Biology subjects

Gokcumen, O.

Publications and source records attributed to Gokcumen, O..

At least 19 recordsLinked to original sources

bioRxiv2026

Gene Expansion and Regulatory Rewiring Shape Sex-Biased Evolution of the Mouse Submandibular Gland Secretome

Background Mammalian saliva plays essential roles in digestion, immunity, and host-microbiome interactions, yet its protein composition varies widely across species and sexes. This diversity makes saliva a powerful model to study evolution of gene expression. Here, we compared mouse and human salivary glands at the genomic, transcriptomic, and proteomic levels to understand how saliva composition evolves. Results We found that evolution of gene expression in mouse salivary glands is driven by rapid gene turnover and sexual dimorphism. In the submandibular and sublingual glands, 68% and 73% of expression from genes encoding secreted proteins derives from lineage-specific genes that lack one-to-one human orthologs. This contrasts the prevailing view that gene expression is largely conserved across tissues and highlights saliva as an unusually dynamic system of molecular evolution. Mouse submandibular gland shows striking sexual dimorphism, with 1537 tissue specific sex-biased genes, 3.8 times higher than in the liver (p<0.001), a classic model of sex-biased expression. We also identified sex-specific expression of glycosylation genes associated with differential Muc19 sialylation. These results suggest that sexual dimorphism in mouse saliva arises from both transcriptional differences in secreted proteins and sex-specific post-translational modifications. Further, differentially expressed genes in submandibular gland cluster in genomic regions shaped by recent gene duplication, such as the kallikrein gene cluster, a mouse-specific expansion that accounts for ~16.4% of male-biased submandibular gland expression. Our analyses suggest that this bias arises through regulatory changes that are expanded by gene duplication, including the spread of a testosterone-associated regulatory motif and the expansion of a shared chromatin domain that promotes coordinated gene regulation. Conclusions Together, our results reveal that lineage-specific genes disproportionately shape the mouse salivary transcriptome and that gene duplication and regulatory rewiring contribute to the rapid evolution of sex-biased expression in the submandibular gland. We describe a novel mechanism through which lineage-specific gene duplication and regulatory rewiring drive rapid, sex-specific evolution of the mammalian saliva. Our findings support saliva as an evolutionarily dynamic system and are consistent with developmental systems drift, whereby similar phenotypes across species may be maintained despite substantial divergence in their underlying gene-regulatory programs.

evolutionary biology↗

bioRxiv2025

Read mismapping from segmental duplications drives spurious trans associations

Heritable variation in gene regulation shapes both disease risk and evolution. Trans-acting quantitative trait loci (trans-QTLs) are the primary source of this variation within species, but they remain difficult to identify correctly due to false positives stemming from RNA and DNA read mismapping. Here, we identify four categories of RNA and DNA mismapping due to segmental duplications that lead to false-positive trans-QTLs. Such mismapping leaves a footprint in the form of long-range genotypic disequilibrium, which we use to identify spurious trans-QTLs. Applying this method to Genotype-Tissue Expression (GTEx) trans-QTL, we conservatively estimate that 14% of expression QTLs, 10% of splicing QTLs, and 3% of protein QTLs are artifacts. More broadly, this framework could be applied to flag spurious distant peaks in genome-wide association studies, Hi-C contacts, and co-expression between distant genes.

genomics↗

bioRxiv2025

Convergent evolution through independent rearrangements in the primate amylase locus

Structurally complex genomic regions can foster evolutionary convergence by repeatedly generating gene duplications that yield similar expression patterns and traits across lineages. Focusing on the primate amylase locus, we leveraged high-quality genome assemblies from 53 primate species and multi-tissue transcriptomes from Old World monkeys to reconstruct the evolutionary history of recurrent duplications. We show that lineage-specific long terminal repeat retrotransposon insertions may be associated with initial structural instability, while subsequent duplications are primarily driven by non-allelic homologous recombination. Independent duplications in rhesus macaques, olive baboons, and great apes produced distinct amylase copies with convergent expression in pancreas and salivary glands and signals of episodic diversifying selection, consistent with emerging functional divergence. Our analyses indicate that a ancestral gene with dual pancreas and salivary expression in Catarrhini duplicated in great apes, facilitating subfunctionalization and regulatory rewiring. These findings illuminate how modular structural and regulatory variation drives evolutionary innovation and molecular convergence.

evolutionary biology↗

bioRxiv2025

Chronic exposure to PFAS triggers systems-level cellular reprogramming independent of their bioaccumulation

Per- and polyfluoroalkyl substances (PFAS), or "forever chemicals," are linked to metabolic, immune, and neurotoxic disorders, yet their long-term cellular effects remain unclear. Using a 24-week chronic exposure model with non-transformed human epithelial cells, we examined responses to low, environmentally relevant concentrations of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS). Integrated transcriptomic and lipidomic analyses revealed that cellular accumulation was minimal, and molecular changes instead emerged around week 17, marked by activation of oxidative stress responses, cell survival pathways, and lipid metabolism. Our data support a multi-faceted model in which PFAS-induced oxidative stress, mediated by SESN2 and SOD3, alongside increased lipid biosynthesis via SREBP axis and compound-specific disruptions of membrane lipids. These findings highlight the importance of multi-omic, time-resolved approaches in uncovering mechanisms of chronic low-dose chemical exposure and provide a foundation for future in vivo studies.

pharmacology and toxicology↗

bioRxiv2025

Adaptive Increase of Amylase Gene Copy Number in Peruvians Driven by Potato-rich Diets

Summary/AbstractThe salivary amylase gene (AMY1) exhibits remarkable copy number variation linked to dietary shifts in human evolution. While global studies highlight its structural complexity and association with starch-rich diets, localized selection patterns remain under explored. Here, we analyzed AMY1 copy number in 3,723 individuals from 85 populations, revealing that Indigenous Peruvian Andean populations possess the highest AMY1 copy number globally. A genome-wide analysis showed significantly higher amylase copy numbers in Peruvian Andean genomes compared to closely related populations. Further, we identified positive selection (selection coefficient of 0.0124, log likelihood ratio of 11.1543) at the nucleotide level on a haplotype harboring at least five haploid AMY1 copies, with a Peruvian Andean-specific expansion coinciding with potato domestication ([~]6-10 kya). Using ultra-long-read sequencing, we demonstrated that previously described recombination-based mutational mechanisms drive the formation of high-copy AMY1 haplotypes observed in Andean population. Our study provides a framework for investigating structurally complex loci and their role in human dietary adaptation.

genetics↗

bioRxiv2024

Evolvability through segmental duplication follows species-specific dynamics

Segmental duplications are major drivers of evolutionary innovation, yet their dynamics across vertebrates remain poorly understood. Here, we identify segmental duplications from long-read sequenced genomes of 117 vertebrates and the starfish, generating the largest multi-species dataset of its kind. We find that vertebrate genomes show a higher propensity for tandem duplications than for interspersed duplications. However, when focusing only on subtelomeric regions, avian and mammalian genomes show the opposite propensity toward interspersed duplications. We also observe that, across vertebrates, tandem duplications tend to be larger than interspersed duplications. Next, we construct a segmental duplication network for each species, and use network-derived properties to quantify the duplication landscape for that species. Functional enrichment analysis of hyper-duplicated genes reveals a strong enrichment in platypus for pheromone response, driven by the expansion of the vomeronasal pheromone receptor V1R gene family. Overall, our results uncover the general properties of vertebrate segmental duplication, demonstrate the rapid evolution of segmental duplication landscapes, and highlight the utility of network-based approaches for studying genome evolution. SignificanceGene and regulatory region duplications are a fundamental source of evolutionary raw material. Here we generate segmental duplication calls from 117 vertebrate species. We find that vertebrate genomes have a bias towards tandem duplications relative to interspersed duplications. However, in the subtelomeric regions, birds and mammals exhibit an opposite bias toward interspersed duplications. Our analysis of segmental duplication networks demonstrate that duplication landscapes evolve rapidly, following species-specific rather than phylogenetic patterns. These findings indicate that the genomic architecture underlying segmental duplications is highly dynamic, uniquely shaping each lineages potential to adapt. Our study provides the most comprehensive view of vertebrate segmental duplications to date and establishes a network-based framework for studying genomic structural evolution.

evolutionary biology↗

bioRxiv2024

Switch-like Gene Expression Modulates Disease Susceptibility

A fundamental challenge in biomedicine is understanding the mechanisms predisposing individuals to disease. While previous research has suggested that switch-like gene expression is crucial in driving biological variation and disease susceptibility, a systematic analysis across multiple tissues is still lacking. By analyzing transcriptomes from 943 individuals across 27 tissues, we identified 1,013 switch-like genes. We found that only 31 (3.1%) of these genes exhibit switch-like behavior across all tissues. These universally switch-like genes appear to be genetically driven, with large exonic genomic structural variants explaining five ([~]18%) of them. The remaining switch-like genes exhibit tissue-specific expression patterns. Notably, tissue-specific switch-like genes tend to be switched on or off in unison within individuals, likely under the influence of tissue-specific master regulators, including hormonal signals. Among our most significant findings, we identified hundreds of concordantly switched-off genes in the stomach and vagina that are linked to gastric cancer (41-fold, p<10-4) and vaginal atrophy (44-fold, p<10-4), respectively. Experimental analysis of vaginal tissues revealed that low systemic levels of estrogen lead to a significant reduction in both the epithelial thickness and the expression of the switch-like gene ALOX12. We propose a model wherein the switching off of driver genes in basal and parabasal epithelium suppresses cell proliferation therein, leading to epithelial thinning and, therefore, vaginal atrophy. Our findings underscore the significant biomedical implications of switch-like gene expression and lay the groundwork for potential diagnostic and therapeutic applications.

bioinformatics↗

bioRxiv2024

Emergence of saliva protein genes in the secretory calcium-binding phosphoprotein (SCPP) locus and accelerated evolution in primates

Genes within the secretory calcium-binding phosphoprotein (SCPP) family evolved in conjunction with major evolutionary milestones: the formation of a calcified skeleton in vertebrates, the emergence of tooth enamel in fish, and the introduction of lactation in mammals. The SCPP gene family also contains genes expressed primarily and abundantly in human saliva. Here, we explored the evolution of the saliva-related SCPP genes by harnessing currently available genomic and transcriptomic resources. Our findings provide insights into the expansion and diversification of SCPP genes, notably identifying previously undocumented convergent gene duplications. In primate genomes, we found additional duplication and diversification events that affected genes coding for proteins secreted in saliva. These saliva-related SCPP genes exhibit signatures of positive selection in the primate lineage while the other genes in the same locus remain conserved. We found that regulatory shifts and gene turnover events facilitated the accelerated gain of salivary expression. Collectively, our results position the SCPP gene family as a hotbed of evolutionary innovation, suggesting the potential role of dietary and pathogenic pressures in the adaptive diversification of the saliva composition in primates, including humans.

evolutionary biology↗

bioRxiv2024

Transcriptomics effects of per- and polyfluorinated alkyl substances in differentiated neuronal cells

Per- and polyfluorinated alkyl substances (PFAS) are pervasive environmental contaminants that bioaccumulate in tissues and pose risks to human health. Increasing evidence links PFAS to neurodegenerative and behavioral disorders, yet the underlying mechanisms of their effects on neuronal function remain largely unexplored. In this study, we utilized SH-SY5Y neuroblastoma cells, differentiated into neuronal-like cells, to investigate the impact of six PFAS compounds-- perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), perfluorodecanoic acid (PFDA), perfluorodecanesulfonic acid (PFDS), 8:2 fluorotelomer sulfonate (8:2 FTS), and 8:2 fluorotelomer alcohol (8:2 FTOH)--on neuronal health. Following a 30 M exposure for 24 hours, PFAS accumulation ranged from 100-7500 ng/mg of protein. Transcriptomic analysis revealed 721 differentially expressed genes (DEGs) across treatments (padj < 0.05), with 11 DEGs shared among all PFAS exposures, indicating potential biomarkers for neuronal PFAS toxicity. PFOA-treated cells showed downregulation of genes involved in synaptic growth and neural function, while PFOS, PFDS, 8:2 FTS, and 8:2 FTOH exposures resulted in upregulation of genes related to hypoxia response and amino acid metabolism. Lipidomic profiling further demonstrated significant fatty acid upregulation with PFDA, PFDS, and 8:2 FTS, alongside triacylglycerol downregulation with 8:2 FTOH. These findings suggest that the neurotoxic effects of PFAS are structurally dependent, offering insights into the molecular processes that may drive PFAS-induced neuronal dysfunction. SynopsisPer- and poly fluorinated alkyl substances (PFAS) have been shown to bioaccumulate in human tissues and affect health. This study aims to provide insights into the specific biological processes through which PFAS exposure affects neuronal cells.

pharmacology and toxicology↗

bioRxiv2023

Ancient AMY1 gene duplications primed the amylase locus for adaptive evolution upon the onset of agriculture

Starch digestion is a cornerstone of human nutrition. The amylase genes code for the starch-digesting amylase enzyme. Previous studies suggested that the salivary amylase (AMY1) gene copy number increased in response to agricultural diets. However, the lack of nucleotide resolution of the amylase locus hindered detailed evolutionary analyses. Here, we have resolved this locus at nucleotide resolution in 98 present-day humans and identified 30 distinct haplotypes, revealing that the coding sequences of all amylase gene copies are evolving under negative selection. The phylogenetic reconstruction suggested that haplotypes with three AMY1 gene copies, prevalent across all continents and constituting about 70% of observed haplotypes, originated before the out-of-Africa migrations of ancestral modern humans. Using thousands of unique 25 base pair sequences across the amylase locus, we showed that additional AMY1 gene copies existed in the genomes of four archaic hominin genomes, indicating that the initial duplication of this locus may have occurred as far back 800,000 years ago. We similarly analyzed 73 ancient human genomes dating from 300 - 45,000 years ago and found that the AMY1 copy number variation observed today existed long before the advent of agriculture ([~]10,000 years ago), predisposing this locus to adaptive increase in the frequency of higher amylase copy number with the spread of agriculture. Mechanistically, the common three-copy haplotypes seeded non-allelic homologous recombination events that appear to be occurring at one of the fastest rates seen for tandem repeats in the human genome. Our study provides a comprehensive population-level understanding of the genomic structure of the amylase locus, identifying the mechanisms and evolutionary history underlying its duplication and copy number variability in relation to the onset of agriculture.

evolutionary biology↗

bioRxiv2022

SREBP1 activation contributes to fatty acid accumulations in necroptosis

Necroptosis is a type of programmed cell death. It is characterized by membrane permeabilization and is associated with a strong inflammatory response due to the release of intracellular components due to compromised membrane integrity. We recently showed that the accumulation of very long chain fatty acids (VLCFAs) contributes to membrane permeabilization during necroptosis. However, the mechanisms that result in the accumulation of these cytotoxic lipids remain unknown. Using comparative transcriptomics, we found that sterol regulatory element-binding protein 1 (SREBP1) is activated and that its downstream gene targets result in the accumulation of VLCFAs during necroptosis. We demonstrated that activation of SREBP1 during necroptosis exacerbates cell death. On the contrary, inactivation of SREBP1 reversed the accumulation of VLCFAs, and restored cell death and membrane permeabilization during necroptosis. Collectively, our results highlight a role for SREBP1 in regulating lipid changes during necroptosis and suggest SREBP1 as a potential target for therapeutics to reduce membrane permeabilization during necroptosis.

cell biology↗

bioRxiv2022

Genomic evidence for ancient migrations routes along South America's Atlantic coast

An increasing body of archaeological and genomic evidence has hinted to a complex settlement process of the Americas. This is especially true for South America, where unexpected ancestral signals have raised perplexing scenarios for the early migrations into different regions of the continent. Here we present ancient genomes from the archaeologically rich Northeast Brazil and compare them to ancient and present-day genomic data. We find a distinct relationship between ancient genomes from Northeast Brazil, Lagoa Santa, Uruguay and Panama, representing evidence for ancient migration routes along South Americas Atlantic coast. To further add to the existing complexity, we also detect greater Denisovan than Neanderthal ancestry in ancient Uruguay and Panama individuals. Moreover, we find a strong Australasian signal in an ancient genome from Panama. This work sheds light on the deep demographic history of eastern South America and presents a starting point for future fine-scale investigations on the regional level.

genomics↗

bioRxiv2022

Balancing selection on genomic deletion polymorphisms in humans

A key question in biology is why genomic variation persists in a population for extended periods. Recent studies have identified examples of genomic deletions that have remained polymorphic in the human lineage for hundreds of millennia, ostensibly owing to balancing selection. Nevertheless, genome-wide investigations of ancient and possibly adaptive deletions remain an imperative exercise. Here, we used simulations to show an excess of ancient allele sharing between modern and archaic human genomes that cannot be explained solely by introgression or ancient structure under neutrality. We identified 63 deletion polymorphisms that emerged before the divergence of humans and Neanderthals and are associated with GWAS traits. We used empirical and simulation-based analyses to show that the haplotypes that harbor these functional ancient deletions have likely been evolving under time- and geography-dependent balancing selection. Collectively, our results suggest that balancing selection may have maintained at least 27% of the functional deletion polymorphisms in humans for hundreds of thousands of years.

evolutionary biology↗

bioRxiv2022

Trade-Offs Between Hepatic Host Defense and Metabolic Programs Underlie Sex-Biased Diseases

Current concepts in evolutionary medicine propose that trade-offs and mismatches with a shifting environment increase disease risk. While biological sex also impacts disease prevalence, contributions of environmental pressures to sex-biased diseases remain unexplored. Here, we show that sex-dependent hepatic programs confer a robust (~300%) survival advantage for male mice during lethal bacterial infection. The transcription factor BCL6, which masculinizes hepatic gene expression at puberty, is essential for this advantage. However, protection by BCL6 comes at a cost following dietary excess, resulting in overt fatty liver and glucose intolerance in males. Deleting hepatic BCL6 reverses these phenotypes but markedly lowers male fitness during infection, thus establishing a sex-dependent tradeoff between host defense and metabolic systems. We suggest that these tradeoffs, coupled with current environmental pressures, drive metabolic disease in males.

physiology↗

bioRxiv2021

Network-based analysis of allele frequency distribution among multiple populations identifies adaptive genomic structural variants

Structural variants have a considerable impact on human genomic diversity. However, their evolutionary history remains mostly unexplored. Here, we developed a new method to identify potentially adaptive structural variants based on a network-based analysis that incorporates genotype frequency data from 26 populations simultaneously. Using this method, we analyzed 57,629 structural variants and identified 577 structural variants that show high population distribution. We further showed that 39 and 20 of these putatively adaptive structural variants overlap with coding sequences or are significantly associated with GWAS traits, respectively. Closer inspection of the haplotypic variation associated with these putatively adaptive and functional structural variants reveals deviations from neutral expectations due to (i) population differentiation of rapidly evolving multi-allelic variants, (ii) incomplete sweeps, and (iii) recent population-specific negative selection. Overall, our study provides new methodological insights, documents hundreds of putatively adaptive variants, and introduces evolutionary models that may better explain the complex evolution of structural variants.

genomics↗

bioRxiv2020

Functional specialization of human salivary glands and origins of proteins intrinsic to human saliva

Salivary proteins are essential for maintaining health in the oral cavity and proximal digestive tract and serve as a diagnostic window into human disease. However, their precise organ origins remain unclear. Through transcriptomic analysis of major adult and fetal salivary glands, and integration with the saliva proteome and transcriptomes of 28+ organs, we linked human saliva proteins to their source, identified salivary gland-specific genes, and uncovered fetal- and adult-specific gene repertoires. Our results also provide new insights into the degree of gene retention during maturation and suggest that functional diversity between adult gland-types is driven by specific dosage combinations of hundreds of transcriptional regulators rather than a few gland-specific factors. Finally, we demonstrate the hitherto unrecognized heterogeneity of the human acinar cell lineage. Our results pave the way for future investigations into glandular biology and pathology, as well as salivas use as a diagnostic fluid.

developmental biology↗

bioRxiv2019

Sex-specific phenotypic effects and evolutionary history of an ancient deletion polymorphism of the human growth hormone receptor

The deletion of the third exon of the growth hormone receptor (GHR) is one of the most common genomic structural variants in the human genome. This deletion (GHRd3) has been linked to response to growth hormone, placenta size, birth weight, growth after birth, time of puberty, adult height, and longevity. However, its evolutionary history and the molecular mechanisms through which it affects phenotypes remain unresolved. Here, we analyzed thousands of genomes and provide evidence that this deletion was nearly fixed in the ancestral population of anatomically modern humans and Neanderthals. However, it underwent a paradoxical adaptive reduction in frequency approximately 30 thousand years ago in East Asia that roughly corresponds with the emergence of archaeological evidence for multiple modern human behaviors, dramatic changes in climate, and a concurrent population expansion. Further, we provide evidence that GHRd3 is associated with protection from edematous severe acute malnutrition primarily in males. Using a mouse line engineered to contain the deletion, we found Ghrd3s effect on the liver transcriptome of male mice grown without any calorie restriction mimics response to calorie restriction through regulation of circadian pathways. In contrast, under calorie restriction, Ghrd3 leads to the female-like gene expression in male livers. As a likely consequence, the dramatic weight difference between male and female mice disappears among GHRd3 mice under calorie restriction. Our data provide evidence for sex- and environment-dependent effects of GHRd3 and are consistent with a model in which the allele frequency of GHRd3 varies throughout human evolution as a response to fluctuations in resource availability.

evolutionary biology↗

bioRxiv2019

Genome-wide selection scan in the Kuwaiti population identifies a TNKS haplotype linked to metabolic traits and hypertension

Despite the extreme and varying environmental conditions prevalent in the Arabian Peninsula, it has experienced several waves of human migrations following the out-of-Africa diaspora. Eventually, the inhabitants of the peninsula region adapted to the hot and dry environment. The adaptation and natural selection that shaped the extant human populations of the Arabian Peninsula region have been scarcely studied. In an attempt to explore natural selection in the region, we analyzed 662,750 variants in 583 Kuwaiti individuals. We searched for regions in the genome that display signatures of positive selection in the Kuwaiti population using an integrative approach in a conservative manner. We highlight a haplotype overlapping TNKS that showed strong signals of positive selection based on the results of the multiple selection tests conducted (integrated Haplotype Score, Cross Population Extended Haplotype Homozygosity, Population Branch Statistics, and log-likelihood ratio scores). Notably, the TNKS haplotype under selection potentially conferred a fitness advantage to the Kuwaiti ancestors for surviving in the harsh environment while posing a major health risk to present-day Kuwaitis.

evolutionary biology↗