Biology subjects

Movasati, A.

Publications and source records attributed to Movasati, A..

3 recordsLinked to original sources

bioRxiv2026

DNA Damage Response Proteins Are Involved in the Formation of Defective HIV-1 Proviruses

Latent HIV-1 proviruses remain the major barrier to curing HIV infection. Although many of these proviruses are defective, with large internal deletions and hypermutations, the mechanisms underlying their formation are still poorly understood. In this study, we applied CRISPR/Cas9 knockout screens to identify DNA damage response (DDR) proteins that contribute to the formation of defective HIV-1 proviruses carrying large internal deletions. Using an HIV-1-based dual-fluorophore vector as a model, we distinguished cells harbouring intact proviruses from those carrying large internal deletions by flow cytometry and cell sorting. We then validated top candidates using CRISPR-mediated gene activation and small interfering RNA-mediated knockdown. Across these approaches, the helicase-like transcription factor HLTF emerged as a consistent modulator of large internal deletions: increased HLTF expression raised the proportion of cells carrying defective proviruses, whereas reduced HLTF expression had the opposite effect. Additional repair factors, including RAD1, RAD18, TREX2, and ZRANB3, also influenced the balance between intact and defective proviruses, suggesting that multiple DNA repair pathways cooperate in this process. Our data indicate that several DNA damage response proteins, including HLTF, are involved in the generation of defective proviruses and may constitute a previously undescribed host defence mechanism against HIV-1.

molecular biology↗

bioRxiv2026

Substantial Deceleration of Adaptation of HIV-1 Within 1,500 Generations in an Experimental Evolution: A Genomic Perspective

Numerous experimental evolution studies have suggested that adaptation rate of microbial populations evolving in stable environments decline over time. Despite the generality of this phenomenon across different domains of life, the timing and magnitude of decline in adaptation can vary greatly based on the idiosyncrasies of the biological system. To investigate the characteristics of adaptation deceleration in a fast-evolving virus, we propagated HIV-1 in two human T-cell lines (MT-2 and MT-4) for approximately 4.8 years and tracked its genome evolution through next-generation sequencing. The curated sequencing data covering the whole-genome can be accessed and explored via LTEEviz, an interactive web application. Time-resolved sequencing data uncovered that despite constant fixation rate of 0.085 (MT-2) and 0.042 (MT-4) mutations per generation, the fixation kinetics of adaptive mutations changed considerably over time. The rate of fixation of adaptive parallel mutations decreased by 44% per 300 generations, while their conferred fitness gain decreased by 27% (MT-2) and 18% (MT-4) per every added adaptive mutation in their genetic background. The early and substantial deceleration of adaptation in our HIV-1 populations can, at least in part, be explained by diminishing gains of adaptive mutations. Furthermore, we identified genomic patterns consistent with a hard selective sweep that occurred in one population later in the experiment. Together, our results confirm that HIV-1 genomic evolution is characterized by a swift and substantial deceleration of adaptation, while also revealing that episodes of positive selection can occur beyond the initial adaptive phase.

evolutionary biology↗

bioRxiv2022

Pan-cancer whole genome comparison of primary and metastatic solid tumors

Metastatic cancer remains almost inevitably a lethal disease. A better understanding of disease progression and response to therapies therefore remains of utmost importance. Here, we characterize the genomic differences between early-stage untreated primary tumors and late-stage treated metastatic tumors using a harmonized pan-cancer (re-)analysis of 7,152 whole-genome-sequenced tumors. In general, our analysis shows that metastatic tumors have a low intra-tumor heterogeneity, high genomic instability and increased frequency of structural variants with comparatively a modest increase in the number of small genetic variants. However, these differences are cancer type specific and are heavily impacted by the exposure to cancer therapies. Five cancer types, namely breast, prostate, thyroid, kidney clear carcinoma and pancreatic neuroendocrine, are a clear exception to the rule, displaying an extensive transformation of their genomic landscape in advanced stages. These changes were supported by increased genomic instability and involved substantial differences in tumor mutation burden, clock-based molecular signatures and the landscape of driver alterations as well as a pervasive increase in structural variant burden. The majority of cancer types had either moderate genomic differences (e.g., cervical and colorectal cancers) or highly consistent genomic portraits (e.g., ovarian cancer and skin melanoma) when comparing early- and late-stage disease. Exposure to treatment further scars the tumor genome and introduces an evolutionary bottleneck that selects for known therapy-resistant drivers in approximately half of treated patients. Our data showcases the potential of whole-genome analysis to understand tumor evolution and provides a valuable resource to further investigate the biological basis of cancer and resistance to cancer therapies.

genomics↗