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Uniparental Disomy More Common in General Population Than Previously Thought

NEW YORK – Uniparental disomy, in which a child inherits two copies of a chromosome from a single parent, is more common than previously thought, according to a new analysis.

Meiotic nondisjunction — when two members of a chromosome pair fail to separate during meiosis — can lead to aneuploidy, a common cause of miscarriage and severe developmental disabilities. But sometimes normal ploidy can be restored if two copies of a missing chromosome are inherited from the other parent, which leads to uniparental disomy. Most known cases of uniparental disomy, about 3,300 to date, have been found in the context of an imprinting disorder or other disease.

Researchers from 23andMe and elsewhere searched through the company's database and the UK Biobank dataset for instances of uniparental disomy. As they reported today in the American Journal of Human Genetics, they found the condition to be about twice as prevalent as expected and developed an approach to detect uniparental disomy based on runs of homozygosity. They additionally reported that many individuals with uniparental disomy appear healthy.

"Our work challenges the typical view that errors in recombination are strongly deleterious, showing that even in extreme cases where individuals are homozygous for an entire chromosome, those individuals can be, to the best of our knowledge, phenotypically normal and healthy," 23andMe's Fah Sathirapongsasuti and colleagues wrote in their paper.

From the 23andMe dataset, the researchers identified 916,712 parent-child pairs, including some parent-child trios. Using those pairs or trios, they identified 199 individuals with uniparental disomy, and using the trios, they estimated the prevalence of uniparental disomy to be about 1 in 2,000 births, about 1.75 times higher than current estimates.

They did not, however, uncover any uniparental disomy cases from the nearly 4,000 parent-child pairs in the UK Biobank dataset.

The instances of uniparental disomy they did find affected nearly all chromosomes, including sex chromosomes, though not chromosome 18. The most commonly affected chromosomes were chromosomes 1, 4, 7, 21, 22, and X.

To be able to identify uniparental disomy from singleton data, the researchers also developed a supervised logistic regression classification framework that examined the lengths of runs of homozygosity. When they applied this approach to simulated data, they found that it could identify 85 percent of true positives within northern European populations. The classifier struggled, however, with data from populations with higher-than-average levels of homozygosity, such as Ashkenazi Jewish, Middle Eastern, and South Asian populations, they noted.

Still, when they applied this classifier to data from 23andMe and the UK Biobank, they identified an additional 304 individuals with putative uniparental disomy in the 23andMe dataset and 172 individuals in the UK Biobank.

As uniparental disomy is expected to be linked to disease due to disrupted imprinting and an increased number of recessive alleles, the researchers examined whether it was associated with any self-reported conditions within the 23andMe dataset and uncovered almost a dozen nominally significant phenotypes. For instance, uniparental disomy of chromosome 6 was associated with lower weight and uniparental disomy of chromosome 22 was associated with a higher risk of autism. However, none of these associations remained significant after statistical correction.

Overall, the results suggest that not all errors of recombination are deleterious, they noted.

Additionally, the researchers conducted a genome-wide association study to search for variants associated with a parent having a child with uniparental disomy, but they did not uncover any such variants that reached genome-wide significance.