All serious butterfly collectors remember their first gynandromorph: a butterfly with a color and pattern that are distinctly male on one wing and female on the other.
Seeing one sparks wonder and curiosity. For biologist Nipam Patel, the sighting offered a possible answer to a question he had been pondering for years: During embryonic and larval development, how do cells know where to stop and where to go?
He was sure that the delicate black outlines between male and female regions appearing on one wing — but not the other — identified a key facet of animal development.
“It immediately struck me that this was telling me something interesting about how the wing was being made,” said Patel, a biologist who now heads the Marine Biological Laboratory, a research institute in Woods Hole, Massachusetts, affiliated with the University of Chicago.
The patterning on the gynandromorph’s wing shows that the body uses signaling centers to control where cells go during development and what tissues they become in creatures as diverse as butterflies and people, Patel said.
Gynandromorph butterflies and other half-male, half-female creatures, particularly birds, have fascinated both scientists and amateurs for centuries. The latest sensation was a half-red, half-taupe cardinal that became a regular visitor in the backyard of Shirley and Jeffrey Caldwell in Erie, Pennsylvania. Although the bird would have to be tested to confirm that it is a gynandromorph, its color division strongly suggests that it is, scientists say.
Split-sex creatures are not as unusual as they may seem when one discovery goes viral, as the cardinal’s did. It extends beyond birds and butterflies to other insects and crustaceans, like lobsters and crabs.
Scientists say these instances of split-sex animals and insects could offer clues to why some human diseases strike one sex more than the other.
Beyond the birds and the bees
Researchers thought they had figured out the genetics of birds and bees, but gynandromorphs suggest that there is more to learn, said Jennifer Marshall Graves, a distinguished professor at La Trobe University in Melbourne, Australia.
Mammals have X and Y chromosomes, birds and insects have Z and W, and some reptiles can change their sex depending on temperature, or a combination of temperature and sex chromosomes, she said.
It was believed that the sex of a bird was determined by a protein made by the DMRT1 gene, which would reach all the cells of the bird through the bloodstream, Graves said. But for two sides of the bird to share the same bloodstream but not the same sex, there must be more to the story.
Hormones cannot be the sole drivers of sex either, but they most likely play some role, said Arthur Arnold, a distinguished research professor at the University of California, Los Angeles. In a paper published in 2003 in PNAS, Arnold showed that in gynandromorphic zebra finches, brain cells on the female side were more masculine than comparable cells in a typical female.
How gynandromorphs are born at all still remains a mystery. For birds, the most likely explanation is that a female makes an unusual double-nucleus egg cell, one with a Z chromosome and one with a W chromosome, and each is fertilized by a Z sperm, making some cells ZZ and others ZW in the same individual, Arnold said.
“Although this happens regularly, it’s very rare,” he added. Gene editing is tricky in birds, so it has not been possible to experimentally induce this phenomenon in birds, so it’s not well understood, he said.
The same process is very unlikely to happen in mammals, he said. Female mammals naturally have two of the same sex chromosomes, and the instant a mammalian egg and sperm fuse, “dramatic changes prevent the entry of a second sperm.”
Gynandromorphs occur naturally, usually resulting from a random genetic error, Patel said. The phenomenon can be inherited — with some flies and moths passing unstable sex chromosomes down to their offspring, he said. But it is also possible that stress can cause the unusual sex split.
It is impossible to track an entire population to understand what percentage have unusual sex chromosomes, Patel said. In the lab, scientists have used radiation to create gynandromorph flies, he said, but it is difficult to sort out the potential causes — including environmental harm — in a wild population.
‘I don’t have a good explanation’
Why cells of opposite sex end up on opposite sides of these gynandromorphs remains unclear, Arnold said. “I don’t have a good explanation,” he said.
Although many of the birds studied have been roughly 50 percent male on one side and 50 percent female on the other, a 2010 study in chickens showed that the cells were not that evenly distributed.
Animals can also develop as mosaics, with some cells genetically different from others. Some of Patel’s butterflies, for instance, show male coloration and patterns on parts of a wing, rather than the entire side.
Arnold said his own research on sex genes has implications for treating a variety of human diseases that seem to vary by gender. His UCLA collaborator, Rhonda Voskuhl, has found, for instance, that in multiple sclerosis, a genetically female mouse with two X chromosomes fares worse than a mouse with an X and a Y, even if they have the same hormones. Understanding why females fare worse could help explain and treat MS in people, where there is also a gender difference, with women accounting for three times as many cases as men.
Obesity, metabolic syndrome, autoimmune disease, Alzheimer’s, even aging differs by sex, Arnold noted. Twenty years ago, he said, scientists did not think that sex chromosomes played any role in causing sex differences in these diseases. “But now we know it makes a difference in mice, so we can say: Where does it make a difference in humans?” he said.
A better understanding of the role of sex in disease would eventually enable better treatments, he said. “That’s the kind of hope — that sex differences are not only important to understanding diseases in men and women, but also to developing a more fundamental understanding of the disease processes, so that you can manipulate them,” Arnold said.
Chromosomes can be deadly
In most cases, losing a chromosome or having an extra one is lethal, said Jeannie Lee, a geneticist and expert on the X chromosome at Harvard Medical School and Massachusetts General Hospital.
Most people have 46 chromosomes, with 23 inherited from each parent. A few chromosomes can come with an extra copy, including chromosomes 13, 18 and 21 — which is commonly called Down syndrome. Losing any chromosome other than a second sex chromosome is always lethal to a fetus.
But the sex chromosome is the only one that people can survive with just one copy, Graves said. “Girls with a single X and no Y suffer few anomalies because the second X is largely inactive anyway. After all, males have only one X,” she said.
People with anomalous numbers of sex chromosomes, such as those with Turner Syndrome, have a range of problems from virtually no issues to infertility, heart problems and cognitive impairment. About 1 in 2,500 girls is born with Turner Syndrome. It is also possible for people to be intersex, born with reproductive or sexual anatomy that does not fit the typical definitions of female or male, which may but does not have to involve sex chromosomes, according to the Intersex Society of North America, an advocacy group.
It is not clear what mechanisms the body has to ensure that most men get only one Y and most women get two X chromosomes, said Karissa Sanbonmatsu, a structural biologist and principal investigator at Los Alamos National Laboratory in New Mexico. In typical females, one X is usually — but not always — turned off, she said, and some research suggests that there is a mechanism that counts how many X chromosomes are present and generally turns off all but one of them.
The interplay between genetics and hormones is complicated, she said. “Genetics produce hormones, but then the hormones can reprogram DNA,” she said, which might explain why there is a mismatch in some people between their sex chromosomes and their sex hormones. “That’s very speculative,” Sanbonmatsu said, adding, “It’s hard to get funding to do this kind of research.”
People with androgen insensitivity syndrome, for instance, are born with XY chromosomes, but develop as female, because their cells cannot process male hormones. “So, it’s as if the testosterone doesn’t exist,” she said. They are infertile.
The more science learns about sex, “the more we find anomalies,” said Alice Dreger, a historian of sexuality.
“Nature’s dealing with conformity all the time in brutal ways and loving ways and all the rest of it,” Dreger said. “It doesn’t follow the human fantasy of everybody having to be normal. And humans don’t follow that ridiculous idea either.”