Sperm mutations that can cause disease in children identified

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

Mosaicism occurs in every human but is mostly unnoticeable. If abnormal cells begin to outnumber normal cells, however, diseases may result. When mosaicism occurs in human sperm or egg cells, the mutations can affect both the man or woman with the mutation and subsequent generations.

In a study recently published in Cell , researchers describe a new method for observing and counting these mutations, and using this data to predict the likely impact of these mutations on future children.

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

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

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

Sperm mutations contribute to the cause of disorders, such as autism and epilepsy, but the implications in men without a family history of disease was completely unknown.

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

They found that each ejaculate from a man shows an average of 30 mutations. Almost all of these were found in serial sampling from a period of six to 12 months, whereas most of the mutations were completely absent from a saliva or blood sample. The data indicates the mutations are restricted to sperm cells, and also validates their detection method.

The comparison between the old and young men showed few differences in mutations, telling us that these mutations probably arose when the father was an embryo, where the mutations could reside undetected until the man has children.

 It also means that sperm cells are well-protected in a stem cell niche, which does a good job at maintaining stem cell populations and their relative contribution to each ejaculate.

Scientists think these mutations contribute a substantial burden on human health potentially causing 15 percent of ASD cases, congenital heart disease and severe pediatric diseases. But scientists  are hopeful that by identifying men at risk, future cases of disease can be avoided.

Xiaoxu Yang et al, Developmental and temporal characteristics of clonal sperm mosaicism, Cell (2021). DOI: 10.1016/j.cell.2021.07.024