New insights into harmful mutations in sperm

Genetic changes that create ever-expanding numbers of identical sperm cells are more widespread than previously thought, according to a new study led by researchers at Harvard Medical School.

The team identified genes underlying these so-called clonal expansions and linked the mutations that result — which can be harmful when passed onto offspring — to a number of single-gene diseases, including certain neurodevelopmental disorders.

The findings, published Oct. 8 in Nature, could improve understanding of genetic diseases driven by clonal expansions in sperm. This, in turn, could lead to better genetic screening tests for newborns.

“Clonal expansions in sperm were a known phenomenon, but we figured out that they are surprisingly common and can be caused by dozens of different genes,” said senior author Shamil Sunyaev, professor of biomedical informatics in the Blavatnik Institute at HMS.

The results also reveal how evolutionary forces can shape genetic mutations at both the individual and population levels, the researchers said.

In a complementary study in Nature, also published on Oct. 8, a team led by researchers at the Wellcome Sanger Institute mapped how harmful genetic changes in sperm stem cells — including clonal expansions — increase as men age.

A common phenomenon

Clonal expansions occur when mutations in stem cells confer a growth or survival advantage. As a result, the affected stem cells can produce large quantities of genetically identical mature cells that outcompete stem cells without the genetic changes. Sperm that arise from clonal expansions are thus more likely to be passed on to offspring — along with the mutations they contain.

“These mutations are like a double-edged sword: They help sperm stem cells thrive, but they can result in devastating disorders in children,” said co-first author Mikhail Moldovan, research fellow in biomedical informatics at HMS.

Scientists previously thought that clonal expansions in sperm — which are difficult to detect — were limited to specific types of mutations in a small number of genes. Sunyaev and his team decided to delve deeper into these genetic alterations to understand how often they actually occur, which genes cause them, and how they can lead to disease.

The researchers analyzed DNA from more than 54,000 parent-child trios and 800,000 healthy individuals in an existing public dataset.

They identified 40 genes that cause clonal expansions via different mechanisms, giving the affected sperm stem cells a competitive edge. Many of these mutations have been linked in other studies to rare developmental disorders and cancers.

The team found that clonal expansions in sperm stem cells can increase mutation rates in mature sperm by roughly 500 times. Thus, clonal expansions have an outsized effect on sperm: Relatively few gene drivers lead to a disproportionately large number of mutations, said co-first author Vladimir Seplyarskiy, HMS instructor in medicine at Brigham and Women’s Hospital who is starting a lab at the University of Texas Southwestern Medical Center.

The result helps explain why some rare genetic disorders occur in offspring whose parents don’t carry the mutation — and why these disorders are more prevalent than expected. However, the commonality and sheer number of mutations in sperm also mean that the alterations can become red herrings; they are sometimes mistakenly blamed for diseases they don’t actually cause.

“Our key finding is that clonal expansions in sperm are not rare oddities; they are widespread across the genome and throughout the human population,” Moldovan said.

The team is now working to identify additional genes that drive clonal expansions in sperm; explore how clonal expansions affect the prevalence of single-gene diseases; investigate whether this information can be incorporated into genetic screening tests for newborns; study the biological roles of the genes they identified; and build evolutionary models of the entire process.

“This is a highly peculiar Darwinian phenomenon that explains how the mutations that make sperm proliferate can also harm the humans that carry them,” Sunyaev said — a phenomenon that is interesting on a basic biology level but also has important implications for human health.

Authorship, funding, disclosures

Additional authors on the paper include Evan Koch, Prathitha Kar, Matthew Neville, and Raheleh Rahbari.

Funding for the research was provided by the National Institutes of Health (grants R35GM12713, R01MH101244, and U01HG012009).