Updated at 10:52 a.m. on October 11, 2019.
Before Natalie Nakles was born, before the egg from which she was conceived was even fully mature, something went slightly awry. The egg that would help form her ended up with two copies of chromosome 16. So today, 24-year-old Nakles does not, as most people do, have one set of chromosomes from each parent. She has two copies of chromosome 16 from her mother and none from her father.
This phenomenon, called uniparental disomy, can happen in any of the 23 pairs of chromosomes. In the scientific literature, it has been linked to spontaneous abortions—and if the fetus survives, skeletal abnormalities, seizures, intellectual disability, and childhood cancers. Nakles has Asperger’s syndrome, but she is otherwise healthy. She has no serious health issues. She only found out about her uniparental disomy after sending in her saliva to 23andMe.
Now a new study of DNA from 4.4 million 23andMe customers—as well as 430,000 people in the U.K. Biobank—suggests many other healthy people, like Nakles, are living with uniparental disomy. The study identified 675 such people and found no significant associations with deleterious traits. Uniparental disomy is both more common and less detrimental than the scientific literature suggested.
“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.
Genomic imprinting does not appear to be spread evenly across all chromosomes though, and uniparental disomy is more serious when on some chromosomes than others. Nakka and her co-authors found that most of the existing papers on uniparental disomy focused on disorders related to chromosomes 6, 7, 11, 14, and 15. But uniparental disomy among relatively healthy people in 23andMe and U.K. Biobank tended to be more common on chromosomes 1, 4, 16, 21, 22, and X.
As at-home DNA tests have become more common, customers have been discovering uniparental disomies on their own. One prominent genetic genealogist, CeCe Moore, told me she had seen about a dozen cases from people who had approached her about their unusual DNA test results. 23andMe doesn’t flag uniparental disomy to customers—and the company says it doesn’t plan to—but it’s possible to deduce from closely scrutinizing the results.
Nakles figured it out after she and her mom both took 23andMe tests, and she noticed they shared more of chromosome 16 than usual. She got her dad to take a test, too, and it confirmed they shared no segments of chromosome 16 at all. Nakles is a medical student, and she quickly pieced together how she came to be in cellular detail. When we talked, she traced for me the initial error in meiosis and the trisomy rescue that “fixed” it. She marveled at how easily she could have not been born at all.