A genetically encoded redox bottleneck constrains human developmental rate

Valdebenito, G. E.; Madden, J. P.; Mendez, C.; Azurdia, L. M.; Zhu, X.; Chen, S.; Atlas, D.; Introcaso, K.; Zhang, H.; Wang, Y.; Dong, F.; Sharma, R.; Mootha, V. K.; Patti, G. J.; Diaz-Cuadros, M.

doi:10.64898/2026.09.10.750701

bioRxiv · 10.64898/2026.09.10.750701

A genetically encoded redox bottleneck constrains human developmental rate

Valdebenito, G. E.·Madden, J. P.·Mendez, C.·Azurdia, L. M.·Zhu, X.·Chen, S.·Atlas, D.·Introcaso, K.·Zhang, H.·Wang, Y.·Dong, F.·Sharma, R.·Mootha, V. K.·Patti, G. J.·Diaz-Cuadros, M.

View original source ↗Export metadata ↓

Abstract

The intrinsically slow pace of human development poses challenges for regenerative medicine and disease modeling. This trait is attributed to low metabolic rates, yet the endogenous mechanisms determining species-specific metabolic flux remain unknown. Here, we identify coupling between glycolytic NADH production and mitochondrial oxidation through the glycerol-3-phosphate (G3P) shuttle as a genetic bottleneck constraining human developmental tempo. Using stem cell-derived models of the segmentation clock, an oscillator whose period reflects developmental rate, we show that low expression of the G3P shuttle enzyme GPD1L limits NADH oxidation in human progenitors compared to mouse. Overexpressing GPD1L boosts metabolic flux, accelerating the segmentation clock, cell cycle, and differentiation across germ layers. G3P-mediated redox coupling is thus a genetically encoded, rate-limiting mechanism that sets the tempo of human development.

Explore related subjects

developmental biology Preprint

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

Valdebenito, G. E., Madden, J. P., Mendez, C., Azurdia, L. M., Zhu, X., Chen, S., Atlas, D., Introcaso, K., Zhang, H., Wang, Y., Dong, F., Sharma, R., Mootha, V. K., Patti, G. J., Diaz-Cuadros, M.. 2026-09-13. A genetically encoded redox bottleneck constrains human developmental rate. https://doi.org/10.64898/2026.09.10.750701

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

KEEP EXPLORING

Related preprints

bioRxiv2026

Extensive loss of HoxA/D genes does not disrupt anterior vertebral patterning in zebrafish

Hox genes play central roles in specifying positional identities along the vertebrate anterior-posterior axis. In mice, genetic analyses have demonstrated that Hox genes distributed among the four Hox clusters contribute to vertebral patterning, with extensive functional redundancy among paralogous genes. Our previous genetic analysis in zebrafish identified important roles for HoxB- and HoxC-related genes in specifying anterior vertebral identities, whereas the contributions of HoxA- and HoxD-related genes remained unresolved. Here, we examined adult zebrafish carrying extensive combinations of hoxaa, hoxab, and hoxda cluster deletions and generated five-gene homozygous mutants carrying frameshift mutations in hoxa3a, hoxa4a, hoxa5a, hoxd3a, and hoxd4a. X-ray micro-CT analysis revealed no obvious alterations in anterior vertebral morphology in either the compound cluster mutants or the five-gene mutants. These results indicate that HoxA/D genes make only a limited detectable contribution to anterior vertebral patterning in zebrafish. Together with our previous findings, they suggest that vertebral patterning functions are distributed unevenly among zebrafish Hox clusters, with a predominant contribution from HoxB/C-related genes.

developmental biology↗

bioRxiv2026

Developmental remodeling of ping-pong piRNA amplification in the vertebrate female germline

The piRNA pathway silences transposable elements (TEs) in the germline, and the ping-pong amplification cycle is the hallmark of this defense.In the male germline, ping-pong is most active during a meiotic window of spermatogenesis, yet its developmental profile in the vertebrate female germline remains less well explored. Most profiling has used adult ovary and mature oocytes, stages at which piRNA pathway components are reported to be low. To address this, we generated matched strand-specific RNA-seq and small RNA-seq from pre-meiotic (E10.5) and meiotic entry (E16.5) chicken ovary, used published single-cell data to track germ-cell composition across the same window, and extended the analysis to the mature chicken ovary and to zebrafish across developmental stages. Ping-pong amplification increases at meiotic entry compared to the pre-meiotic stage across TE classes. In the mature ovary, the signature weakens, and the remaining ping-pong pairs are preferentially associated with LTR/ERV retroelements. We show that activation of a meiotic entry transcriptional program in an in vitro chicken primordial germ cell model increases the fraction of piRNA-sized reads with a partner exhibiting a 10-nt 5' overlap and increases the 1U signature of piRNA-sized reads, consistent with meiotic priming promoting piRNA biogenesis. The zebrafish ovary shows a similar meiosis-associated amplification and preferential targeting of LTR/ERV retroelements at maturity, while carrying roughly 5.7-fold more TE sequences. Similar patterns in two lineages that diverged approximately 430 million years ago suggest that germline development shapes both the timing of ping-pong amplification and the TE classes preferentially associated with it.

developmental biology↗

bioRxiv2026

Allele-Resolved Hybrid Embryos Reveal the Fates of Regulatory Divergence

Developmental programs can remain conserved despite extensive regulatory divergence, but how evolved regulatory differences are transmitted through embryonic lineages remains unclear. Here we generate a time resolved, allele resolved single-cell atlas of hybrid embryogenesis between Ciona intestinalis and Ciona savignyi, enabling regulatory differences accumulated between species to be followed across defined developmental lineages. We find that allelic differences are maintained or remodeled in lineage specific ways, with their outcomes associated with regulatory origin and allele specific chromatin accessibility. Across multiple tissues, allelic divergence increases along gene regulatory network (GRN) hierarchy from upstream regulators toward downstream regulators and effector genes. In the cardiopharyngeal lineage, Foxf illustrates how allelic dominance provides partial compensation for highly divergent regulatory sequences and thereby contributes to developmental system drift. Together, our results reveal that regulatory divergence is dynamically sorted during development according to lineage context and GRN hierarchy. This lineage resolved framework provides a developmental basis for understanding how extensive regulatory evolution can accumulate while conserved embryonic programs are maintained.

developmental biology↗