DNA Shows A Mother Was Also Her Daughter's Uncle - How Scientists Solved This Medical Mystery

DNA Shows A Mother Was Also Her Daughter’s Uncle – How Scientists Solved This Medical Mystery

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

The answer to this medical mystery, sparked by a puzzling paternity test result, is “When the genes of a missing twin brother live 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. .

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

Over the past few decades, DNA studies have opened up a new view of the truly messy biology of human reproduction, which isn’t always as neat as the health class pictures of a sperm encountering an egg and nine months later, a resulting baby. The early weeks of human development during pregnancy see rapid cell development in the embryos, all orchestrated by genetic shuffling that sometimes takes a more complicated course. This leads to outcomes ranging from triplets to miscarriages (which are said to result from DNA abnormalities in about half of all known cases). One of these curious pathways could lead to chimerism, where in an undetermined number of cases, the genes of a “disappearing twin” end up mixed with those of a surviving sibling. There are usually few outward signs of the disease, which puts it under the medical radar.

Similarly, the case presented by Yunis at the International Symposium on Human Identification in Washington, DC, in November, was initially just a routine paternity test on a young girl. However, this quickly became confusing: First, parts of the test suggested that the child’s biological mother was not, in fact, his mother – a so-called “maternal exclusion” result. Second, others have suggested that the alleged father of the child was not his father, a result of “paternal exclusion”. Finally, the biological mother’s blood sample tested as male, containing the XY chromosomes found in biological males – 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.)

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

The answer to this riddle 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 revealed she was a “tetragametic” chimera – where tetra means four and gametes mean the sex cells, such as sperm and egg. Her genes were a mix of four eggs and sperm instead of the normal two. Her genetics come 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’s report on her case. (In a related incident from that time in Washington state, a woman nearly lost custody of her children because of 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 cheeks showed a preponderance of XX cells. This type of mixed assortment of chromosomes in different tissue types, which develop separately from the onset of pregnancy, is a signature of chimerism. The appearance of this Y chromosome from a lost twin and other chimeric genes was what confounded the paternity test result.

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

Although there are few published cases of chimerism, the condition is estimated to exist in up to 10% of the population, he added. This suggests that around 30% of births that initial testing suggests are twins lead to the birth of a single child, the “disappearing twin” syndrome mentioned above. In rare cases of chimerism where XY or XX cells do not predominate in the sex organs, chimeric people can develop both male and female anatomy (a condition called intersex), Wenk said, but that’s very unusual. . “Because many chimeras appear normal and may not exhibit reproductive dysfunction, most human chimeras go undetected.”

“This is all a little strange to understand, 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 cases where the mother is also an aunt, which is a little weird.” Or in the case of 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 global rise in the number of babies born through in vitro fertilization technology, more than 8 million over the past two decades. Often more than one embryo is implanted in a mother as part of fertility treatments. “It increases the chances that there will be embryos that fuse together,” he said.

Obviously, chimerism can cause all sorts of problems if it confuses paternity tests, Yunis said, from lost alimony to divorces to social fraud cases like that of Lydia Fairchild, a woman from the Washington State who nearly lost her children after genetic testing suggested she was not the biological mother of her children. Another telltale sign of the condition are large bands of different pigmented skin, like that of model Taylor Muhl, which is another naturally occurring chimera. Such stripes also spotted a 34-year-old man whose paternity test, reported in 2015, suggested a sibling he did not have was the father of his child. A 2004 episode of the crime drama “CSI: Crime Scene Investigation” centered on a chimera who blames her crimes on a missing twin who left her DNA at crime scenes.

More profoundly, the existence of natural chimerism plays a role in bioethicists’ arguments about human embryo experiments, with the observation that embryonic fusion leading to chimerism (or conversely, embryo splitting leading to identical twins) only occurs two weeks or less into a pregnancy. This delay partly explains the long-observed “14-day rule” in biomedicine, limiting experiments on human embryos to the first two weeks of development. This is the threshold that British developmental biologist Anne McLaren has pointed to as a point where human identity begins, and which is now the subject of debate in scientific circles. It should be noted that the natural chimerism found from the paternity test case is different from an acquired type that is much more common in adults, where mothers may acquire genes from their children during fetal development (“microchimerism “) – another biological curiosity captured by DNA testing – and bone marrow transplants, which mix donor genes into the bloodstream of a recipient patient (“mixed” chimerism).

While following up with the family of the woman who confused the paternity test, Yunis and her team also checked 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 scientists need more analysis to rule out the possibility that these are everyday DNA mutations. “The thing is, 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 examine a whole family when they found a case. They were trying to control the phenomenon.

In particular, the paternity testing team looked to see if the woman’s earlier-born son had the male chromosome of her missing fraternal twin, Yunis said, “to see if this was the first case of transmission of the Y chromosome from mother to son But no, he was not a Nobel laureate.

Thanks to Alicia Benjamin for writing this article.

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