rs2305957 — HSPA4L

HSPA4L/PLK4 rs2305957 — Embryo Aneuploidy, Blastocyst Formation, and Spermatogenesis

A 2015 landmark study in Science identified rs2305957 — a variant on chromosome 4 within a low-recombination haplotype block spanning several genes including HSPA4L and PLK4 — as a maternal genetic risk factor for mitotic-origin embryo aneuploidy¹¹ mitotic-origin embryo aneuploidy
chromosome copy-number errors arising from cell-division mistakes after fertilisation, as distinct from meiotic aneuploidy arising during egg or sperm formation. The A allele of rs2305957 was associated with an odds ratio of 1.244 for embryo mitotic aneuploidy (P=8.68×10⁻¹⁶) across 2,362 mothers and 20,798 preimplantation embryos, replicated independently in both European and East Asian ancestry subgroups. The same variant has since been linked to reduced blastocyst formation rates and early recurrent miscarriage in Chinese Han women undergoing IVF.

The Mechanism

The associated region spans over 600 kilobases of chromosome 4q28 and contains multiple genes. PLK4²² PLK4
Polo-like kinase 4, the master regulator of centriole duplication and therefore of spindle pole number during cell division is the primary functional candidate: both overexpression and underexpression of PLK4 can trigger chromosome instability through multipolar spindle formation. A subsequent study demonstrated that the A allele haplotype is specifically enriched in embryos undergoing tripolar mitosis³³ tripolar mitosis
cell division into three daughter cells instead of two, generating complex multi-chromosome aneuploidies incompatible with development, explaining why AA-genotype mothers contribute fewer viable blastocysts for IVF biopsy. The association is strictly maternal — paternal genotype at this locus showed no significant effect on embryo aneuploidy rates.

The variant is physically located within an intron of HSPA4L (Heat Shock Protein Family A Member 4-Like), which is independently relevant to male reproductive biology. HSPA4L belongs to the HSP110 family and is the most highly expressed gene in testis among broadly expressed heat-shock proteins (101.7 nTPM, Human Protein Atlas), with peak expression in pachytene spermatocytes and round and elongating spermatids⁴⁴ pachytene spermatocytes and round and elongating spermatids
the cells undergoing and completing meiosis. Male mice lacking Hspa4l show a ~42% infertility rate, reduced sperm count and motility, and excess germ-cell apoptosis within seminiferous tubules ⁵⁵ Held et al. 2006, Mol Cell Biol. In human studies, decreased HSPA4L protein in spermatozoa correlates with asthenozoospermia and poor sperm-oocyte penetration ⁶⁶ Liu et al. 2019, Mol Reprod Dev. Whether rs2305957 modulates HSPA4L expression in human testicular tissue via eQTL effects has not been formally established, so the male fertility relevance of this specific intronic variant remains an open question.

The Evidence

The original discovery by McCoy et al. 2015 (Science)⁷⁷ McCoy et al. 2015 (Science)
Common variants spanning PLK4 are associated with mitotic-origin aneuploidy in human embryos is among the most statistically robust GWAS findings in reproductive genetics: a discovery cohort of 2,362 mothers contributing 20,798 blastomere biopsies, validated in a separate cohort of 34 mothers and 283 embryos. The minor A allele displayed a dose-dependent effect: aneuploidy prevalence was 24.6% (GG), 27.0% (AG), and 31.7% (AA) for paternal- chromosome aneuploidies. The association was absent from Neanderthal and Denisovan genomes, suggesting the risk variant arose recently in modern humans and may have hitchhiked to intermediate frequency during a selective sweep.

A Chinese Han cohort study (Zhang et al. 2017, Fertil Steril)⁸⁸ Chinese Han cohort study (Zhang et al. 2017, Fertil Steril)
Maternal common variant rs2305957 spanning PLK4 is associated with blastocyst formation and early recurrent miscarriage enrolled 2,015 IVF patients, 530 early recurrent miscarriage (ERM) cases, and 600 fertile controls. AA-genotype women showed the lowest blastocyst formation rate among IVF patients, and the A allele was significantly associated with ERM under both additive and dominant models, though no differences in implantation rate, early miscarriage rate, or live birth rate were observed in the IVF cohort itself.

However, a Japanese case-control study (Yoshihara et al. 2020)⁹⁹ Japanese case-control study (Yoshihara et al. 2020)
PLK4 and STAG3 are not associated with recurrent pregnancy loss caused by embryonic aneuploidy of 184 RPL cases with aneuploid products of conception and 190 fertile controls found no significant association, providing a negative replication for the RPL endpoint specifically. A further study in the International Journal of Research in Medical Sciences also reported no association of rs2305957 with recurrent pregnancy loss.

The cumulative evidence supports a genuine association with embryo aneuploidy at a population scale, particularly in IVF contexts where it may affect embryo viability and blastocyst yield, but the clinical significance for recurrent pregnancy loss in the general population remains unresolved.

Practical Actions

For women: The A allele (particularly AA genotype) may be associated with a modestly higher rate of embryo aneuploidy during IVF cycles, potentially manifesting as a lower proportion of euploid blastocysts available for transfer. This does not translate to certainty of failed pregnancy — many AA-genotype women conceive without difficulty — but it is a factor that reproductive specialists may consider when counselling on expected embryo yields and the potential benefit of preimplantation genetic testing. No dietary supplement or intervention is known to modify centriole fidelity or PLK4 function.

For men: HSPA4L protein levels in sperm may be a useful functional readout in the context of asthenozoospermia, though no intervention targeting HSPA4L expression is currently available. Men with this variant who show sperm motility problems should prioritise clinical andrological evaluation.

Interactions

The functional biology of PLK4 is essentially maternal in the context of this variant — the original GWAS detected no paternal genotype association with embryo aneuploidy, implying the effect operates through maternal spindle regulation in the early embryo rather than paternal sperm contribution.

For male fertility specifically, HSPA4L function is closely intertwined with the broader heat-shock chaperone network in spermatogenesis, which includes HSPA4 and HSPA1L. Double knockout of Hspa4l and Hspa4 in mice causes neonatal lethality, while single knockouts each show male fertility defects, suggesting the two paralogs have partially redundant roles in spermatocyte and spermatid viability.

Compound action proposal (for supervisor review): SOX5 rs2305957 + DNAH10 rs12032124: the original assignment proposed a dual male fertility compound action for these two SNPs. Based on the research completed here, rs2305957 (HSPA4L/PLK4 region) has limited direct evidence for male fertility effects at the SNP level (the HSPA4L knockout mouse data and human sperm protein data are gene-level, not variant-level). rs12032124 (DNAH10, chr1) has no documented GWAS associations or published compound-effect data with rs2305957. A compound action for this pair is not supported by current published evidence and should not be created. If a compound action is desired, it would be speculative (combining two male fertility candidate-gene variants lacking variant-level interaction data), warranting at minimum an emerging evidence level with a very limited scope. Recommendation: do not write a compound action for this pair.