How can a paternity test suggest that a mother is also the father of her daughter?
The answer to that medical mystery, fueled by a confusing paternity test result, is: “If the genes of a missing twin 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 — are 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 have been documented, he said: “There are probably more. And it can have a profound effect on someone’s life.”
In recent decades, DNA studies have opened up a new perspective on the truly messy biology of human reproduction, which isn’t always as textbook-neat as health-class images of a sperm meeting an egg and a baby nine months later as a result. The first weeks of human development during pregnancy see rapid cell development in embryos, all orchestrated by a genetic rearrangement that sometimes takes a more complicated course. That leads to outcomes ranging from triplets to miscarriages (thought to be due to DNA abnormalities in about half of all known cases). One such curious pathway could lead to chimerism, where in an unknown number of cases, genes from a “vanishing twin” get mixed up with those from a surviving sibling. There are usually few outward signs of the condition, which is why it flies under the medical radar.
Similarly, the case Yunis presented in November at the International Symposium on Human Identification in Washington, D.C., was initially just a routine paternity test on a young girl. Things quickly got confusing, though: First, some parts of the test suggested that the child’s biological mother was not, in fact, her mother — what’s known as a “maternal exclusion” result. Second, others suggested that the child’s alleged father was not her father, a result of “paternal exclusion.” Finally, the birth mother’s blood sample was tested as male, with the XY chromosomes found in birth males – instead of 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.)
“Someone made a mistake, there’s contamination in the lab, stop everything,” Yunis said of the initial response. However, the team saw identical results when they repeated the test using the original blood samples. When the scientists took the mother out of the test, it turned out that the alleged father was clearly the girl’s father, and the other male genes disappeared in the result, adding more confusion.
The answer to this puzzle came from 2002, when Yunis was part of a team reporting news about a 52-year-old woman named Karen Keegan, whose genetic testing for a kidney transplant had revealed that she was a “tetragametic” chimera – where tetra means four and gametes means sex cells, such as sperm and eggs. Her genes were a mixture of four egg and sperm cells instead of the normal two. Her genetics are derived from two separately fertilized eggs that fused together 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 the time in Washington state, a woman nearly lost custody of her children because of her chimerism.)
The mother described by Yunis this month had an XY genetic signature that predominated in her blood and saliva samples, confusing the paternity test. But her hair and cheek cells showed a predominance of XX cells. This kind of mixed assortment of chromosomes in different types of tissues, growing separately from the beginning of pregnancy, is a hallmark of chimerism. The appearance of that lost twin Y chromosome and other chimeric genes were what had messed up the paternity test result.
“The child’s mother is a natural chimera,” Robert Wenk, a genetic pathologist from Baltimore, said by email. “One twin (one male) fused with the other (female) twin and disappeared early in the pregnancy.”
While there are few published cases of chimerism, there are estimates that the condition may affect up to 10 percent of the population, he added. Suggestive of this are findings that about 30 percent of births that initial tests suggest are twins result in the birth of only one child, the “vanishing twin” syndrome mentioned above. In rare cases of chimerism where XY or XX cells don’t predominate in the genitals, chimeric people can develop both male and female anatomy (a condition called intersex), Wenk said, but this is very unusual. “Since many chimeras appear normal and may not show functional limitations of reproduction, most human chimeras go unnoticed.”
“This is all a bit strange to get your head around because it’s 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 instances where the mother is also an aunt, which is kind of weird.” Or in the paternity test, he added, where the mother is also an uncle.
Chimerism could be on the rise in the human population, Butler added, because of the global increase in babies born through in vitro fertilization technology, more than 8 million in the past two decades. Fertility treatments often involve implanting more than one embryo into a mother. “That increases the chance of embryos fusing together,” he said.
Clearly chimerism can cause all sorts of problems if it confuses paternity tests, Yunis said, from lost child support, to divorces, to welfare fraud cases like that of Lydia Fairchild, a Washington state woman who nearly lost her children after genetic testing suggested she was not the biological mother of her children. Another telltale sign of the condition is large streaks of differently pigmented skin, such as that of model Taylor Muhl, another natural chimera. Such streaks also speckled a 34-year-old man whose paternity test, reported in 2015, suggested that a brother he didn’t have was the father of his child. A 2004 episode of the crime drama ‘CSI: Crime Scene Investigation’ centered on a chimera who blamed his crimes on a missing twin brother who left his DNA at crime scenes.
At a deeper level, the existence of natural chimerism plays a role in bioethicists’ arguments about human embryo experimentation, with the observation that embryonic fusion leading to chimerism (or vice versa, the splitting of an embryo leading to identical twins) occurs only twice. weeks or less in a pregnancy. This time limit partially explains the long-observed “14-day rule” in biomedicine, limiting experiments on human embryos to the first two weeks of development. That is the threshold identified by British developmental biologist Anne McLaren as a point at which human identity begins, and which is now under debate in scientific circles. It is worth noting that the natural chimerism found in the paternity test differs from an acquired kind much more common in adults, where mothers can acquire 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 a patient recipient’s bloodstream (“mixed” chimerism).
In a follow-up with the family of the woman who confused 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 one of the chimeric genes. There are signs that some of their mother’s chimeric “uncle” genes may have been passed on to them in the results he presented, Butler said, but the scientists need more analysis to rule out the prospect that this is instead everyday DNA. are mutations. “The point is that no one is actually looking for these things. So we don’t know how many there are,” he added. “That explains why the team wanted to investigate an entire family when they found a case. They tried to embrace the phenomenon.”
In particular, the paternity testing team looked to see if the son previously born to the woman possessed the male chromosome of her missing fraternal twin, Yunis said, “to see if this was the first case of a Y chromosome transfer from mother to son. But no, it was not a Nobel Prize winner.”
Thanks to Alicia Benjamin for editing this article.