Maternal CENP-C restores centromere symmetry in mammalian zygotes to ensure proper chromosome segregation

Tower, C. A.; Manske, G.; Ferrell, E. L.; Anbarci, D. N.; Jorgensen, K.; Ma, B.; Aboelenain, M.; Ranjan, R.; Chakraborty, S.; Moritz, L.; Das, A.; Boiani, M.; Black, B. B.; Chavez, S.; Marsh, E. E.; Shikanov, A.; Schindler, K.; Chen, X.; Hammoud, S. S.

doi:10.1101/2025.07.23.666394

bioRxiv · 10.1101/2025.07.23.666394

Maternal CENP-C restores centromere symmetry in mammalian zygotes to ensure proper chromosome segregation

Tower, C. A.·Manske, G.·Ferrell, E. L.·Anbarci, D. N.·Jorgensen, K.·Ma, B.·Aboelenain, M.·Ranjan, R.·Chakraborty, S.·Moritz, L.·Das, A.·Boiani, M.·Black, B. B.·Chavez, S.·Marsh, E. E.·Shikanov, A.·Schindler, K.·Chen, X.·Hammoud, S. S.

View original source ↗Export metadata ↓

Abstract

Across metazoan species, the centromere-specific histone variant CENP-A is essential for accurate chromosome segregation, yet its regulation at the parental-to-zygote transition in mammals is poorly understood. To address this, we developed a CENP-A-mScarlet knock-in mouse model, which revealed sex-specific dynamics: mature sperm retains 10% of the CENP-A levels present in MII-oocytes. However, in zygotes prior to the first mitosis, this difference is resolved, using maternally inherited cytoplasmic-CENP-A. Notably, the increase in CENP-A at paternal centromeres is independent of sensing CENP-A asymmetry or the presence of maternal chromosomes. Instead, CENP-A equalization relies on asymmetric recruitment of maternal CENP-C to paternal centromeres. Depletion of maternal CENP-A decreases total CENP-A in pronuclei without disrupting equalization. In contrast, reducing maternal CENP-C or disruption of its dimerization domains impairs CENP-A equalization and chromosome segregation. Therefore, maternal CENP-C acts a key epigenetic regulator that resets centromeric symmetry at fertilization to preserve genome integrity. Highlights[bullet] CENP-A asymmetry between sperm and oocyte centromeres is a conserved feature from flies to mammals including mice and humans. [bullet]CENP-A asymmetry between parental centromeres is resolved prior to the first zygotic division via maternally inherited, cytoplasmic CENP-A. [bullet]Zygotic CENP-A levels in zygotes are regulated in a pronucleus-autonomous manner. [bullet]CENP-A equalization relies on asymmetric CENP-C recruitment to the paternal pronucleus and requires CENP-C dimerization. Key TermsCentromere; CENP-A; CENP-C; sperm; oocyte; zygote; intergenerational; epigenetics; mouse

Source connections

Published article ↗

Explore related subjects

genetics Preprint

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

Tower, C. A., Manske, G., Ferrell, E. L., Anbarci, D. N., Jorgensen, K., Ma, B., Aboelenain, M., Ranjan, R., Chakraborty, S., Moritz, L., Das, A., Boiani, M., Black, B. B., Chavez, S., Marsh, E. E., Shikanov, A., Schindler, K., Chen, X., Hammoud, S. S.. 2025-07-28. Maternal CENP-C restores centromere symmetry in mammalian zygotes to ensure proper chromosome segregation. https://doi.org/10.1101/2025.07.23.666394

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Genetic ancestry influences the relative expression of ancestral haplotypes within admixed individuals

Allele-specific expression (ASE) reflects differences between the two haplotypes a person carries, but most ASE studies have been done in European-descent samples. Admixed individuals carry haplotypes from different ancestral backgrounds within the same cell, which allows ancestry effects on regulation to be measured directly. We integrated phased whole-blood RNA-seq with local ancestry inference in 779 participants from the MAGENTA cohort, including non-Hispanic White, African American, Caribbean Hispanic, and Peruvian individuals. Higher West African (YRI) ancestry proportion was associated with more ASE-positive genes per person, and the association remained after adjusting for age, sex, Alzheimer's disease status, APOE genotype, and the number of heterozygous genes. Peruvian ancestry showed no significant association. A gene-level test of imbalance across population groups found 2,053 of 15,008 genes with significant differences, including the major histocompatibility complex in all four groups. A genome-wide scan of 2,213 1 Mb windows compared people carrying two haplotypes of different ancestries with those carrying two of the same ancestry. It identified 52 non-redundant loci that replicated across all four population groups, containing 201, 60, and 110 ancestry-associated genes under the CEU, YRI, and PEL reference baselines. A haplotype-resolved directional analysis showed no genome-wide advantage for either ancestry. It found locus-specific dominance at 11 loci, and only chr8:2-3 Mb (CSMD1) showed the same direction in more than one population group. Genetic ancestry therefore shapes allelic regulation at global, gene, and locus scales.

genetics↗

bioRxiv2026

Assembly-independent measurement of human Yq12 heterochromatin reveals population-scale variation and Yq12-derived RNA in testis

Despite advances in long-read sequencing and telomere-to-telomere assembly, population-scale analysis of large satellite arrays remains challenging. Human Yq12 is a megabase-scale heterochromatic region composed primarily of DYZ1/HSat3A6 and DYZ2/HSat1B repeats, whose near-equal proportions are maintained despite extensive variation in total array length. Here, using complete Y-chromosome assemblies, we developed k-mer-based tools to estimate Yq12 size directly from short- and long-read sequencing data without requiring sample-specific complete assemblies. Across 1,597 males from the 1000 Genomes Project, Yq12 length ranged from ~1 to 52 Mb (mean 26.5 Mb) and varied substantially within and between Y haplogroups. Phylogenetic analyses supported long-term constraint of total Yq12 length near an equilibrium of 26 Mb and strongly coupled evolution of DYZ1 and DYZ2 around near-parity composition. In 303 father-son pairs, fathers had longer estimated Yq12 regions in 70.6% of pairs, while sons more often showed DYZ1:DYZ2 ratios closer to 1:1. Testis Iso-Seq identified transcripts containing DYZ1 and DYZ2 satellite sequences, while single-cell RNA-seq revealed their expression in haploid spermatids. These results establish a scalable framework for studying Yq12 population variation, intergenerational dynamics, and transcription, providing new opportunities to investigate how extreme satellite-array variation relates to Y-chromosome evolution and male germ-cell biology.

genetics↗

bioRxiv2026

Continuous ancestry profiles from genomes and genealogies

Using a single population label to represent an individual's ancestry may offer convenience, but ancestry is multidimensional, continuous, and reflects contributions from multiple ancestral sources. Here, we demonstrate empirically that ancestry profiles outperform categorical ancestry labels in capturing this complexity. Relatedness among 28,332 genotyped individuals was measured using haplotype painting and ordination and was regressed on regional ancestry proportions from the deep genealogies available for one-third of the cohort. When tested on participants in a validation set, predicted profiles placed 78% of documented ancestry in the correct region, against 48% for the training set average. Giving each participant a single regional label placed only 32% of their documented ancestry correctly, and a perfect classifier naming each person's largest documented region would reach only 38%, because most individuals carry ancestry from several regions. Thus, the continuous profile captures substantially more ancestry than any classification, providing support for representing ancestry as a continuum rather than a label.

genetics↗