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“I was really excited to see this paper,” says Wendy Robinson, a medical geneticist at the University of British Columbia who was not involved in the study. She had suspected that uniparental disomy occurs in healthy people more often than reported. But until recently, healthy people were not taking DNA tests by the millions. A doctor might see a few patients with an unusual disorder, order DNA tests to discover uniparental disomy, and then publish a paper. It’s like only searching for flowerpots under streetlights and concluding that every flowerpot must be under a streetlight.
The people in 23andMe and U.K. Biobank, on the other hand, skew healthy, and it turns out that even healthy people can have what might seem to be big genetic anomalies. “I like to say it’s normal to be abnormal,” Robinson says. She adds that uniparental disomy sometimes comes up in prenatal tests, and the results can make parents anxious because the existing scientific research is essentially a catalog of everything that can go wrong. This study might add some reassurance. “Just because you have that doesn’t automatically mean there’s going to be anything wrong with your child,” she says.
Uniparental disomy is the result of an error during meiosis, the process that forms eggs and sperm. Scientists have proposed different mechanisms, but the most common scenario probably goes like this: The error in meiosis gives the egg or sperm an extra copy of one chromosome, so the resulting embryo ends up with three copies on it. Sometimes, these embryos are spontaneously aborted, but other times, they are able to go through “trisomy rescue,” in which some cells lose that extra third chromosome and eventually outcompete the non-normal cells. The resulting child ends up with the right number of chromosomes, but not necessarily one from each parent.
This is all much more complicated than the standard story of sperm meets egg, yet the result is still a healthy child. “It goes against so many of the rules of biology you’ve memorized in school,” says Priyanka Nakka, a postdoctoral fellow at Boston Children’s Hospital and former 23andMe intern who co-wrote the study. Scientists have theorized and later discovered other ways that conception can go very much awry yet still result in healthy children, such as sesquizygotic twins.
When uniparental disomy does lead to health problems, it is for one of two reasons. First, a child might inherit two copies of a rare, recessive mutation from one parent. Second, some genes are normally turned off or on depending on which parent they’re inherited from in a phenomenon called “genomic imprinting.” That means inheriting two copies from the same parent can cause various health issues. For example, two maternal copies of chromosome 15 leads to Prader-Willi syndrome; two paternal copies leads to Angelman syndrome. They are distinct genetic disorders with very distinct symptoms.