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Health & Physiology

Mutations in the germline: How the mother repairs the father’s damaged genome

Germline mutations can have a severe impact on genetic diseases, genome evolution and the fate of a species. The vast majority of inheritable mutations are passed on by the paternal genome. We discovered how paternal DNA damage is repaired by maternal repair leading to the inheritance of structural variants.

Credits: Ella Maru Studio ©
by Siyao Wang | Principal Investigator

Siyao Wang is Principal Investigator at .

Siyao Wang is also an author of the original article

, David Meyer | PhD studen

David Meyer is PhD studen at .

David Meyer is also an author of the original article

, Björn Schumacher | Principal Investigator

Björn Schumacher is Principal Investigator at University of Cologne.

Björn Schumacher is also an author of the original article

Edited by

Christina Elsner

Junior Scientific Editor

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published on Oct 30, 2023
The genome is passed on from generation to generation. Germ cells, which are sperm and egg cells and any precursory cells they developed from, are tasked with maintaining the genomes. These cells are fundamental for maintaining the genomes across generations. The DNA, however, can be exposed to a myriad of damage and damaged DNA can lead to mutations and thus alter the genetic information. 

Mutations that occur in the germline can have long-lasting effects. Genome evolution is driven by germline mutations, but also genetic diseases are caused by inheritable mutations. 80% of new mutations including single nucleotide variants (SNVs), i.e. mutations affecting the change of a single building block of DNA, and the more severe structural variants (SVs), i.e. more severe changes in the structure of the DNA, are generated in the paternal genome that is passed on by the father. 

The vulnerability of the paternal genome has been the source of long debates about the consequences of exposure to radiation or other sources of DNA damage on the children. Such debates were held in the context of the nuclear bombings in Hiroshima and Nagasaki, the nuclear accident in Chernobyl, or radiation exposure of nuclear power plant workers. A major limitation in those debates, however, has been the lack of mechanistic understanding of the consequences of DNA damage in the genomes of the paternal germ cells. 

Using the simple nematode worm, Caenorhabditis elegans, as a model, we recently showed that specific irradiation of mature sperm resulted in transgenerational lethality that only showed in the next generation. Just like in humans, the DNA in the worm’s mature sperm is densely packed and thus cannot repair the damage inflicted by radiations. Only once the sperm fertilizes an egg (forming a “zygote”), the damage is repaired by the mother’s DNA repair machinery. 

However, the zygote uses a highly error-prone repair mechanism, the so-called “theta-mediated endjoining”, short TMEJ. TMEJ is a special DNA repair mechanism that joins the ends rather randomly resulting in structural variants (SVs), within the paternal genome. These SVs give rise to ongoing breaks in the genome, while the zygote develops into an embryo, which then grows into an adult animal. These adult animals that were fathered with damaged sperm DNA then produce a high degree of dead progeny. 

On the molecular level, we realized that these animals had a high degree of densely packed DNA structures. Such structures are generated by high levels of so-called linker histones, which are proteins that wrap up the DNA. When we alleviated the density of those histone structures, an error-free repair mechanism could gain access to repair the damage and restore viability. 

Strikingly, we found the very same SVs in human genomes and here also, they were almost exclusively generated in the fathers’ germ cells. Our data thus opens the possibility to specify when the father’s genomes are vulnerable and suggest potential interventions to enhance the stability of inheritable genomes and prevent the occurrence of inheritable diseases in humans. 
Original Article:
Wang, S., Meyer, D. H. & Schumacher, B. Inheritance of paternal DNA damage by histone-mediated repair restriction. Nature 613, 365–374 (2023).

Edited by:

Christina Elsner , Junior Scientific Editor

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