Investigating the genetics behind male infertility

Researchers from Newcastle University (UK) are investigating the genetic causes of male infertility — an often-overlooked condition about which very little is known. With a NovaSeq sequencing system from Illumina at their disposal, plus 1500 study participants suffering from infertility, the researchers hope to better understand some of the underlying genetic factors behind this condition.

“The link between genetics and infertility is not immediately obvious, as infertility cannot be passed on to the next generation without the use of assisted reproductive technologies,” said Joris Veltman, Director of the Institute of Genetic Medicine at the university. “Much of the research done in this field so far has focused on looking for recessive causes of syndromic forms of infertility, often in patients from consanguineous families — those descended from the same ancestor. We want to broaden the research into male infertility by using the NovaSeq to sequence large cohorts of infertile men and their parents, who clearly were not infertile.

“My previous research on the genetic of intellectual disability, using exome and genome sequencing, pointed to a major role for dominant de novo germline mutations — or new mutations — in disorders affecting fitness. As infertility also affects fitness, we hypothesise that de novo mutations can also play a prominent role in severe forms of male infertility, especially in outbred populations.”

Veltman has set up study protocols to collect DNA from infertile men and their parents, helping to link mutations to infertility and identify novel genes for this understudied disorder. He noted that genetic information can also help identify a person’s risk of developing other disorders and aim to prevent these, as infertility is associated with many co-morbidities including cancer. In addition, it may point to novel fertility treatments and could help to prevent passing the infertility problems onto the next generation.

“If you know the genetic cause of infertility, you are able to provide a couple with much better information about the chances of reproduction using different assisted reproductive technologies,” Veltman said. “Based on this information, couples may be better informed to decide whether or not to undergo treatment or choose from other options, including adoption.”

The Institute of Genetic Medicine team is made up of scientists with a range of experience, spanning from technicians who are familiar with next-generation sequencing to others who are sequencing for the first time. Veltman and his colleague Jonathan Coxhead, head of the university’s Genomics Core Facility, said the team jumped right into using the NovaSeq system after their training to perform rapid large-scale exome and genome sequencing for the different research groups within the male infertility cohort.

“Our ability to perform whole-exome sequencing has increased tenfold with the NovaSeq at our disposal,” Coxhead said. “The genomics core facility has been involved in single-cell sequencing for a number of years now; however, the integration of 10X Genomics library prep with NovaSeq’s throughput has enabled us to provide a sequencing service and prepare data for grant applications linked with the Human Cell Atlas project.”

Recognising how crucial international collaboration and data sharing is for genomics research, Veltman set up the International Male Infertility Genomics Consortium (IMiGC) with colleagues from Australia, the US and Europe. The consortium’s mission is to identify and characterise the genetic causes of male infertility, allowing for improved diagnostics, development of novel treatments and enhanced patient care. Within the consortium there are three key working groups, each focused on specific aspects of male infertility research and diagnostics — including clinical phenotyping and patient inclusion, genetic studies and bioinformatics, and functional studies.

“My feeling is that male infertility is becoming less of a taboo — men are speaking out more and the topic is getting more attention in the media,” Veltman said. “Most men are very happy to contribute to our research and willing to contact their parents to participate by providing a saliva sample. The fact that we got significant funding from both the Dutch Scientific Organization as well as the Wellcome Trust also indicates that funding agencies see the need to invest in this research.”

Image credit: ©iStockphoto.com/Alexandr Mitiuc