Next generation sequencing (NGS) technologies have revolutionized our approach to studying the genetic basis of diseases and caused a paradigm shift in biological sciences. With the cost of whole genome sequencing (WGS) well-below the much-anticipated $1000 level, it is now affordable to sequence the whole genome of hundreds to thousands of patients or healthy people. As a result, our knowledge of genome and its regulation in health and disease has increased tremendously: Since the completion of the Human Genome Project (HGP), millions of variants and mutations have been identified and thousands of them have been associated with both inherited and sporadic diseases. So far, an overwhelming majority of clinical genomics studies have focused on the “exome” – protein-coding parts of the genome, mainly due to its much lower cost compared to WGS. ENCODE (Encyclopedia of DNA Elements) Project and similar efforts have provided peek into the functional organization of the genome, however, our knowledge of how genomic information is utilized is far from complete and limited. A better understanding of such fundamental principles of genome regulation will undoubtedly help us explain the molecular basis of pathologic disease states. The overarching goal of our research efforts is to unravel these principles within the context of nervous system disorders.
The overarching goal of the Neuro-genomics Lab at IBG is the elucidation of mechanisms leading from genomic variation to diseases of the human nervous system. Our efforts can be grouped into two stages: Identification of such variants (i.e. in neurodevelopmental disorders) and their modeling in cellular and animal models with the help of genome editing tools.
Elucidation of the cellular mechanisms underlying the genetic predisposition to complex diseases and phenotypes of the nervous system is a major focus of our lab. In this respect, we utilize tools of the functional genomics to understand the molecular basis of genetic susceptibility to lethal brain tumors, namely gliomas. A multidisciplinary approach using genomic, epigenomic, transcriptomic, bioinformatic and cell biology methods is employed to achieve an integrative understanding of the early stages of gliomagenesis, as well as to identify prognostic biomarkers and therapeutic targets. We have recently identified the molecular basis of genetic predisposition to IDH-mutant gliomas and established the proto-oncogene MYC as the culprit of 8q24-associated glioma risk.
Another major focus of our research is to develop models and methods that will facilitate identification of DNA variants that cause or contribute to the etiopathogenesis of neurodevelopmental diseases. To this end, we perform whole-exome sequencing of trios and multiplex families to identify candidate variants, and test them with functional studies in cell and animal models, frequently employing CRISPR/Cas9 genome-editing tools. We have recently identified several new disease genes and variants in a large consanguineous cohort of neurodevelopmental disorders. Our current efforts are aimed towards finding therapeutic targets by utilizing a multi-omic analyses of this cohort.
A better grasp of the genotype-phenotype relationships in neurodevelopmental, as well as neurooncological, diseases is a must to translate the power of genomics into clinical benefit. Our multi-disciplinary approach will be expected to provide valuable guidance to development of therapeutic, prognostic and diagnostic tools.
Our recent work on low-grade gliomas (LGGs) has focused on understanding the genetic basis of genetic predisposition to IDH-mutated gliomas, which comprise 70-80 % of LGGs. These studies were conducted by a multi-disciplinary approach that employed transcriptomic, proteomic, immunohistochemical, clinical and epidemiologic analyses of tumor and blood samples from LGG patients. A manuscript based on these studies is under review. Also, a TUBITAK 1001 grant has recently (2015) been awarded for 3 years to study the mechanistic basis of 8q24.21-associated genetic predisposition to glioma. Within this project, neural stem cell (NSC) lines are being edited by using the CRISPR-Cas9 system to obtain isogenic cell lines that differ at only the disease-associated variants/loci, in the absence and presence of IDH1-R132H mutation due to the strict association of these variants with IDH1/2 mutations. An integrated analysis of these cells will be carried out by 4C-seq, RNA-seq, enhancer assays, etc.
International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD) has just been established and awarded 5-year funding by the Medical Research Council (MRC)-UK. The centre brings together clinicians and researchers from UK, Turkey, India, South Africa, Brazil and Zambia to advance genomic medicine in neuromuscular diseases. The inauguration ceremony of the centre took place on April 3, 2019 at House of Lords in London, with attendance by Turkish counsellor and Prof. Lord Kakkar among the audience.
Ana Töpf, Yavuz Oktay, Sunitha Balaraju, Elmasnur Yilmaz, Ece Sonmezler, Uluc Yis, Steven Laurie, Rachel Thompson, Andreas Roos, Daniel G MacArthur, .... Severe neurodevelopmental disease caused by a homozygous TLK2 variant. European journal of human genetics. 2020 June ; 28 (3) : 383-387. doi:10.1038/s41431-019-0519-x.
Ahmet Yaramis, Hanns Lochmüller, Ana Töpf, Ece Sonmezler, Elmasnur Yilmaz, Semra Hiz, Uluc Yis, Serdal Gungor, Ayse Ipek Polat, Pinar Edem, Sergi Beltran, Steven Laurie, Aysenur Yaramis, Rita Horvath, Yavuz Oktay. COL4A1-related autosomal recessive encephalopathy in 2 Turkish children. Neurology Genetics. 2020 January ; 6 (1) : 1. doi:10.1212/NXG.0000000000000392.
Eskier D, Karakülah G, Suner A, Oktay Y. RdRp mutations are associated with SARS-CoV-2 genome evolution.. PeerJ. 2020 July ; 8 : e9587. doi:10.7717/peerj.9587.
Yiş U., Hız S., Güneş S., Diniz G., Sönmezler E., Yılmaz E., Oktay Y. . Dihydropyridine receptor congenital myopathy in a consanguineous Turkish family. Journal of Neuromuscular Diseases. 2019 June ; 6 (3) : 377-384. doi:10.3233/JND-190383.
Ege Ulgen, Ozge Can, Kaya Bilguvar, Yavuz Oktay, Cemaliye Akyerli, Ayça Danyeli, Cengiz Yakicier, Ugur Sezerman, Necmettin Pamir Koray Özduman. Whole Exome Sequencing-Based Analysis Identifies DNA Damage Repair Deficiency as a Major Contributor to Gliomagenesis in Adult Diffuse Gliomas. J Neurosurg. 2019 April : 1-12. doi:10.3171/2019.1.JNS182938.
Akyerli CB, Yüksel Ş, Can Ş, Erson-Omay EZ, Oktay Y, Coşgun E, Ülgen E, Erdemgil Y, Sav A, von Deimling A, Günel M, Yakıcıer MC, Pamir MN, Öz............ Use of telomerase promoter mutations to mark specific molecular subsets with reciprocal clinical behavior in IDH mutant and IDH wild-type diffuse gliomas. J Neurosurg. 2018 April ; 128 (4) : 1102-1114. doi:10.3171/2016.11.JNS16973.
Oktay Y., Boylu C.A., Özduman K.. Gliom gelişiminde genetik yatkınlığın rolü. Türk Nöroşir Derg. 2017 March ; 27 (2) : 122-130. doi: .
Pavlopoulou, Athanasia; Oktay, Yavuz; Vougas, Konstantinos; Louka, Maria; Vorgias, Constantinos E.; Georgakilas, Alexandros G.. Determinants of resistance to chemotherapy and ionizing radiation in breast cancer stem cells. CANCER LETTERS. 2016 October ; 380 (2) : 485-493. doi:10.1016/j.canlet.2016.07.018.
Oktay, Yavuz; Ulgen, Ege; Can, Ozge; Akyerli, Cemaliye B.; Yuksel, Sirin; Erdemgil, Yigit; Durasi, I. Melis; Henegariu, Octavian Ioan; Nanni, E. Paolo; Selevsek, Nathalie; Grossmann, Jonas; Erson-Omay, E. Zeynep; Bai, Hanwen; Gupta, Manu; Lee, William; Turcan, Sevin; Ozpinar, Aysel; Huse, Jason T.; Sav, M. Aydin; Flanagan, Adrienne; Gunel, Murat; Sezerman, O. Ugur; Yakicier, M. Cengiz; Pamir, M. Necmettin; Ozduman, Koray. IDH-mutant glioma specific association of rs55705857 located at 8q24.21 involves MYC deregulation. SCIENTIFIC REPORTS. 2016 June ; 6 . doi:10.1038/srep27569.
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