Understanding and investigating the causes of infertility

Genome Biology has published work investigating the causes of fertility problems, and finds the earliest known human embryonic lethality phenotype with a known genetic cause. Here to answer our questions on the research is co-author Fowzan Alkuraya.


GBAuthorFowzan Alkuraya is a Professor of Human Genetics at Alfaisal University and a Senior Consultant and Principal Clinical Scientist at King Faisal Specialist Hospital and Research Center.

He completed a fellowship in clinical genetics and another in molecular genetics at Harvard Medical School. He also did a postdoctoral research fellowship in the area of developmental genetics in the lab of Prof. Richard Maas at Harvard Medical School. In late 2007 he returned to Saudi Arabia to establish the Developmental Genetics Lab at KFSHRC, which he still directs.

You say in the paper that the causes of early embryonic lethality have been hard to study in humans. Can you tell us why?

Classically, molecular diagnosis in human genetics has largely been clinically-driven. In other words, you needed to suspect a specific clinical entity in order to request the corresponding molecular assay. With early embryonic lethality, the phenotype is often too nonspecific to trigger an appropriate molecular analysis.

The one exception to this has been karyotyping, and later molecular karyotyping, where products of conception could be interrogated genome-wide for chromosomal abnormalities. However, this approach will essentially miss single gene causes of embryonic lethality, hence the need for more innovative assays.

How did you overcome these challenges in your study?

Whole genome and whole exome sequencing is such an innovative assay that interrogates the entire genome (or at least its coding regions) for any possible single gene cause of embryonic lethality without having to formulate any specific hypothesis clinically.

This allowed us to identify TLE6 as a novel candidate gene without any prior anticipation of what the likely candidate could be.

The gene that you pinpointed as being affected is a ‘maternal effect gene’. Can you explain what that means?

Although the zygote is formed by the fusion of the maternal and paternal pro-nuclei, it takes time for the newly formed fused nucleus to ‘kick in’ by sending the right instruction for making RNA and protein.

Thus, the embryo relies heavily in its very early stages on the action of maternal genes that had been active in the egg around the time of fertilization. These are called ‘maternal effect genes’.

What implications does this study have for people experiencing fertility problems?

Our study shows that such early form of embryonic lethality does not have to be caused by recessive or de novo mutations in the zygote but rather by a mutation in a mother’s gene.

Had it not been for the fact that the couples we described in our paper had undergone IVF, we would never have known that the cause of infertility is so specific to zygote formation and early zygote cleavage. So one implication of our study is that even in the absence of clinical signs of pregnancy, apparent infertility may in fact be caused by an extremely early form of embryonic lethality.

More importantly, our study shows that such early form of embryonic lethality does not have to be caused by recessive or de novo mutations in the zygote but rather by a mutation in a mother’s gene. The women we show in our study to have TLE6 mutations are perfectly healthy otherwise and we also show that men with the exact same TLE6 mutation are in fact fertile.

Do you think there are likely to be more mutations of this type underlying fertility issues in humans? If so, how will we find them?

Other maternal effect genes are going to be obvious candidates, especially the other three components of the subcortical maternal complex. We are very much interested in screening infertile couples with history of failed IVF for mutations in these genes and it will be fantastic if we or others identify mutations in these candidates.

Are there other conditions that could be understood more readily using your approach?

In this same journal we had shown the power of this approach to explain embryonic lethality at the single gene level in a carefully selected cohort. This new study builds on that earlier success and shows that we could also interrogate embryonic lethality at the single gene level in its earliest possible form, in other words, at the cleavage stage of the zygotes.

This opens up for human genetics investigation the entire time period of human development in an unprecedented way, which we think will most certainly increase the number of pathological developmental disorders that we can start to understand at the genetic level.

Louisa Flintoft

Editor at Genome Biology
Louisa did a PhD and Postdoc on developmental genetics, both in London, before moving into science publishing in 2002. She spent 5 years as Chief Editor of Nature Reviews Genetics before joining BioMed Central, and is currently Chief Editor of Genome Biology.
Louisa Flintoft

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One Comment

Smith Shah

Truly, there are some pathological development disorders that need to be well understood at genetic levels. The causes of early embryonic lethality need to be well sorted too. Good post!

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