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Clonal Mosaic Variants in Sperm Are Stable Over Time, Play Role in Hereditary Disease Transmission

NEW YORK — Clonal mosaic variants in sperm are stable over time and appear to play a role in inherited disease transmission, according to a new study. Moreover, they likely arise during embryogenesis.

In human development and aging, cells acquire variants that lead to genetic mosaicism. But when these changes arise in gonadal tissue like germ cells, they not only affect that person but also their offspring and future generations.

By sequencing sperm and blood samples collected from almost 20 men of different ages, a team led by researchers at the University of California, San Diego found that the clonal mosaic variants they harbored could be detected in repeat sperm samples, and that those variants present in sperm were often not present in blood. The mutational patterns of the sperm clonal variants, and their stability over time, suggested that they arose during embryonic development, as the researchers reported in Cell on Thursday.

"We conclude that every man's semen harbors clonal mosaic variants that likely originate in embryonic development," senior author Joseph Gleeson, a neuroscientist at UCSD, and his colleagues wrote in their paper.

The variants, though, still can be passed on to future generations and would lead to a high-impact pathogenic exonic change for 1 in 15 cases, according to the researchers' estimates.

The team collected blood, sperm, and, for some, saliva samples from 12 young men between the ages of 18 and 22 for sequencing analysis. For nine of the men, they obtained additional sperm samples over a period of six months to a year. At the same time, they collected blood and sperm samples from five older men between the ages of 48 and 62. On average, the sperm samples from the cohort of young men contained 33.3 clonal mosaic variants.

When the researchers folded in data from the additional sperm samples, they found a high correlation between the variants uncovered at the first time point and the later time points, indicating that the variants are stable over time. Older men, meanwhile, did not have an increased burden of sperm-specific variants, though they did have a higher burden of blood-specific ones.

Further, the sperm-specific variants showed a mutational pattern distinct from those in other tissues — C to G and T to C mutations were depleted among sperm clonal variants — and the mutational patterns themselves indicated that they likely arose during early development.

Together, these findings suggested that the clonal mosaic variants in sperm arose early in embryogenesis and that the stem cell niche remains stable during aging.

At the same time, the changes can represent health risks for future generations. Across all age groups, the researchers found an average 30.9 sperm mosaic variant of which 1.6, on average, were exonic and 0.3 were predicted to be deleterious. Based on this, they estimated that about a third of men are expected to harbor a loss-of-function variant in their sperm — with 1 in 15 having a high-impact pathogenic variant — and that clonal mosaic mutations may lead to adverse outcomes in about 1 in 300 conceptions.

"As a consequence, the subset of mutations that are predicted to impact a conceptus's health represents a lifelong threat of transmission," the researchers wrote in their paper.

In particular, they estimated that about 15 percent of the monogenic component of a condition like autism could be due to clonal mosaicism.

The researchers noted, though, that their analysis has several limitations, including that they did not assess non-clonal sperm-specific mosaicism. Future studies, they wrote, could include larger cohort sizes or additional time points for resampling.