copy of the
gene had no impact on her offspring's growth. Shortly thereafter, Ms.
Tilghman discovered another imprinted gene. She was curious about the
function of a gene called H19, so she mutated it in mice and then bred
them. She found that the gene must function normally to reduce growth
because the offspring of mothers with the damaged gene were very large.
She also found that, because the babies of fathers with the mutated gene
were normal, the fathers must have evolved a method to turn off the genes
in their offspring. "This was the first hint, really, to us that this
parent-specific regulation of genes was somehow tied to mammalian growth,"
she says. About half of today's 33 or 34 known imprinted genes control
growth. Other imprinted genes may also control growth, but scientists
are not certain. They do know that some of the genes affect more than
growth, however. In the past two years, researchers at the University
of Cambridge have discovered that two imprinted genes also affect behavior.
The mother's genetic contribution silences both genes in her children,
so offspring can receive active copies only from their fathers. In experiments
with mice, researchers found that if a father's copy of either gene was
mutated, female offspring lost their maternal instinct. When those daughters
had children of their own, they neglected them: They did not build nests
or groom their offspring. Researchers don't know why the mother mouse
silences genes that ensure her daughters will become responsible mothers
themselves. Shutting off one parent's copy of a gene is a curious pattern
of inheritance not only because it is unusual but because it can endanger
the offspring. When an organism has a pair of genes, if one gets damaged,
the second still functions. But with imprinting, says Ms. Tilghman, "we
throw away that advantage." One copy of the gene is permanently switched
off, putting the animal at greater risk. That disadvantage becomes clear
in such human diseases as Beckwith-Wiedemann syndrome. A mutation in a
single copy of an imprinted gene causes children both to grow very rapidly
in the womb and to develop childhood cancer. If such children had a second,
functioning copy of the gene, scientists think, they would be healthy.
If imprinting can cost an organism its life, why did it evolve in the
first place? David Haig, an associate professor of biology at Harvard
University, has outlined how mammalian reproductive behavior may have
led to a genetic arms race. Mammals raise their young in an unusual way
for an animal, with an embryo taking nutrients from its mother throughout
gestation. As Ms. Tilghman puts it, "mammalian embryos develop as parasites
of their mothers." That means that an embryo, as it grows, can influence
how much food its mother delivers to it. If the father's genome turns
on genes in the offspring that make it grow quickly, the mother will deliver
more nutrients to the embryo through the placenta. In egg-laying animals,
by contrast, a growing embryo can obtain the nutrients deposited in the
egg and no more. In birds, says Ms. Tilghman, "there is no renegotiation
of the amount of nutrients in that egg once the egg is laid." And birds
do not imprint genes. If, long ago in mammalian evolution, a father pulled
a genetic trick to give his offspring a greater share of nutrients, then
he might have had greater success in passing on his genes than other males.
His trick would have spread throughout the population. But then natural
selection would have favored a mother who could keep the growth of her
offspring in check, and thereby have the energy and resources to feed
other offspring. Her genetic trick would have soon spread as well. Those
incremental adjustments would have continued as species evolved, with
embryonic growth increasing and decreasing but hovering around an optimal
size. "It's like a tug of war," explains Rudolf Jaenisch, a professor
of biology at the Massachusetts Institute of Technology. "Both parties
pull on a rope. As long as they pull with equal strength, it's balanced."
Although the conflict theory seems logical, some scientists say the research
doesn't fully back it up. One problem, according to Laurence D. Hurst,
a professor of evolutionary genetics at Britain's University of Bath,
is that on the rare occasions when mice and even humans inherit two copies
of a certain gene from one parent, they often don't grow according to
the conflict theory's predicted pattern. An offspring receiving two copies
of a gene from its father and none from its mother, the theory says, should
grow large. But in a review of reports of such cases, Mr. Hurst found
that only one out of seven examples in human beings followed that pattern.
Mr. Hurst was surprised to find results that didn't fit the theory. "Intellectually,"
he says, it is "a very compelling argument. I just want to know why the
data isn't adding up." Ms. Tilghman says that's a fair criticism. "Even
the toughest critic of the conflict model agrees that it's the best explanation
right now. It's just that the rush to embrace it and to ignore all other
possible models, they would argue, is extremely premature," she says.
Ms. Tilghman decided to test the theory in another way, by studying a
mammal that mates for life. Mothers and fathers of that species should
be equally interested in the well-being of all their offspring, and so
might have stopped imprinting. She chose to study a monogamous species
of mouse, called Peromyscus polionotus, which lives in Georgia and Florida.
Elsewhere in North America, a related species of mouse, Peromyscus maniculatus,
enjoys a promiscuous lifestyle. If the monogamous mice do not imprint
genes, a cross between the two species of mice should result in marked
size differences, depending on which parent was monogamous, Ms. Tilghman
reasoned. A monogamous mother's genome should have "forgotten" how to
shut down growth genes, and her offspring with a polygamous father should
be large. Conversely, a monogamous father and a polygamous mother should
have small offspring. Ms. Tilghman dug up 30-year-old reports of experiments
that found that hybrids of the two Peromyscus species followed those predictions
precisely, producing either such large embryos that they couldn't be delivered,
or such tiny ones that the offspring could not survive in the wild. But
when Ms. Tilghman looked directly at the genes, she found to her surprise
that the monogamous mice did imprint them. She thinks that somehow the
hybrids were not recognizing signals to turn off certain genes. Because
the polygamous mice seemed to have stronger imprinting than the monogamous
mice, Ms. Tilghman thinks the latter might have had less evolutionary
pressure to develop -- or maintain -- imprinting mechanisms. Alternatively,
the differences might have arisen by chance, as one species randomly escalated
its arms race and the other engaged in disarmament. More crosses between
related species could help sort out whether polygamy correlates with more-intense
imprinting, Ms. Tilghman believes. She hopes next to study imprinting
in the prairie vole, a mammal that mates for life and that, unlike the
monogamous mouse, becomes celibate after its partner dies. An inability
to maintain imprinting may have driven mammalian species apart over the
course of their evolution, some researchers think, because size prevents
hybrids of closely related species from surviving in the wild. One example
of such size differences occurs in zoos that have mated lions with tigers,
Ms. Tilghman says. The cub of a male lion and a female tiger, a liger,
grows to be more than 1,000 pounds, towering over its parents. But a female
lion and a male tiger produce a very small cat called a tigon. Imprinting
could have further implications for scientists hoping to improve the efficiency
of cloning. The method that was used to make Dolly, the sheep cloned in
Scotland in 1997, is extremely inefficient. In that method, an adult cell
is fused with an egg from which the genetic information has been stripped.
Scientists are happy when a few percent of such cloning attempts survive.
Dolly was the only survivor of 277 implanted eggs. The other embryos may
have died because somehow the imprinting in the fused cell did not function
properly. Many of the defective fetuses that die in cloning experiments
are extremely large. If scientists could learn enough about imprinting
to turn it off altogether, they could produce something far more astonishing
than clones: a mammal born of two mothers or even of two fathers, if their
genetic material were injected into a DNA-free egg. So says M.I.T.'s Dr.
Jaenisch. He argues that if the imprinted growth effects produced by the
father are exactly balanced by those passed on by the mother, then erasing
them all should produce a normal embryo. He's already done experiments
suggesting that such a total disarmament in the genetic arms race could
come to a peaceful conclusion. He produced mouse cells with imprinting
turned off and injected those cells into a mouse embryo. "They behave
like normal cells," he says. But Dr. Jaenisch hasn't yet made a mouse
in which all of the cells lack imprinting. "Will it live or not?" he wonders.
"We don't know the answer."
(from Kabai
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