New research has unearthed a new genetic mechanism that could prove to be a “paradigm shift” in the way we understand some severe forms of male infertility. As reported in the journal Nature Communications earlier this month, the research suggests that some severe forms of fertility are the result of de novo mutations, which emerge in an individual for the first time despite not being seen in their parents. De novo mutations occur in a sex cell of the parent, either the sperm or egg cell, but all the other cells in that parent are “normal” and don’t feature the mutation. Alternatively, other de novo mutations can occur once the egg is fertilized and begins to divide during the early development, while others emerge in single cells in later stages of embryo development. Whatever the cause, it means that the mutation is passed onto the next generation, appearing to emerge for the first time in the offspring. The new study links some of these de novo mutations to forms of severe male infertility. An international team of scientists led by Newcastle University in the UK and Radboud University Medical Center in the Netherlands studied DNA from a global cohort of 185 infertile men and their parents, identifying 145 rare protein-altering mutations that are likely to have an impact on male fertility. One of the identified mutations was found in the gene RBM5, a gene that previous research has shown plays a role in male infertility in mice. Promisingly, at least 29 of the mutations appear to affect genes directly involved in processes related to sperm cell development or other cellular processes related to reproduction, further hinting that their findings are on the right track. Infertility affects approximately 10 percent of couples globally, with a male being a primary or contributing cause in around 50 percent of heterosexual couples struggling to conceive. However, the cause of male infertility remains unknown in around half of these cases. As explained by the researchers, this new study is a distinctly different way of looking at the genetic underpinnings of male infertility and could potentially guide people towards the best course of action in order to conceive. "This is a real paradigm shift in our understanding of the causes of male infertility. Most genetic studies look at recessively inherited causes of infertility, whereby both parents are a carrier of a mutation in a gene, and the infertility occurs when the son receives both mutated copies, resulting in problems with their fertility,” Professor Joris Veltman, study author and Dean of Newcastle University's Biosciences Institute, said in a statement. "However, our research has found that mutations which occur when the DNA is replicated during reproduction in parents plays a significant role in the infertility in their sons. At present, we don't understand the underlying cause in the majority of infertile men, and this research will hopefully increase the percentage of men for whom we can provide answers," Professor Veltman added. Source
