Ozdemir, Y. C. | Search bioRxiv

bioRxiv2026

Ancient human genomes from the Altai region reveal population continuity and shifts in the 4th-12th centuries

The Altai region is a crossroads of the Asian steppes. However, the population history of the region remains understudied. We analyse ancient human genomes from the Altai and Ob regions, creating a ca. 1400-year-long time transect with 91 new data. We demonstrate an Iron Age genetic variety that continued into the Medieval era, with additional large-scale spread of East Asian genetic ancestry coinciding with the rise and spread of the Turkic cultural customs. Furthermore, we find a unique lineage in the Early Medieval Altai with elevated Ancient North Eurasian ancestry, providing a missing link between the North Eurasian hunter-gatherers and modern North Asian people. We identify distinct genetic patterns and connections among populations of the Mountainous and the Forest-Steppe Altai in the 4th-8th centuries.

genetics↗

bioRxiv2025

Recurrent Breast Cancer Cells Depend on De novo Pyrimidine Biosynthesis to Suppress Ferroptosis

Breast cancer recurrence remains a major clinical challenge, often associated with therapy resistance and altered metabolic states. To define metabolic vulnerabilities of recurrent disease, we performed a CRISPR knockout screen targeting 421 metabolic genes in paired primary and recurrent HER2-driven breast cancer cell lines. While both primary and recurrent tumors shared dependencies on core metabolic pathways, recurrent tumors exhibited selective essentiality for the de novo pyrimidine synthesis pathway, including Cad, Dhodh, and Ctps. Pharmacologic inhibition of the rate-limiting enzyme DHODH with BAY-2402234 selectively impaired the growth of recurrent tumor cells, while primary tumor cells were relatively resistant. BAY treatment robustly inhibited pyrimidine synthesis in all lines, but only recurrent cells underwent iron-dependent lipid peroxidation and ferroptotic cell death. Lipidomic profiling revealed enrichment of polyunsaturated ether phospholipids in recurrent cells, which may predispose them to ferroptosis. A sensitizer CRISPR screen in primary cells further identified nucleotide salvage and lipid metabolic pathways as modifiers of DHODH inhibitor sensitivity. Stable isotope tracing and nutrient depletion experiments showed that primary cells can compensate for DHODH inhibition through nucleotide salvage, whereas recurrent cells exhibit impaired salvage capacity, likely due to reduced expression of Slc28/Slc29 nucleoside transporters. Together, these findings reveal that breast cancer recurrence is associated with increased dependence on de novo pyrimidine synthesis to suppress ferroptosis, highlighting a therapeutically actionable metabolic vulnerability in recurrent disease.

cancer biology↗