Biology subjects

Gokcumen, O.

Publications and source records attributed to Gokcumen, O..

25 records · Page 2Linked to original sources

bioRxiv2019

Loss-of-function tolerance of enhancers in the human genome

Previous studies have surveyed the potential impact of loss-of-function (LoF) variants and identified LoF-tolerant protein-coding genes. However, the tolerance of human genomes to losing enhancers has not yet been evaluated. Here we present the catalog of LoF-tolerant enhancers using structural variants from whole-genome sequences. Using a conservative approach, we estimate that each individual human genome possesses at least 28 LoF-tolerant enhancers on average. We assessed the properties of LoF-tolerant enhancers in a unified regulatory network constructed by integrating tissue-specific enhancers and gene-gene interactions. We find that LoF-tolerant enhancers are more tissue-specific and regulate fewer and more dispensable genes. They are enriched in immune-related cells while LoF-intolerant enhancers are enriched in kidney and brain/neuronal stem cells. We developed a supervised learning approach to predict the LoF-tolerance of enhancers, which achieved an AUROC of 96%. We predict 5,677 more enhancers would be likely tolerant to LoF and 75 enhancers that would be highly LoF-intolerant. Our predictions are supported by known set of disease enhancers and novel deletions from PacBio sequencing. The LoF-tolerance scores provided here will serve as an important reference for disease studies.

genomics↗

bioRxiv2019

A candidate causal variant underlying both higher intelligence and increased risk of bipolar disorder

Bipolar disorder is a highly heritable mental illness, but the relevant genetic variants and molecular mechanisms are largely unknown. Recent GWASs have identified an intergenic region associated with both cognitive performance and bipolar disorder. This region contains dozens of putative fetal brain-specific enhancers and is located [~]0.7 Mb upstream of the neuronal transcription factor POU3F2. We identified a candidate causal variant, rs77910749, that falls within a highly conserved putative enhancer, LC1. This human-specific variant is a single-base deletion in a PAX6 binding site and is predicted to be functional. We hypothesized that rs77910749 alters LC1 activity and hence POU3F2 expression during neurodevelopment. Indeed, transgenic reporter mice demonstrated LC1 activity in the developing cerebral cortex and amygdala. Furthermore, ex vivo reporter assays in embryonic mouse brain and human iPSC-derived cerebral organoids revealed increased enhancer activity conferred by the variant. To probe the in vivo function of LC1, we deleted the orthologous mouse region, which resulted in amygdala-specific changes in Pou3f2 expression. Lastly, humanized rs77910749 knock-in mice displayed behavioral defects in sensory gating, an amygdala-dependent endophenotype seen in patients with bipolar disorder. Our study suggests a molecular mechanism underlying the long-speculated link between enhanced cognitive performance and neuropsychiatric disease.

genetics↗

bioRxiv2018

Resolving the insertion sites of polymorphic duplications reveals a HERC2 haplotype under selection

Polymorphic duplications in humans have been shown to contribute to phenotypic diversity. However, the evolutionary forces that maintain variable duplications across the human genome are largely unexplored. To understand the haplotypic architecture of the derived duplications, we developed a linkage-disequilibrium based method to detect insertion sites of polymorphic duplications not represented in reference genomes. This method also allows resolution of haplotypes harboring the duplications. Using this approach, we conducted genome-wide analyses and identified the insertion sites of 22 common polymorphic duplications. We found that the majority of these duplications are intrachromosomal and only one of them is an interchromosomal insertion. Further characterization of these duplications revealed significant associations to blood and skin phenotypes. Based on population genetics analyses, we found that the partial duplication of a well-characterized pigmentation-related gene, HERC2, may be selected against in European populations. We further demonstrated that the haplotype harboring the partial duplication significantly affects the expression of the HERC2P9 gene in multiple tissues. Our study sheds light onto the evolutionary impact of understudied polymorphic duplications in human populations and presents methodological insights for future studies.

genomics↗

bioRxiv2018

Amylase copy number analysis in several mammalian lineages reveals convergent adaptive bursts shaped by diet

The amylase gene (AMY), which codes for a starch-digesting enzyme in animals, underwent several gene copy number gains in humans1, dogs2, and mice3, presumably along with increased starch consumption during the evolution of these species. Here we present evidence for additional AMY copy number expansions in several mammalian species, most of which also consume starch-rich diets. We also show that these independent AMY copy number gains are often accompanied by a gain in enzymatic activity of amylase in saliva. We used multi-species coalescent modeling to provide further evidence that these recurrent AMY gene copy number expansions were adaptive. Our findings underscore the overall importance of gene copy number amplification as a flexible and fast adaptive mechanism in evolution that can independently occur in different branches of the phylogeny.

evolutionary biology↗

bioRxiv2018

Fine-scale characterization of genomic structural variation in the human genome reveals adaptive and biomedically relevant hotspots

Genomic structural variants (SVs) are distributed nonrandomly across the human genome. These \"hotspots\" have been implicated in critical evolutionary innovations, as well as serious medical conditions. However, the evolutionary and biomedical features of these hotspots remain incompletely understood. In this study, we analyzed data from 2,504 genomes from the 1000 Genomes Project Consortium and constructed a refined map of 1,148 SV hotspots in human genomes. By studying the genomic architecture of these hotspots, we found that both nonallelic homologous recombination and non-homologous mechanisms act as mechanistic drivers of SV formation. We found that the majority of SV hotspots are within gene-poor regions and evolve under relaxed negative selection or neutrality. However, we found that a small subset of SV hotspots harbor genes that are enriched for anthropologically crucial functions, including blood oxygen transport, olfaction, synapse assembly, and antigen binding. We provide evidence that balancing selection may have maintained these SV hotspots, which include two independent hotspots on different chromosomes affecting alpha and beta hemoglobin gene clusters. Biomedically, we found that the SV hotspots coincide with breakpoints of clinically relevant, large de novo SVs, significantly more often than genome-wide expectations. As an example, we showed that the breakpoints of multiple large de novo SVs, which lead to idiopathic short stature, coincide with SV hotspots. As such, the mutational instability in SV hotpots likely enables chromosomal breaks that lead to pathogenic structural variation formations. Our study contributes to a better understanding of the mutational landscape of the genome and implicates both mechanistic and adaptive forces in the formation and maintenance of SV hotspots.

genomics↗

bioRxiv2018

An evolutionary transcriptomics approach links CD36 to membrane remodeling in replicative senescence

Cellular senescence, the irreversible ceasing of cell division, has been associated with organismal aging, prevention of cancerogenesis, and developmental processes. As such, the evolutionary basis and biological features of cellular senescence remain a fascinating area of research. In this study, we conducted comparative RNAseq experiments to detect genes associated with replicative senescence in two different human cell lines and at different time points. We identified 841 and 900 genes (core senescence-associated genes) that are significantly up- and downregulated in senescent cells, respectively, in both cell lines. Our functional enrichment analysis showed that downregulated core genes are primarily involved in cell cycle processes while upregulated core gene enrichment indicated various lipid-related processes. We further demonstrated that downregulated genes are significantly more conserved than upregulated genes. Using both transcriptomics and genetic variation data, we identified one of the upregulated, lipid metabolism gene, CD36 as an outlier. We found that overexpression of CD36 induces a senescence-like phenotype and, further, the media of CD36-overexpressing cells alone can induce a senescence-like phenotype in proliferating young cells. Moreover, we used a targeted lipidomics approach and showed that phosphatidylcholines accumulate during senescence in these cells, suggesting that upregulation of CD36 could contribute to membrane remodeling during senescence. Overall, these results contribute to the understanding of evolution and biology of cellular senescence and identify several targets and questions for future studies.

cell biology↗

bioRxiv2018

Complex haplotypes of metabolizing GSTM1 gene deletion harbors signatures of a selective sweep in East Asian populations

The deletion of the metabolizing Glutathione S-transferase Mu 1 (GSTM1) gene was previously associated with multiple cancers, metabolic and autoimmune disorders, as well as drug response. It is unusually common, with allele frequency reaching up to 75% in some human populations. Such high allele frequency of a derived allele with apparent impact on an otherwise conserved gene is a rare phenomenon. To investigate the evolutionary history of this locus, we analyzed 310 genomes using population genetics tools. Our analysis revealed a surprising lack of linkage disequilibrium between the deletion and the flanking single nucleotide variants in this locus, indicating gene conversion events. Tests that measure extended homozygosity and rapid change in allele frequency identified signatures of an incomplete soft-sweep in the locus. Using empirical approaches, we identified the Tanuki haplogroup, which carries the GSTM1 deletion and is found in approximately 70% of East Asian chromosomes. This haplogroup has rapidly increased its frequency in East Asian populations, contributing to a high population differentiation among continental human populations. We showed that extended homozygosity and population differentiation for this haplogroup is incompatible with simulated neutral expectations in East Asian populations. In parallel, we revealed that the Tanuki haplogroup is significantly associated with the expression levels of other GSTM genes. Collectively, our results suggest that the Tanuki haplogroup has likely undergone a soft sweep in East Asia with multiple functional consequences. Our study provides the necessary framework for further studies to elucidate the evolutionary reasons that maintain disease-susceptibility variants in the GSTM1 locus.\n\nLay summaryHere, we describe the evolutionary forces that shape the variation in a genomic region, which has been associated with bladder cancer, metabolic and autoimmune disorders and response to different drugs. Our results reveal a new genetic type common in Asian populations that may have important evolutionary and biomedical implications.

genetics↗