Mutations in human sperm that can cause illnesses in children identified

Throughout development, life, and aging processes, all human cells accumulate mutations, resulting in what is called mosaicism, a condition in which different cells from the same person have sequences of Different DNA or genetic makeup.

Mosaicism occurs in every human being, but is usually imperceptible. However, if the abnormal cells start to outnumber normal cells, disease can result. When mosaicism occurs in human sperm or eggs, the mutations can affect both the male or female carrying the mutation and subsequent generations.

In a study published August 12, 2021 in Cell, researchers at the Rady Children’s Institute of Genomic Medicine and the University of California San Diego School of Medicine describe a new method to observe and count these mutations, and use this data to predict the probable impact of these mutations on future children.

All human cells, including sperm, accumulate mutations over time and during aging processes. Photo credit: Joseph Gleeson laboratory

Notably, they report that one in 15 men are likely to carry mutations in their sperm that could harm their offspring.

Previous research has suggested that older men have a higher risk of certain diseases in their children, such as autism spectrum disorders (ASD) and certain forms of birth defects. In the latest study, researchers compared the semen of older men with younger men to determine the differences in mutations.

They found that the detectable mutations did not differ in number, suggesting that these mutations create a stable risk of disease in the offspring. The results also indicated that age-associated mutations seem more likely to occur in single sperm, which occur below current levels of detection.

“Our previous studies told us that sperm mutations contribute to the cause of disorders, such as autism and epilepsy, but the implications in men without a family history of the disease were completely unknown,” the author said. Principal Joseph Gleeson, MD, Rady Professor of Neuroscience. at UC San Diego School of Medicine and Director of Neuroscience Research at the Rady Children’s Institute for Genomic Medicine.

Researchers have sequenced sperm in multiple samples hundreds of times across their entire genome to find mutations only showing up in a small percentage of cells, using state-of-the-art machine learning tools.

“We found that each ejaculate from a man has an average of 30 mutations,” said co-first author Xiaoxu Yang, PhD, a postdoctoral researcher in Gleeson’s lab. “Almost all of these mutations were found in serial samples over a period of six to 12 months, while most of the mutations were completely absent from a saliva or blood sample.” The data, said Yang, indicates that the mutations are limited to sperm and also validates their method of detection.

“Surprisingly,” said co-lead author Martin Breuss, PhD, assistant professor of clinical pediatric genetics and metabolism at the University of Colorado School of Medicine and former postdoctoral researcher at the Gleeson Lab, “the comparison between men old and young showed little difference in mutations, telling us that these mutations probably arose when the father was an embryo, where mutations could reside undetected until the man had children.

Breuss said this also means that the sperm are well protected in a stem cell niche, which helps maintain stem cell populations and their relative contribution to each ejaculate.

“We believe these mutations contribute to a substantial burden on human health,” Gleeson said, “potentially causing 15 percent of cases of ASD, congenital heart disease, and severe pediatric disease. But we hope that by identifying men at risk, future cases of illness can be avoided. “

Future research, the authors said, will focus on identifying the causes of mutations occurring in older men and environmental exposures that might explain the observed increases in mutations. The team is recruiting families where a child has an illness due to a new mutation, and where the father can donate a sperm sample to look for evidence of the mutation. For more information about enrolling in the study, please email [email protected] or visit

Researchers are also working with infertility clinics to assess whether these mosaic mutations are passed on to embryos, with the ultimate goal of preventing disease in children.

Co-authors include: Xin Xu, Danny Antaki, Kiely N James, Valentina Stanley, Laurel L Ball, Renee D George, Sara A Wirth, Beibei Cao, An Nguyen, Jennifer McEvoy-Venneri, Guoliang Chai, Shareef Nahas, Kraan Van Der Lucitia, Yan Ding, and Jonathan Sebat, all at UC San Diego.

Funding for this research came, in part, from the National Institutes of Health (grants U01MH108898, R01NS083823) and the Simons Foundation Autism Research Initiative (SFARI 571583).

Disclosure: Martin W Breuss, Danny Antaki, Kiely N. James, Jonathan Sebat and Joseph G Gleeson are the inventors of a patent (PCT / US2018 / 024878, WO2018183525A1) filed by UC, San Diego entitled “Methods for evaluation risk of or diagnosing defects by identifying de novo mutations or somatic mosaic variants in semen or somatic tissues. Dr Gleeson is a personal consultant and receives income from Ionis Pharmaceuticals, Inc.

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