Solving a genetic mystery: DNA showed a mom was also her child's uncle: how scientists solved this medical mystery

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How can a paternity test suggest a mother is also her daughter's father?

The answer to that medical mystery, sparked by a confusing paternity test result, is "When the genes of a vanished twin brother live on in the mother's DNA." The finding, which genetics experts reported earlier this month, suggests that such human "chimeras" — people with DNA from more than one embryo — could be more common than we thought.

"What is the frequency of this? We don't really know," said Juan Yunis of Colombia's Instituto de Genetica. Only about 20 confirmed cases are documented, he said: "Probably there are more. And it can have a profound effect on one's life."

In recent decades, DNA studies have opened a new view on the truly messy biology of human reproduction, which is not always as textbook-neat as health class images of a sperm meeting an egg and nine months later, a baby resulting. The opening weeks of human development during pregnancy see rapid cell development in embryos, all orchestrated by a genetic shuffle that sometimes takes a more complicated course. That leads to outcomes ranging from triplets to miscarriages (which are thought to result from DNA abnormalities in about half of all known cases). One of those curious paths might lead to chimerism, where in an unknown number of cases, genes from a "vanishing twin" end up mixed in with those of a surviving sibling. There's usually few outward signs of the condition, leading it to fly under the medical radar.

Just so, the case Yunis presented at the International Symposium on Human Identification in Washington, D.C., in November was at first just a routine paternity test on a young girl. However, it quickly turned confusing: First, some parts of the test suggested the child's birth mother was not in fact her mother — what is known as a "maternal exclusion" result. Second, some others suggested the child's alleged father was not her father, a "paternal exclusion" result. Finally, the birth mother's blood sample tested as male, containing the XY chromosomes found in biological men — rather than the two XX chromosomes responsible for female sex organs. (Some intersex women have XY chromosomes and develop female sexual anatomy, but they are usually infertile.)

"Somebody made a mistake, there's contamination in the lab, stop everything," said Yunis of the initial reaction. However, the team saw identical results when they repeated the test with the original blood samples. When the scientists took the mother out of the test, it showed the alleged father was clearly the father of the girl, and the other male genes in the result disappeared, causing more confusion.

The answer to this puzzle came from 2002, when Yunis was part of a team that reported news of a 52-year-old woman named Karen Keegan, whose genetic testing for a kidney transplant had revealed she was a "tetragametic" chimera — where tetra means four and gametes means sex cells, like sperm and eggs. Her genes were a mixture from four egg and sperm cells instead of the normal two. Her genetics derive from two separately fertilized eggs that fused early when her mother was pregnant with her. In Keegan's case, both embryos were XX, or biologically female, according to the New England Journal of Medicine report on her case. (In a related incident from that time in Washington State, a woman almost lost custody of her children because of her chimerism.)

The mother described by Yunis this month had an XY genetic signature predominate in her blood and saliva samples, confusing the paternity test. But her hair and cheek cells showed a preponderance of XX cells. This kind of mixed assortment of chromosomes in different types of tissues, which grow separately starting early in pregnancy, is a signature of chimerism. The appearance of that Y chromosome from a lost twin and other chimeric genes were what had confused the paternity test result.

"The child's mother is a natural chimera," said Robert Wenk, a genetic pathologist based in Baltimore, by email. "One twin (a male) fused with the other (female) twin and disappeared early in pregnancy."

Although there are few published cases of chimerism, there are estimates that the condition may exist in up to 10 percent of the population, he added. Suggestive of this are findings that around 30 percent of births that initial tests suggest are twins lead to the birth of only one child, the "vanishing twin" syndrome mentioned above. In rare cases of chimerism where either XY or XX cells don't predominate in the sexual organs, chimeric people can develop both male and female anatomy (a condition referred to as intersex), said Wenk, but this is very unusual. "Since many chimeras appear normal and may not show functional impairments of reproduction, most human chimeras go undetected."

"This is all a little strange to get your head around, because it is outside the normal paradigm," said John Butler, NIST Fellow at the National Institute of Standards and Technology and president of the International Society for Forensic Genetics. "You can have cases where the mother is also an aunt, which is a little weird." Or in the paternity test case, he added, where the mother is also an uncle.

Chimerism might be on the increase in the human population, Butler added, because of the worldwide increase in babies born through in vitro fertilization technology, more than 8 million in the last two decades. Often more than one embryo is implanted in a mother in fertility treatments. "That increases the chances there might be embryos fusing," he said.

Obviously, chimerism can cause all kinds of problems if it confuses paternity tests, said Yunis, from lost child support, to divorces, to welfare fraud cases like that of Lydia Fairchild, a Washington state woman who almost lost her children after genetic tests suggested she was not her children's biological mother. Another telltale sign of the condition are large stripes of different pigmented skin, like those of the model Taylor Muhl, who is another natural chimera. Such stripes also speckled a 34-year-old man whose paternity test, reported in 2015, suggested a brother he didn't have was the father of his child. A 2004 episode of the criminal drama "CSI: Crime Scene Investigation" centered on a chimera who blamed his crimes on a vanished twin who left his DNA at crime scenes.

On a deeper level, the existence of natural chimerism plays a role in bioethicists' arguments over experiments on human embryos, with the observation that embryonic fusion leading to chimerism (or vice versa, the splitting of an embryo leading to identical twins) only happens two weeks or less into a pregnancy. This time limit partly explains the long-observed "14-day rule" in biomedicine, keeping experiments on human embryos to the first two weeks of development. That is the threshold that the British developmental biologist Anne McLaren pointed to as a point where human identity begins, and which is now under debate in scientific circles. Worth noting, the natural chimerism found from the paternity test case is different from an acquired kind that is far more common in adults, where mothers can gain genes from their children during fetal development ("microchimerism") — another biological curiosity picked up by DNA tests — and from bone marrow transplants, which mix donor genes into the bloodstream of a patient recipient ("mixed" chimerism).

In a follow-up with the family of the woman who confounded the paternity test, Yunis and his team also looked at her two older children, a girl and a boy, to see if they had received any of the chimeric genes. There are signs that some of their mother's chimeric "uncle" genes might have been passed along to them in the results he presented, Butler said, but the scientists need more analysis to rule out the prospect these are everyday DNA mutations instead. "The thing is that nobody is looking for these cases, really. So we don't know how many there are," he added. "That explains why the team wanted to look at a whole family when they found a case. They were trying to get their arms around the phenomenon."

In particular, the paternity test team looked to see if the son born earlier to the woman possessed her vanished fraternal twin's male chromosome, Yunis said, "to see if it was the first case of a Y chromosome transmission from mother to son. But no, it was not a Nobel Prize winner."

Thanks to Alicia Benjamin for copy editing this article.