De Novo Mutations may Play a Role in Male Infertility

Thought LeadersDr. Miguel J. XavierSenior Research AssociateMale Infertility Group, Newcastle University

With nearly 10% of American males suffering from infertility, more research is needed to understand its causes. In this interview, we speak to Dr. Miguel J. Xavier about his latest research into male infertility and how de novo mutations may play a part.

What provoked your latest research into de novo mutations and male infertility?

The idea to investigate the role of de novo mutations in the context of human infertility and particularly in male infertility originated with my colleague and PI in the Male Infertility Genetics Group at the Newcastle University, Prof. Joris Veltman, who pioneered the implementation of genomics approaches in medicine and showed that de novo germline mutations are the major cause of severe intellectual disability.

Similar to intellectual disability, epilepsy, and autism, infertility is a severe early-onset disorder with reduced fitness. Which by nature cannot be directly inherited from one generation to the next. If you are infertile, by definition you cannot conceive via natural methods so there is no next generation. This means that for genetics to play a role in infertility, genetic mutations must occur de novo or inherited under a recessive model.

Indeed, following the recessive model, a small number of genes have been identified as known causes of infertility, however with all that is known about male infertility most cases that present to the clinics remain unexplained. Also, something that had been noticed by clinicians and researchers alike was that these men carried an elevated number of genetic mutations in their genome.

With this in mind and the similarities to intellectual disability, we decided it was time to investigate the role that de novo mutations play in the most extreme forms of male infertility.

What is meant by the term ‘de novo’ mutation and how do they differ from other genetic mutations?

The term “de novo mutation” refers to mutations found in an individual that have not been inherited from either, or both, parents. In essence, all mutations start their life as de novo mutations at some point as when a copy error occurs during DNA replication or damage to the DNA is incorrectly repaired.

Each person carries somewhere between 50 and 100 de novo mutations (and millions of inherited variants) in their genome. A large proportion of these mutations will be benign or have little impact on the health and well-being of the person carrying them and so will become part of their genome to be transmitted to the next generation. A few of these de novo mutations however can occur in essential genes that will negatively impact the health of the individual.

Male Infertility

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Statistics show that nearly 10% of American males suffer from infertility and approximately one in seven couples worldwide struggle to conceive yet infertility is still relatively understudied. Why is this?

As you correctly point out, the prevalence of male infertility is quite high in the human population but the disorder itself remains understudied. A major reason for this is that historically the blame for a couple’s infertility has been incorrectly placed on the female partners without thought of the male side of the equation.

We know this is factually wrong as the split is close to 50/50 on male and female factors being the cause of the couple’s failure to conceive. Due to this assumption, there is an imbalance in the research into what causes infertility between the sexes.

At the same time, advances have been made in the field of medically assisted reproduction meaning that now there are reliable means for couples to reproduce without having to fully understand or cure the individuals of the reasons underlying their difficulties to conceive. The safety of these techniques and the chances of infertility being passed to the children conceived via medically assisted reproduction is another area of research that my research group is investigating.

What are some of the common causes of male infertility?

The term male infertility is quite broad and encompasses a large number of features with a variety of risks factors and causes, including hormone imbalances, physical issues, environmental and lifestyle choices, and genetic factors.

In the same cases, patients approaching the clinics can be advised to modify their lifestyle to improve their chances to conceive. However, in a large number of cases, the cause of the infertility is much more difficult to pin down and may be practically irreversible such as in the case of patients affected by microdeletions in the so-called Azoospermia Factor (AZF) regions of chromosome Y. These microdeletions affect 2-10% of infertile men by removing essential genes necessary in the production of sperm cells in men, meaning that otherwise healthy men lack the necessary cells to fertilize an egg and conceive an embryo.

The longest known cause of male infertility, Klinefelter syndrome, was identified back in 1959 when infertile men were found to carry an additional X chromosome in their genome (47, XXY). Men affected by this syndrome do not produce sperm cells due to lower levels of testosterone resulting in underdeveloped male reproductive organs or incomplete puberty.

A few other causes of male infertility are known but I wanted to highlight these two prevalent causes because the genetic mutations we were investigating occur de novo in affected individuals.

Men affected by AZF microdeletions or Klinefelter Syndrome have fertile parents that do not carry either these deletions or an extra chromosome. Which was an initial observation that led us to the hypothesis that other previously unidentified de novo genetic mutations could be the cause of male infertility.

Can you describe how you carried out your latest research into male infertility? What did you discover?

For the purpose of investigating de novo mutations, it was necessary that we had access to the genomic information of the patients but also that of their parents, otherwise, we would not be able to identify which genetic variants were inherited and which were occurring de novo in the patients. So, we approached two fertility clinics where couples go to get consultations and specialist advice, one in the Netherlands at the Radboud University Medical Centre and another in the United Kingdom at the Newcastle Fertility Centre, to recruit patients with unexplained male infertility, particularly those patients which produced little to no sperm cells at all, in other words, the severest form of male infertility.

Here, we found one of the first challenges to conduct our research as culturally there is still a social stigma in discussing the topic of male infertility which made recruitment a difficult issue with several men not wanting to discuss the subject or disclose their status to their parents. The parents however would have to be informed as they would ask why we were asking them to provide a DNA sample.

Fortunately, we were able to recruit close to 200 male patients and their respective parents to form the first cohort of this size in the field of male infertility. Here, I must say that while the size of our cohort is not that impressive when compared to other diseases, it is unique for our understudied field of research.

Having recruited these patient-parent trios we proceeded to sequence their entire exome and via bioinformatic analysis, we were not only able to identify all genetic variants but whether each was inherited or de novo. Each variant was then individually investigated to determine if it could be disruptive enough to be the cause of the infertility observed in the patients. In several patients where testis biopsies were available, we conducted further analysis to investigate how spermatogenesis was being disrupted and how the affected gene was negatively impacting sperm production.

In the 185 patients investigated in this study, we found 145 rare protein-altering DNMs that are likely to negatively impact the fertility of these men. 29 of which are affecting genes directly involved in processes related to spermatogenesis or cellular processes related to reproduction, with an additional 50 candidate genes identified where there is little to no information to determine the real impact of the de novo mutations.

It should be said that none of these DNMs occurred in a gene known for its involvement in dominant human male infertility, but this was not unexpected as only 4 genes have so far been linked to act in such a manner in male infertility.

Man with his Parents

Image Credit: BearFotos/

You identified 29 de novo mutations that could likely impact male fertility but RBM5 was of particular interest. Why was this and what role does RBM5 play in sperm cells?

Something we noticed when investigating the de novo mutations in these infertile men was that several of the genes (U2AF2, HNRNPL, CDC5L, CWC27, and RBM5 specifically) affected a disruptive pathogenic mutation and that they interact at a protein level regulating mRNA splicing and process vital in the development and maturation of sperm cells. Knowing what molecular process is being compromised is the first step to learning how a mutation in a gene directly affects the normal biological functions and may lead to infertility.

Among these five genes, RBM5 came to the forefront due to more than 1 infertile man carrying a distinct pathogenic mutation in this gene and no other relevant genetic mutation, indicating that in all these men the cause of their infertility is due to this gene stopping to function as it should.

Your research also relied upon external data. What is the importance of researchers and organizations sharing their work and data so that other researchers can use it?

Indeed, the strength of our findings relied on the sharing of anonymized patient information to identify multiple cases where the same gene or the same molecular process is being disrupted to cause the infertility.

Without multiple cases, our findings could be attributed to random chance but, using RBM5 as an example, with several infertile men carrying pathogenic mutations in RBM5 and knowing that fathers in a control cohort of verified fertile men carried none we can statistically prove that there is a clear association of having mutations in this gene and being infertile. While more needs to be done before we can conclusively say that this gene is responsible for male infertility, this is the first step in that process.

This is why some of the other genes we identified as candidate genes in this study remain unclear while we further investigate their functions and find additional men similarly affected. And to find these men, researchers and clinicians need to come together to share their findings and their data.

For this purpose, we have the International Male Infertility Genomics Consortium ( that brings together experts from all around the world to discuss ideas and approaches, share data and expertise to advance the field.

How will your research not only help clinicians to advise patients on the best course of action to take in order to conceive but also help males that are suffering from infertility?

By expanding our knowledge of what can cause male infertility we can not only provide an explanation to previously unexplained cases giving a concrete answer to these men of what is causing their infertility. While we cannot cure infertility, we can at least provide peace of mind to these men and their partners.

Something we also would like to see implemented more often is the usage of exome and genome sequencing in a clinical setting as the information that can be gathered from this approach can be more cost-effective and reliable than performing multiple specialized tests that focus only on a minuscule portion of the patient's genome.

With the information gathered in this manner, we and others are conducting we hope that clinicians can provide better counseling to couples and recommend what is the best course of action to take to conceive, either by proposing which medically assisted reproduction is appropriate, or in cases where none is suitable, provide appropriate alternatives.

Fertility Appointment

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Are you hopeful that with continued research into male infertility, we can potentially develop tools and treatments that could overcome infertility? What further research needs to be carried out to make this a reality?

The long-term aim is that in the near future, we are not only able to find the cause, but can start developing the means to overcome and hopefully reverse male infertility. But first, we need to better understand the basics of spermatogenesis and the genetic causes that disrupt it.

What are the next steps for you and your research?

With this study, we hope to convince the wider research and medical community of the importance of de novo mutations in male infertility. While we answered some questions with this research, a great

number of patients continue to have unexplained infertility, and among the candidate genes identified by us in this study, the role each plays in causing infertility is not well understood.

We are also continuing to examine these patients in hopes of finding additional genetic causes among the recessively inherited genetic mutations while at the same time we have started to perform whole-genome sequencing in the patients with unexplained infertility to investigate the non-coding portion of the genome where the genetic cause may be.

At the same time, we need to expand the recruitment of patient-parent trios to the levels seen in other fields so we can better investigate this disease. And finally, we must follow up this research by conducting further functional studies into the role that these newly identified candidate genes play in spermatogenesis and overall fertility in humans.

Where can readers find more information?

About Dr. Miguel J. Xavier

Miguel J. Xavier is the Senior Research Associate in the Male Infertility Genetics Group of the Newcastle University, United Kingdom (since July 2018).Dr. Miguel J. Xavier

From 2013, he has been investigating the genetics of reproduction first during his Ph.D. identifying genetic regions susceptible to DNA damage in infertile men and later as a postdoc and research associate in employing his bioinformatics skills to investigate the genetic causes of male infertility in patients affected by azoospermia or severe oligozoospermia.

Dr. Xavier graduated in Biology at the University of Aberdeen, UK, and obtained an MSc in Bioinformatics and Theoretical Systems Biology from Imperial College London, UK, and then a Ph.D. in Biological Sciences focusing on Reproductive Sciences from the University of Newcastle, Australia.


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