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Sperm RNA-seq Study Reveals Potential Biomarkers for Diagnosing Male Infertility

NEW YORK (GenomeWeb) – Sperm RNA could be used as a biomarker diagnose male fertility, according to a new paper published today in Science Translational Medicine.

Scientists led by Meritxell Jodar and Stephen Krawetz of Wayne State University performed a retrospective RNA sequencing study on semen samples from both fertile and infertile men and discovered 648 sperm RNA elements (SREs) that they said are critically associated with male fertility.

"Current standard tests have a limited capacity to discern male factor infertility and thereby be predictive of fertility treatment success for couples presenting with idiopathic infertility," the authors wrote. "The use of spermatozoal RNA [next-generation sequencing] identified a set of molecular biomarkers that shows potential to predict the success rate of fertility treatments."

The scientists surveyed 278,605 SREs of a positive control group to find the 648 key markers, including in that group only the most prevalent and reliably found markers across control group samples. Members of this control group were able to achieve live birth after their first attempt at conception using timed intercourse. The authors pointed out that a microarray-based study of sperm RNA was only able to identify 26 potential RNA biomarkers.

The authors said that nine of the 648 SREs corresponded to intergenic regions, while 12 corresponded to sperm-specific intronic elements, and 42 were within 24 different non-coding RNAs, "all of which are likely regulatory." They added that most of the SREs, 585, were within exonic regions of 262 different genes. Of those genes, 40 percent were "ontologically classified as associated with spermatogenesis, sperm physiology, fertility, and early embryogenesis before implantation."

They noted that approximately 13 percent of all couples of reproductive age have problems of infertility, and while physical examination of men can reveal lowered sperm count, shape, or motility, in some cases there's no apparent cause of infertility. RNA sequencing could help resolve those unknown cases.

The scientists found that fertile men carried a complete set of the sperm RNA elements; however, most of the infertile men did not. Men whose sperm lacked the full transcriptional profile were less successful at impregnating their partner. Men with the whole package of required SREs were able to achieve live births without the aid of reproductive assistance in 22 of 30 cases, but men with at least one missing required SRE were only able to do so in 3 of 11 cases.

The authors acknowledged that their biomarkers need validation in a larger, prospective, blinded, controlled study, which would "clarify which are essential for diagnosis and may contribute to the birth of a healthy child." But they noted the decreasing cost of NGS and said RNA sequencing could produce a clinical benefit.

RNA sequencing could help identify the most effective fertility treatments for couples struggling to conceive. In the study, 14 men with at least one critical SRE absent from their sperm RNA profile attempted to conceive with their partner using assisted reproductive technologies such as in vitro fertilization. Of those, 11 were successful.

The authors noted that women are more likely to bear the burden of extensive evaluation in the case of failure and that non-invasive RNA sequencing of sperm might reduce risks associated with that evaluation. "This may permit an informed choice of a treatment paradigm that would help the female partner avoid undergoing invasive procedures such as egg collection," the authors wrote.

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