Nearly 80 percent of all new mutations in children come from the father. The fact that mutations occur primarily in the sperm is due to several factors. Men produce hundreds of millions of sperm every day, which means that the male germ cells are constantly undergoing cell division, increasing the risk of harmful mutations. This may also explain why the DNA in a man’s germ cells may be more sensitive to external mutagenic factors compared to the female germ cells.
"Mutations that occur in male germ cells can sometimes go unnoticed by the cell’s repair mechanisms, perhaps because of a paucity of the DNA repair enzymes found in the female's egg cells", says Jonatan Axelsson, researcher at Lund University and associate chief physician at the Reproductive Medicine Center at Skåne University Hospital.
Nevertheless, mutations in germ cells are rarer than in other cells, and they have been difficult to detect partly because most sequencing techniques do not capture these changes. Now, researchers from Lund and North America using duplex sequencing, have been able to identify DNA mutations in sperm with a high accuracy and specificity.
"The result of elevated DNA mutations in sperm could lead to an increased number of so-called de novo mutations, spontaneous mutations, in the child. These mutations occur for the first time either in a parent’s germ cell or early in the child’s embryonic development and become a new genetic change in the child. De novo mutations are driving factors behind a wide range of diseases and genetic conditions, especially neuropsychiatric disorders, cancer, metabolic diseases, and various syndromes."
The pilot study included six men recruited at the Reproductive Medicine Centre at Skåne University Hospital, from whom blood and sperm samples were collected, and their DNA was extracted and sequenced. In this way, the researchers could get a comprehensive picture of mutation frequency, which may ultimately be linked to children's health. The frequency of mutations in sperm DNA was comparable to the frequency of de-novo-mutations that have been reported in previous so-called parent-child trio studies, an important tool for understanding how genes are inherited and how they influence health and disease. The types of the most common mutations were also very similar to the pattern of de novo mutations in children.
"We also found a high proportion of circular DNA located outside the chromosomes in sperm and shaped like rings, which was surprising. These might contribute to an increased risk of genomic changes, but we still know very little about whether and how these circular DNA molecules are inherited by the child."
In earlier studies, Jonatan Axelsson showed that sons whose fathers smoked at the time of pregnancy had half as many sperm as sons of non-smoking fathers. The next step is to use duplex sequencing to study mutations in a larger group of men to see if men with a suspected mutagenic exposure have an elevated frequency of mutations in their sperm and to explore the correlation between mutation frequency and other parameters of semen quality.
"One hypothesis we want to explore is whether a higher frequency of mutations in sperm could be linked to low sperm quality and reduced chances of successful conception", concludes Jonatan Axelsson.
