DNA showed that a mother was also her son’s uncle

How can a paternity test suggest that a mother is also the father of her daughter?

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

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

In recent decades, DNA studies have opened up new insight into the truly messy biology of human reproduction, which isn’t always as textbook sharp as the health-class pictures of a sperm meeting an egg and nine months later, resulting in a baby. . The first few weeks of human development during pregnancy see rapid cellular development in embryos, all orchestrated by a genetic shuffle that sometimes takes a more complicated course. This leads to outcomes ranging from triplets to miscarriages (believed to result from DNA abnormalities in about half of all known cases). One of those curious paths could lead to chimerism, where in an untold number of cases, the genes of a “disappearing twin” end up mixing with those of a surviving sibling. There are usually few outward signs of the condition, causing it to fly under the medical radar.

That’s right, the case Yunis presented at the International Symposium on Human Identification in Washington, DC in November was initially just a routine paternity test on a girl. However, it quickly became confusing: First, parts of the test suggested that the child’s birth mother was not actually mother to her—what is known as a “maternal exclusion” result. Secondly, some others have 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, 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 a female sexual anatomy, but are usually infertile.)

“Someone made a mistake, there’s contamination in the lab, stop everything,” Yunis said of the initial reaction. However, the team found identical results when they repeated the test with the original blood samples. When the scientists excluded the mother from the test, it emerged that the alleged father was clearly the girl’s father, and the other male genes in the result disappeared, causing further confusion.

The answer to this conundrum came in 2002, when Yunis was part of a team reporting on a 52-year-old woman named Karen Keegan, whose genetic tests for a kidney transplant revealed she was a “tetragametic” chimera. – where tetragametic means four and gametes means sex cells, such as sperm and eggs. Her genes were a blend of four eggs and sperm instead of the normal two. Her genetics come 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 nearly lost custody of her children to her chimerism.)

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

“The baby’s mother is a natural chimera,” Robert Wenk, a Baltimore-based genetic pathologist, said in an email. “One twin (a boy) fused with the other twin (a girl) and disappeared early in the pregnancy.”

While there are few published cases of chimerism, the condition is estimated to exist in 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 lead to the birth of only one child, the “vanishing twin” syndrome mentioned above. In rare cases of chimerism in which XY or XX cells don’t predominate in sex organs, chimeric people can develop both male and female anatomy (a condition called intersex), Wenk said, but this is highly unusual. “Because many chimeras appear normal and may not show functional impairment of reproduction, most human chimeras go undetected.”

“This is all a little strange to understand, because it’s outside the normal paradigm,” said John Butler, a 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 bit strange.” Or in the paternity test, he added, where the mother is also an uncle.

Chimerism may be on the rise in the human population, Butler added, due to the worldwide increase in babies born through IVF technology, more than 8 million in the past two decades. Often more than one embryo is implanted in a mother in fertility treatments. “This increases the chances that there could be embryos that fuse,” she said.

Of course, chimerism can cause all kinds of problems if it confuses paternity tests, Yunis said, from failed child support to divorces to welfare fraud cases like that of Lydia Fairchild, a Washington state woman who has nearly lost her children after genetic tests suggested she was not the biological mother of his children. Another telltale sign of the condition is large swathes of skin of varying pigmentation, such as those on model Taylor Muhl, who is another natural chimera. Those streaks also spotted a 34-year-old man whose paternity test, reported in 2015, suggested that a sibling he didn’t have was the father of his children. A 2004 episode of the crime drama “CSI: Crime Scene Investigation” centered around a chimera who blamed her crimes on a missing twin who left his DNA at the crime scene.

At a deeper level, the existence of natural chimerism plays a role in the arguments of bioethicists on human embryo experiments, with the observation that embryonic fusion leading to chimerism (or vice versa, the splitting of an embryo leading to twins identical) occurs only twice weeks or less in a pregnancy. This time limit partly explains the long-observed “14-day rule” in biomedicine, which keeps experiments on human embryos through to the first two weeks of development. This is the threshold that British developmental biologist Anne McLaren has pointed to as a point at which human identity begins, and which is now the subject of debate in scientific circles. It is worth noting that the natural chimerism found by paternity testing is different from an acquired type that is much more common in adults, where mothers can obtain genes from their children during fetal development (“microchimerism”) – another biological curiosity detected by DNA testing – and by bone marrow transplants, which mix donor genes into the bloodstream of a recipient patient (“mixed” chimerism).

In a follow-up with the family of the woman who botched the paternity test, Yunis and her team also tested her two oldest children, a girl and a boy, to see if they had received any of the chimeric genes. There are signs that some of the mother’s “uncle’s” chimeric genes may have been passed on to them in the results she presented, Butler said, but scientists need further analysis to rule out the prospect that they are instead everyday mutations of the DNA. “The thing is, nobody is looking for these cases, really. So we don’t know how many there are,” she added. “That explains why the team wanted to look at an entire family when they found a case. They were trying to embrace the phenomenon.

Specifically, the paternity test team looked to see if the woman’s first-born child carried the male chromosome of her missing fraternal twin, Yunis said, “to see if it was the first case of mother-to-mother Y-chromosome transmission.” son. But no, he wasn’t a Nobel Prize winner.

Thanks to Alicia Benjamin for copy editing this article.

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