Do Fathers Matter?: What Science Is Telling Us About the Parent We've Overlooked (5 page)

The offspring of the attractive red-banded males were found to have distinct advantages. They begged for food more often than the others and were rewarded: mothers gave them more food. Females laid eggs containing more growth hormones when the eggs had been fertilized by the attractive males. You might guess that the attractive fathers simply had better genes, but that wasn’t the case. Somehow, making the male finches more attractive encouraged mothers to devote more resources to the offspring. The attractive males didn’t have better genes than their green-ringed competitors, although the females might have been tricked into thinking that they did.

Curley called the findings so unexpected as to seem ridiculous. How could a colored leg band have such an important effect on mothers’ behavior? He decided to see whether he could replicate the experiment with his mice, comparing males raised in isolation to “enriched males” raised in a more natural environment. Then he mated each one with a female. The females who mated with the enriched males devoted more resources to their offspring and engaged in more thorough maternal behavior. It was similar to what was going on with the finches—females invested more in their offspring when they had a more desirable mate.

Encouraged, Curley did another test, this one with stressed and normal males. Females who mated with normal males nursed and licked their offspring more often, and their pups exhibited less anxiety than the offspring of the stressed males. It was yet another demonstration of the same effect: making the males more desirable turned the females into better mothers. And that was good for their pups.

Continuing along these lines, Curley looked at whether a male’s anxiety could affect his pups in the same way that stress did. To produce high-anxiety males, he took males out of their cages and dropped them into unfamiliar enclosures. Those who were the least willing to explore their new surroundings were the mice with the highest anxiety. He bred these males with females and found that the daughters of the high-anxiety fathers exhibited similar symptoms. The pups were raised solely by their mothers. The researchers concluded that marks on the fathers’ sperm were being passed on to affect daughters’ behavior, independent of any change in mothers’ behavior. (These marks are referred to as epigenetic changes, because they change the operation of genes—whether they are turned on or off—without actually changing the DNA.) And the sons did not inherit their fathers’ anxiety. This, too, parallels other findings. The nutritional status of the Överkalix grandfathers affected only their sons, not their daughters. It’s clear that some of these effects apply only to sons and others only to daughters. The inability to explain this is a sign of how much more researchers need to find out about these odd generational effects.

Curley and his colleagues are now exploring a gene called
Peg3
that likewise has different effects on sons and daughters. The name stands for “paternally expressed genes”: in this family of genes only the father’s copy is expressed in his offspring, while the copy from mothers is silenced. “That means what your father passes on to you is of massive significance,” Curley said. He is studying the gene in mice, but a form of
Peg3
occurs in humans, too. So anything he discovers in his mice is likely to be true in us as well. To help me understand what the gene does, Curley started with a short lecture on mouse sex. Virgin male mice, he explained, begin with a trial-and-error mating strategy: they pursue any female they can, whether or not the female is in estrus, ready to reproduce. The males usually manage to mate, and then their troubles are over. Once they’ve mated, they develop the ability to detect, by smell, which females are in estrus. Curley wanted to know how
Peg3
might be involved in this behavior, and so he used a lab trick to inactivate, or “knock out,” the
Peg3
gene in some of his mice. The knockout mice were unable to detect when females were in estrus, even after they’d mated. They continued to try mating with females who were not ready to reproduce. After a while, the directionless males gave up. So now Curley knew that
Peg3
is essential for the development of proper behavior regarding sex and mating in males.

Curley then looked at females. There he discovered that knocking out
Peg3
had a very different effect. Knocking out
Peg3
in female mice doesn’t affect mating, the way it does in males. Instead, females whose
Peg3
gene is knocked out become poor caretakers. They don’t eat as much as they should early in their pregnancies. After birth, they are supposed to lick their pups, nurse them, eat the placenta (a source of nourishment), and build a nest. Females whose
Peg3
has been knocked out do those things much less frequently than normal mice.

To sum all this up,
Peg3
affects how well a father’s male pups will mate and how well his female pups will care for their offspring. The mating ability of his sons and the nurturing qualities of his daughters will both affect the health of his grandpups. Once again, we have an effect that extends from males not only to their children but also to their grandchildren. It’s reasonable to expect that the human version of
Peg3
has similar effects in human males and their offspring. That’s not the same as proving the connection, but it gives Curley and others confidence to look for a similar phenomenon in humans.

We can’t put people in cages, tag them with colorful jewelry, and allow them to mate. Unlike finches, who had no say in which leg band they got, human males might object to being made unattractive for the sake of an experiment. Nor would they appreciate being manipulated in a way that could harm their children. But mice, finches, and humans are enough alike that’s what true in them is often true in us. Even though these findings haven’t been confirmed in humans, it might be wise for men who are about to become fathers to think about their health and about what they should be eating even before their wives or partners become pregnant. This would be good advice for fathers even if it doesn’t have any beneficial effects on their children. And it would be an even better idea if it does.

TWO

Conception
: The Genetic Tug-of-War

Years ago, when I had just started work as a science reporter at the Associated Press, I happened to get into a cab with a biology student from MIT. We were both on the way to a conference on cancer in Houston, and he was nervously preparing to make one of his first scientific presentations at a national meeting—on a study of the Y chromosome, the vehicle for fathers’ genetic contributions to their kids. Our paths have crossed several times over the years, and I’ve watched his career soar. That student, David C. Page, is now the director of the distinguished Whitehead Institute for Biomedical Research in Cambridge, Massachusetts, affiliated with MIT. And he’s still pursuing the questions he was interested in when we shared that cab.

He recently published a fascinating analysis of the history of the Y chromosome. It is, of course, essential for sexual reproduction. Males have one X chromosome and one Y; females have two Xs. Mothers pass one or the other of their Xs to each child; fathers pass an X, which makes the child a girl, or a Y, which makes it a boy. Page and his team showed that the Y chromosome, which is much smaller than the X when seen under a microscope, is only a fragmentary remnant of what it once was. At one point, the X and Y chromosomes had about eight hundred genes in common. The Y has now lost all but nineteen of those genes.

Are males disappearing?

Not quite: the
genes
have been disappearing, but males themselves are not withering away. Most of the gene loss occurred a long time ago, and the Y now seems to have stabilized. It’s a lucky thing for fathers and for us: new research on the Y chromosome leads us on a fascinating tale of male genetics, which is far more complicated and important than you might expect, despite the loss of all those genes.

*   *   *

Until recently, we thought we had a pretty good understanding of how conception worked. Fathers and mothers each contribute 23 chromosomes to a fertilized egg, giving it the full complement of 46. (They all occur in matched pairs except the X and Y.) The fertilized egg then begins to divide into many kinds of cells, and ultimately grows into a fetus sharing traits from both its mother and its father. It seems simple enough. But as scientists developed the tools to fertilize eggs in the laboratory and study the process in greater detail, they discovered a much more interesting story.

In the late 1970s, M. Azim Surani was a young developmental biologist in Cambridge, England, in the laboratory of the physiologist Robert G. Edwards—better known as half of the team of Steptoe and Edwards, who developed in vitro fertilization, or IVF. Edwards and gynecologist Patrick C. Steptoe were responsible for the 1978 birth of the world’s first so-called test-tube baby, Louise Brown, an achievement that would later be recognized with a Nobel Prize. Surani found the lab an enormously exciting place to be. The research on IVF was moving quickly when Surani joined the team, and Edwards wanted Surani to get involved in it. But Surani had a different idea.

He was interested in the phenomenon known as parthenogenesis, which gets its name from the Greek words for virgin birth. It’s a form of reproduction in which healthy offspring arise from only a mother’s genes or only a father’s genes—not from a mix of the two, as is the case in sexual reproduction. Scientists knew at the time that it could occur in some fish, reptiles, and other animals. But it was not known to occur in mammals, including humans or laboratory mice. Surani wanted to see if he could manipulate mice in the lab to force a virgin birth.

In mice and humans, the sperm and the egg each contribute one set of chromosomes to a fertilized egg, which then has a pair of them. That’s what it needs to divide and diversify. Combining two sets of a mother’s genes in an egg would theoretically accomplish the same thing: it would give the egg the correct number of chromosomes. Everything that was then known about genetics suggested that such an egg, even though all its genes came from females, should develop normally.

By the time he left the Edwards lab, Surani and his assistant Sheila C. Barton had developed the tools he would need to manipulate genes and eggs. He used those tools to “fertilize” a mouse egg by inserting a copy of genes from another female. It didn’t work. He tried the experiment repeatedly and failed each time. The eggs with only mothers’ genes developed into tiny, fragile fetuses, but none of them survived. Shortly after they were implanted into foster mouse mothers, they died, riddled with genetic defects. Some grew more slowly and were smaller than normal embryos; others had abnormally large yolk sacs. One had poorly organized brain tissue. Another had a beating heart, but no head.

It was clear that fathers contributed something essential to the survival of developing embryos. No one had any idea what that essential contribution was, but Surani was determined to find out. Surani tried reversing the experiment: he produced fertilized eggs with two sets of fathers’ genes. Those embryos did not survive either. He knew his experimental technique was correct, because when he used the same equipment to combine fathers’ genes with mothers’ genes, the embryos survived. His conclusion was that mothers and fathers each contributed something with their genes that marked them as “paternal” or “maternal”—and that both were essential to the survival of the fertilized egg.

He knew that “something” wasn’t in the genetic code itself, which is the same for mothers’ and fathers’ genes. A maternal hemoglobin gene is essentially indistinguishable from a paternal hemoglobin gene (although there are minor individual variations). The genes had to be marked in some way that didn’t alter the code. This was unexpected and difficult to accept at first. But it was an important new genetic phenomenon. The principal reason that Surani’s colleagues didn’t believe the finding was that the discovery violated the genetic principles known as Mendel’s laws, discovered by the German monk Gregor Mendel in the mid-nineteenth century. His work—which was lost for more than three decades before being rediscovered in 1900—forms the bedrock upon which modern genetics was built. Mendel painstakingly bred pea plants for eight years to see how different traits were passed from one generation to the next. He bred tall plants with short plants, green peas with yellow peas, and so on, to see what would emerge in the offspring. The results were entirely unexpected and groundbreaking.

Before Mendel, biologists thought that crossing two different plants would produce something of a mix: crossing a plant with wrinkled seeds with another that had smooth seeds would produce plants with slightly wrinkled seeds. But that wasn’t the case. Some plants had smooth seeds, and some had wrinkled seeds, depending on which way Mendel crossbred the plants. There
was
no in-between. These characteristics arrived in the next generation as discrete traits; they did not blend with each other. The traits were associated with genes that are passed from each parent to offspring and that do not blend with each other. Mendel could not know that; genes had not yet been discovered. He knew only what he saw in his pea plants.

To Mendel, whether a trait came from a mother or father made no difference. Genes combined in certain predictable ways no matter where they originated. Surani’s work posed a direct challenge to this principle. Scientists had to decide whom they were going to believe—Mendel or Surani. That was no contest. Most scientists concluded that if Surani’s work violated Mendel’s principles, Surani was wrong. “Around 1983, people in Cambridge were starting to hear about these strange experiments, and I was invited to give a seminar in the department of genetics. I could see they were very skeptical,” he recalled. “But I was convinced.” He soon got some help from another researcher in the United States—Davor Solter, then at the Wistar Institute, an independent biomedical research center in Philadelphia. It so happened that Solter had been doing similar experiments, and he was coming up with the same findings. This was crucial: controversial results such as these are harder to dismiss when they’re found independently in more than one laboratory.