Sperm AluY Epimutations in Male Partners of Couples with Unexplained Recurrent Pregnancy Loss
- 1UT Health San Antonio
Abstract
Recurrent pregnancy loss (RPL) affects 5% of couples worldwide. Over half of cases remain unexplained (uRPL), in part because paternal factors are rarely evaluated beyond paternal karyotype. Sperm DNA methylation is a putative paternal contributor to RPL. Using ONT direct whole methylome sequencing, we generated the first and largest cohort of locus-resolved, single-molecule sperm methylome maps from men with uRPL to date (n=39). We identified 294 differentially methylated regions (DMRs), of which 158 (53.7%) overlapped AluY repetitive elements, representing significant enrichment (z=40.9); most were hypomethylated in uRPL sperm and spanned the full length of individual AluY insertions. Because of single-molecule resolution, we show that the methylation differences found in uRPL sperm occur in a subpopulation of sperm rather than a uniform DNA methylation change across all sperm. Affected loci were underrepresented for imprinting-associated chromatin marks and instead overrepresented for H2A.Z. Although DMR-associated genes were enriched for neuronal GO terms, many converge on reported roles in implantation, placentation, and early embryonic development. AluY epimutation represents a previously unrecognized, predominant signature of paternal epigenetic perturbation in uRPL, establishing repetitive elements as a new axis of sperm epigenetic risk.
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BibTeX
@misc{kamaraj2026sperm,
title = {{Sperm AluY Epimutations in Male Partners of Couples with Unexplained Recurrent Pregnancy Loss}},
author = {E. Kamaraj and J. Moore and M. Keni and A. Terry and N. Salehisedeh and N. Biju and M. Susiarjo and J. T. Hill and T. Jenkins and W. mak},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.24.753615},
url = {https://www.biorxiv.org/content/10.64898/2026.09.24.753615v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Sperm AluY Epimutations in Male Partners of Couples with Unexplained Recurrent Pregnancy Loss
AU - E. Kamaraj
AU - J. Moore
AU - M. Keni
AU - A. Terry
AU - N. Salehisedeh
AU - N. Biju
AU - M. Susiarjo
AU - J. T. Hill
AU - T. Jenkins
AU - W. mak
PY - 2026
DA - 2026/09/24
PB - bioRxiv
DO - 10.64898/2026.09.24.753615
UR - https://www.biorxiv.org/content/10.64898/2026.09.24.753615v1
AB - Recurrent pregnancy loss (RPL) affects 5% of couples worldwide. Over half of cases remain unexplained (uRPL), in part because paternal factors are rarely evaluated beyond paternal karyotype. Sperm DNA methylation is a putative paternal contributor to RPL. Using ONT direct whole methylome sequencing, we generated the first and largest cohort of locus-resolved, single-molecule sperm methylome maps from men with uRPL to date (n=39). We identified 294 differentially methylated regions (DMRs), of which 158 (53.7%) overlapped AluY repetitive elements, representing significant enrichment (z=40.9); most were hypomethylated in uRPL sperm and spanned the full length of individual AluY insertions. Because of single-molecule resolution, we show that the methylation differences found in uRPL sperm occur in a subpopulation of sperm rather than a uniform DNA methylation change across all sperm. Affected loci were underrepresented for imprinting-associated chromatin marks and instead overrepresented for H2A.Z. Although DMR-associated genes were enriched for neuronal GO terms, many converge on reported roles in implantation, placentation, and early embryonic development. AluY epimutation represents a previously unrecognized, predominant signature of paternal epigenetic perturbation in uRPL, establishing repetitive elements as a new axis of sperm epigenetic risk.
ER -