Biology subjects

Turhan, B.

Publications and source records attributed to Turhan, B..

4 recordsLinked to original sources

bioRxiv2026

Perturbation-induced gene programs map the hidden regulatory architecture of complex diseases

Steady-state molecular profiles incompletely capture the regulatory programs through which genetic variation influences complex disease, particularly programs that emerge only when cells are perturbed. Here, we introduce Perturbscape, a computational framework that learns multiscale gene programs for individual perturbations in a CRISPR Perturb-seq screen using linear and nonlinear contrastive approaches alongside complementary program-learning methods, and integrates them with human genetics to prioritize disease-relevant genes, perturbations and downstream regulatory pathways. Across 15,859 perturbation-by-context profiles from 7 Perturb-seq systems and 53 complex diseases and traits (mean GWAS N=291K), perturbation-induced programs showed up to 4.3-fold higher heritability informativeness than analogous steady-state multi-tissue gene prioritization, and retained significant conditional heritability informativeness across all 34 matched cell system-trait comparisons after accounting for steady-state prioritization. Preserving perturbation-specific programs further yielded 2.5-5.3-fold higher trait relevance scores than programs derived from control cells, pooled perturbations or differential-expression summaries. In K562, Perturbscape-prioritized genes showed stronger enrichment for rare-variant burden genes than steady-state prioritization and were supported by orthogonal enhancer CRISPRi screens. In HepG2, LDL cholesterol-associated perturbation-induced programs specifically revealed statin-responsive pathways not significantly enriched by steady-state PoPS prioritization, supported by pharmacological transcriptional responses and population plasma proteomics. Perturbscape also recovered blood-related trait-conditioned trans-regulatory relationships that were specifically supported by population trans-eQTLs in IFN-gamma-stimulated monocytes (OR = 1.30, P=1.6e-05). Perturbscape further revealed developmental-stage-specific convergence between monogenic diabetes regulators and polygenic T2D risk during pancreatic islet differentiation, and neuronal-subclass-specific autism-associated regulatory programs in vivo. Together, these findings establish perturbation-induced gene programs as a complementary layer of disease-relevant regulatory information, revealing genetically informative pathways and context-specific regulatory relationships incompletely represented by steady-state molecular atlases.

genetics↗

bioRxiv2026

A dish-to-biobank framework links β-cell nutrient-stress programs to genetic and dietary risk for Type 2 Diabetes

Type 2 diabetes (T2D) arises from genetic susceptibility and chronic metabolic stress, but whether these converge on shared molecular programs in human populations remains unclear. Here, we develop a dish-to-biobank framework linking controlled {beta}-cell perturbation to population-scale disease genetics through the circulating plasma proteome, and apply it to T2D. scRNA-seq of human stem cell-derived islets under factorial glucose and palmitate exposure identifies their combination (glucolipotoxicity) as the condition eliciting the strongest SC-{beta} cell transcriptional response, with glucolipotoxicity-upregulated genes uniquely enriched for T2D heritability, monogenic diabetes genes, and rare-variant burden signals. CRISPR knockout of {beta}-cell identity regulators PAX6 and PDX1 aligns with this program, establishing convergence of environmental and genetic perturbations on a shared disease-relevant state. We then used the plasma proteome as an accessible population-scale readout of these experimentally defined {beta}-cell stress programs, scoring 45,956 UK Biobank White British participants. We define heritable stress signatures that associate with refined carbohydrate and saturated fat intake, and undergo trans-tissue genetic regulation, with a subset of variants showing diet-dependent effects. Together, these findings establish glucolipotoxicity as a genetically anchored model of {beta}-cell dysfunction and provide a generalizable framework for linking controlled cellular perturbations to human disease genetics at population scale.

genetics↗

bioRxiv2021

The mutation profile of SARS-CoV-2 is primarily shaped by the host antiviral defense

Understanding SARS-CoV-2 evolution is a fundamental effort in coping with the COVID-19 pandemic. The virus genomes have been broadly evolving due to the high number of infected hosts world-wide. Mutagenesis and selection are the two inter-dependent mechanisms of virus diversification. However, which mechanisms contribute to the mutation profiles of SARS-CoV-2 remain under-explored. Here, we delineate the contribution of mutagenesis and selection to the genome diversity of SARS-CoV-2 isolates. We generated a comprehensive phylogenetic tree with representative genomes. Instead of counting mutations relative to the reference genome, we identified each mutation event at the nodes of the phylogenetic tree. With this approach, we obtained the mutation events that are independent of each other and generated the mutation profile of SARS-CoV-2 genomes. The results suggest that the heterogeneous mutation patterns are mainly reflections of host (i) antiviral mechanisms that are achieved through APOBEC, ADAR, and ZAP proteins and (ii) probable adaptation against reactive oxygen species. ImportanceSARS-CoV-2 genomes are evolving worldwide. Revealing the evolutionary characteristics of SARS-CoV-2 is essential to understand host-virus interactions. Here, we aim to understand whether mutagenesis or selection is the primary driver of SARS-CoV-2 evolution. This study provides an unbiased computational method for profiling and analyzing independently occurring SARS-CoV-2 mutations. The results point out three host antiviral mechanisms shaping the mutational profile of SARS-CoV-2 through APOBEC, ADAR, and ZAP proteins. Besides, reactive oxygen species might have an impact on the SARS-CoV-2 mutagenesis.

evolutionary biology↗

bioRxiv2020

Phylogenetic Analysis of SARS-CoV-2 Genomes in Turkey

COVID-19 has effectively spread worldwide. As of May 2020, Turkey is among the top ten countries with the most cases. A comprehensive genomic characterization of the virus isolates in Turkey is yet to be carried out. Here, we built a phylogenetic tree with globally obtained 15,277 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genomes. We identified the subtypes based on the phylogenetic clustering in comparison with the previously annotated classifications. We performed a phylogenetic analysis of the first thirty SARS-CoV-2 genomes isolated and sequenced in Turkey. We suggest that the first introduction of the virus to the country is earlier than the first reported case of infection. Virus genomes isolated from Turkey are dispersed among most types in the phylogenetic tree. We find two of the seventeen sub-clusters enriched with the isolates of Turkey, which likely have spread expansively in the country. Finally, we traced virus genomes based on their phylogenetic placements. This analysis suggested multiple independent international introductions of the virus and revealed a hub for the inland transmission. We released a web application to track the global and interprovincial virus spread of the isolates from Turkey in comparison to thousands of genomes worldwide.

genomics↗