Dr Caglayan graduated from Eskisehir Osmangazi University, School of Medicine with third degree in 2001.
After completed 4 years of residency training at Department of Medical Genetics, Faculty of Medicine, Erciyes University in 2007, he started his obligatory assignment as a specialist medical doctor at Department of Medical Genetics in Kayseri Education and Research Hospital in 2008.
He gave theoretical and practical lectures about biotechnology and genetics in Perugia in Italy in 2008.
He worked as a Post-Doc Associate and then Associate Research Scientist at Yale School of Medicine, Program on Neurogenetics beginning from 2010.
Using homozygosity mapping in combination with whole exome sequencing, he has successfully identified novel genes for microcephaly, intellectual disability, as well as neurodegenerative diseases.
News related his work:
Too much of a bad thing can be good in brain tumors
DNA mutations can cause cancer but in some cases, more mutations may mean a better prognosis for patients. A Yale-led comprehensive genomic analysis of more than 700 brain tumors has revealed one such subtype of the most malignant brain tumor, called glioblastoma, or GBM. This subtype possesses thousands of tumor-specific DNA errors or mutations instead of dozens observed in most glioblastoma cases. It is also associated with longer survival.
The findings, reported in Journal Neuro-Oncology, suggest it may be possible to develop personalized treatments for more aggressive forms of brain cancer, including immunotherapy for these hyper- or ultra-mutated tumors, said Murat Günel, professor and chair of neurosurgery, who leads the Brain Tumor Research Program at Yale and Smilow Cancer Hospital at Yale-New Haven Hospital.
"We have been able to translate various complementary cutting-edge genomic technologies, which were once solely research tools, to our clinical programs to analyze individual cancers," said Günel, who is also a professor of genetics and a researcher for the Yale Cancer Center. "We can now gain comprehensive understanding of the molecular make-up of a cancer to pinpoint specific vulnerabilities and leverage these weak spots for precision treatments in our Recurrent Brain Tumor Treatment Program."
While as many as 10,000 mutations were found in the newly described subset of glioblastomas, a more typical tumor contains less than 100. This counterintuitive pattern has also been observed in gynecological and colon cancers: An extraordinary number of mutations means a better chance of survival.
One theory holds that cells with greater number of mutations are able to trigger an aggressive immune system response against cancer cells, while cells with fewer mutations might escape detection, Gunel said.
Although the number of GBMs in this newly identified group is small, the use of standard chemotherapy in some cases has been shown to inadvertently result in a hyper-mutated tumor. Indeed, the drug temozolomide, used as the first line of chemotherapy in GBM, has been shown to sometimes increase mutations. "But perhaps the naïve immune system is not strong enough to eliminate the cancer cells in these brain tumors," Gunel noted.
However, if a new generation of immunotherapy drugs called checkpoint inhibitors were used in these hyper-mutated tumors, perhaps more cancer cells might be targeted for destruction, he said. Clinical trials currently underway might be improved by considering the molecular genetic make-up of the individual tumor, he concluded.
The Gregory Kiez and Mehmet Kutman Foundation funded the work.
Zeynep Erson-Omay and Ahmet Okay Çağlayan from Yale co-first authored the paper.
Healthy brain development balanced on edge of a cellular 'sword'
A new Yale-led study of children with neurodevelopmental abnormalities of the brain identifies a "cutting" enzyme crucial to the shaping and division of brain cells as well as the replenishment of neural stem cells.
The study, appearing online Dec. 17 in the journal Neuron, helps explain the molecular basis of complex brain abnormalities, including small brain size (microcephaly) observed in children who were suffering from a wide variety of clinical problems, ranging from severe cognitive deficits to autism spectrum disorders.
The Yale team was led by Ketu Mishra-Gorur and Ahmet Caglayan in the lab of Murat Gunel, the Nixdorff-German Professor and chair in the Department of Neurosurgery, and professor of genetics and neurobiology at Yale School of Medicine. The team sequenced all protein-coding genes (exome) of children with inherited cerebral cortex malformations at the Yale Center for Mendelian Genetics. In collaboration with Joseph Gleeson's group at University of California-San Diego, they identified five harmful mutations in the KATNB1 gene, which encodes for a portion of the Katanin protein. Katanin, named after the Japanese sword, or katana, is an enzyme that severs microtubules that support the structure of cells and are crucial to their division.
The Gunel group showed that in diverse organisms ranging from zebrafish to fruit flies, silencing KATNB1 resulted in dramatically reduced brain size. The mutations severely impact asymmetric, rather than symmetric, cell division. Asymmetric cell division replenishes the neural stem cell population by producing both a "progenitor" and a "daughter" cell in each division. This allows for an exponential increase in cell numbers during early brain development, which is lost in brains with mutant KATNB1.
"It was generally understood that asymmetric cell division plays a vital role in cerebral cortical development," Gunel said. "The discovery of KATNB1 mutations now reveals a beautiful example of the fundamental importance of this mechanism and how the loss of asymmetric cell division results in a small brain size."
In an accompanying paper in Neuron, a team lead by Christopher Walsh of Harvard University also independently found that the lack of the same gene causes severe brain deformities in humans, mice, and zebrafish.
The work was funded by the Yale Program on Neurogenetics, the National Institutes of Health, Howard Hughes Medical Institute, and the Gregory M. Kiez and Mehmet Kutman Foundation.
Genetic legacy from the Ottoman Empire: Single mutation causes rare brain disorder
An international team of researchers have identified a previously unknown neurodegenerative disorder and discovered it is caused by a single mutation in one individual born during the height of the Ottoman Empire in Turkey about 16 generations ago.
The genetic cause of the rare disorder was discovered during a massive analysis of the individual genomes of thousands of Turkish children suffering from neurological disorders.
"The more we learn about basic mechanisms behind rare forms of neuro-degeneration, the more novel insights we can gain into more common diseases such as Alzheimer's or Lou Gehrig's Disease," said Murat Gunel, the Nixdorff-German Professor of Neurosurgery, and professor of genetics and neurobiology at Yale.
Gunel is a senior co-author of one of two papers published in the April 24 issue of the journal Cell that document the devastating effects of a mutation in the CLP1 gene. Gunel and colleagues at Yale Center for Mendelian Genomics along with Joseph Gleeson's group at University of California-San Diego compared DNA sequencing results of more than 2,000 children from different families with neurodevelopmental disorders. In four apparently unrelated families, they identified the exact same mutation in the CLP1 gene. Working with the Frank Bass group from the Netherlands, the researchers also studied how CLP1 mutations interfered with the transfer of information encoded within genes to cells' protein-making machinery.
The discovery of the identical mutation in seemingly unrelated families originally from eastern Turkey suggested an ancestral mutation, dating back several generations, noted the researchers.
Affected children suffer from intellectual disability, seizures, and delayed or absent mental and motor development, and their imaging studies show atrophy affecting the cerebral cortex, cerebellum, and the brain stem.
The second Cell paper by researchers from Baylor School of Medicine and Austria also found the identical founder mutation in CLP1 in another 11 children from an additional five families originally from eastern Turkey.
Gunel said that the high prevalence of consanguineous marriages [between closely related people] in Turkey and the Middle East leads to these rare recessive genetic neurodegenerative disorders. Affected children inherit mutations in the same gene from both of their parents, who are closely related to each other, such as first cousins. Without consanguinity between parents, children are very unlikely to inherit two mutations in the same gene.
"By dissecting the genetic basis of these neurodevelopmental disorders, we are gaining fundamental insight into basic physiological mechanisms important for human brain development and function" Gunel said. "We learn a lot about normal biology by studying what happens when things go wrong."
Funding for the Gunel study was provided by National Human Genome Research Institute and the Gregory M. Kiez and Mehmet Kutman Foundation.
Scientists Discover New Genetic Forms of Neurodegeneration
In a study published in the January 31, 2014 issue of Science, an international team led by scientists at the University of California, San Diego School of Medicine report doubling the number of known causes for the neurodegenerative disorder known as hereditary spastic paraplegia. HSP is characterized by progressive stiffness and contraction of the lower limbs and is associated with epilepsy, cognitive impairment, blindness and other neurological features.
Over several years, working with scientific colleagues in parts of the world with relatively high rates of consanguinity or common ancestry, UC San Diego researchers recruited a cohort of more than 50 families displaying autosomal recessive HSP – the largest such cohort assembled to date. The scientists analyzed roughly 100 patients from this cohort using a technique called whole exome sequencing, which focuses on mapping key portions of the genome. They identified a genetic mutation in almost 75 percent of the cases, half of which were in genes never before linked with human disease.
"After uncovering so many novel genetic bases of HSP, we were in the unique position to investigate how these causes link together. We were able to generate an 'HSP-ome,' a map that included all of the new and previously described causes," said senior author Joseph G. Gleeson, MD, Howard Hughes Medical Institute investigator, professor in the UC San Diego departments of Neurosciences and Pediatrics and at Rady Children's Hospital-San Diego, a research affiliate of UC San Diego.
The HSP-ome helped researchers locate and validate even more genetic mutations in their patients, and indicated key biological pathways underlying HSP. The researchers were also interested in understanding how HSP relates to other groups of disorders. They found that the HSP-ome links HSP to other more common neurodegenerative disorders, such as Alzheimer's disease and amyotrophic lateral sclerosis.
"Knowing the biological processes underlying neurodegenerative disorders is seminal to driving future scientific studies that aim to uncover the exact mechanisms implicated in common neurodegenerative diseases, and to indicate the path toward development of effective treatments," said Gleeson.
"I believe this study is important for the neurodegenerative research community," said co-lead author Gaia Novarino, PhD, a post-doctoral scholar in Gleeson's lab. "But more broadly, it offers an illustrative example of how, by utilizing genomics in specific patient populations, and then building an 'interactome,' we greatly expand knowledge around unknown causes of disease."
"This is very exciting since identifying the biological processes in neurological disorders is the first step toward the development of new treatments," agreed co-lead author Ali G. Fenstermaker. "We identified several promising targets for development of new treatments."
Co-authors include Maha S. Zaki, Ghada M.H. Abdel-Salam, Mahmood Y. Issa and Hisham Megahed, National Research Centre, Cairo; Matan Hofree, UCSD Departments of Medicine and Engineering and Neurosciences; Jennifer L. Silhavy, Andrew D. Heiberg, Mostafa Abdellatef, Basak Rosti, Eric Scott, Massimo Mascaro, Jana Schroth, Emily G. Spender, Rasim O. Rosti, Naiara Akizu, Keith A. Vaux and Alice A. Koh, Howard Hughes Medical Institute; Lobna Mansour, Iman Gamal El Din Mahmoud and Laila Selim, Cairo University Children's Hospital; Amira Masri, University of Jordan; Hulya Kayserili, Istanbul University; Jumana Y. Al-Aama, King Abdulaziz University, Saudi Arabia; Ariana Karminejad and Bita Bozorgmehri, Kariminejad-Najmabadi Pathology and Genetics Center, Iran; Majdi Kara, Tripoli Children's Hospital, Libya; Bulent Kara, Kocaeli University, Turkey; Tawfeq Ben-Omran, Hamad Medical Corporation, Qatar; Faezeh Mojahedi, Mashhad Medical Genetic Counseling Center, Iran; Naima Bouslam, Ahmed Bouhouche and Ali Benomar, University Mohammed C Souissi, Morocco; Sylvain Hanein, Laure Raymond and Sylvie Forlani, Centre de Recherche de I'Institut du Cerveau et de la Moelle Epiniere; Nabil Shehata, Saudi German Hospital, Saudi Arabia; Nasir Al-Allawi, University of Dohuk, Iraq; P.S. Bindu, NIMHANS, India; Matloob Azam, Wah Medical College, Pakistan; Murat Gunel, Ahmet Caglayan and Kaya Bilguvar, Yale University School of Medicine; Alexandra Durr, Centre de Recherche de I'Institut up Cerveau et de la Moelle Epiniere and APHP, Federation de Genetique, France; Alexis Brice, Centre de Recherche de I'Institut up Cerveau et de la Moelle Epiniere, APHP, Federation de Genetique and Institut du Cerveau et de la Moelle Epiniere, France; Giovanni Stevanin, Centre de Recherche de I'Institut up Cerveau et de la Moelle Epiniere, APHP, Federation de Genetique and Institut du Cerveau et de la Moelle Epiniere, France; Stacy Gabriel, Broad Institute of Harvard and Massachusetts Institute of Technology, and Trey Ideker, UCSD Departments of Medicine and Engineering and Neurosciences.
Funding for this research came, in part, from the Deutsche Forschungsgemeinschaft, the BBRF, National Institutes of Health grants R01NS041537, R01NS048453, R01NS052455, P01HD070494 and P30NS047101, the French National Agency for Research, the Verum Foundation, the European Union, Fondation Roger de Spoelberch, Investissements d'avenir and the Princess Al Jawhara Center of Excellence in Research of Hereditary Disorders.
Genetic landscape of common brain tumors holds key to personalized treatment
Nearly the entire genetic landscape of the most common form of brain tumor can be explained by abnormalities in just five genes, an international team of researchers led by Yale School of Medicine scientists report online in the Jan. 24 edition of the journal Science. Knowledge of the genomic profile of the tumors and their location in the brain make it possible for the first time to develop personalized medical therapies for meningiomas, which currently are only managed surgically.
Meningioma tumors affect about 170,000 patients in the United States. They are usually benign but can turn malignant in about 10 percent of cases. Even non-cancerous tumors can require surgery if they affect the surrounding brain tissue and disrupt neurological functions.
Approximately half of the tumors have already been linked to a mutation or deletion of a gene called neurofibromin 2, or NF2. The origins of the rest of the meningiomas had remained a mystery.
The Yale team conducted genomic analyses of 300 meningiomas and found four new genetic suspects, each of which yields clues to the origins and treatment of the condition. Tumors mutated with each of these genes tend to be located in different areas of the brain, which can indicate how likely they are to become malignant.
"Combining knowledge of these mutations with the location of tumor growth has direct clinical relevance and opens the door for personalized therapies," said Dr. Murat Gunel, the Nixdorff-German Professor of Neurosurgery, professor of genetics and of neurobiology, and senior author of the study. Gunel is also a member of Yale Cancer Center's Genetics and Genomics Research Program.
For instance, two of the mutations identified — SMO and AKT1 — have been linked to various cancers. SMO mutations had previously been found in basal cell carcinoma and are the target of an already approved drug for that form of skin cancer. Another, KLF4, activates a suite of genes and is known for its role in inducing stem cell formation, even in cells that have fully differentiated into a specific tissue type. Mutations in a TRAF7, a gene not previously associated with cancer, were found in approximately one-fourth of tumors. Meningiomas with these mutations are found in the skull base and are unlikely to become cancerous. In contrast, NF2 mutant tumors that flank the brain's hemispheres are more likely to progress to malignancy, especially in males.
Doctors may be able to use targeted chemotherapy on patients with non-NF2 mutations, especially those with recurrent or invasive meningiomas and those who are surgically at high risk. Individualized chemotherapies could also spare patients irradiation treatment, a risk factor for progression of these generally benign tumors. Gunel said it may also be possible to extend these approaches to more malignant tumors. Funding for the study was provided by Gregory M. Kiez and Mehmet Kutman Foundation.
Mutations in Single Gene May Have Shaped Human Cerebral Cortex
The size and shape of the human cerebral cortex, an evolutionary marvel responsible for everything from Shakespeare's poetry to the atomic bomb, are largely influenced by mutations in a single gene, according to a team of researchers led by the Yale School of Medicine and three other universities.
The findings, reported April 28 in the American Journal of Human Genetics, are based on a genetic analysis of in one Turkish family and two Pakistani families with offspring born with the most severe form of microcephaly. The children have brains just 10 percent of normal size. They also lacked the normal cortical architecture that is a hallmark of the human brain. This combination of factors has not been seen in other genes associated with the development of the human brain, the authors note.
The researchers found that mutations in the same gene, centrosomal NDE1, which is involved in cell division, were responsible for the deformity.
The degree of reduction in the size of the cerebral cortex and the effects on brain morphology suggest this gene plays a key role in the evolution of the human brain," said Murat Gunel, co-senior author of the paper and the Nixdorff-German Professor of Neurosurgery and professor of genetics and neurobiology at Yale.
Scientists from Yale, the University of Cambridge, Harvard and Northwestern universities collaborated on the study with colleagues around the world, including those in Turkey and Saudi Arabia.
"These findings demonstrate how single molecules have influenced the expansion of the human cerebral cortex in the last five million years," Gunel said. "We are now a little closer to understanding just how this miracle happens."
The research was funded by the Yale Program on Neurogenetics, the Yale Center for Human Genetics and Genomics, the National Institutes of Health and the Wellcome-Trust.
Mehmet Bakircioglu of Yale was co-first author of the paper. Other Yale authors on the paper are Tanyeri Barak, Saliha Yilmaz, Okay Caglayan and Kaya Bilguvar.
Tiny Variation in One Gene May Have Led to Crucial Changes in Human Brain
The human brain has yet to explain the origin of one its defining features – the deep fissures and convolutions that increase its surface area and allow for rational and abstract thoughts.
An international collaboration of scientists from the Yale School of Medicine and Turkey may have discovered humanity's beneficiary – a tiny variation within a single gene that determines the formation of brain convolutions – they report online May 15 in the journal Nature Genetics.
A genetic analysis of a Turkish patient whose brain lacks the characteristic convolutions in part of his cerebral cortex revealed that the deformity was caused by the deletion of two genetic letters from 3 billion in the human genetic alphabet. Similar variations of the same gene, called laminin gamma3 (LAMC3), were discovered in two other patients with similar abnormalities.
"The demonstration of the fundamental role of this gene in human brain development affords us a step closer to solve the mystery of the crown jewel of creation, the cerebral cortex," said Murat Gunel, senior author of the paper and the Nixdorff-German Professor of Neurosurgery, co-director of the Neurogenetics Program and professor of genetics and neurobiology at Yale.
The folding of the brain is seen only in mammals with larger brains, such as dolphins and apes, and is most pronounced in humans. These fissures expand the surface area of the cerebral cortex and allow for complex thought and reasoning without taking up more space in the skull. Such foldings aren't seen in mammals such as rodents or other animals. Despite the importance of these foldings, no one has been able to explain how the brain manages to create them. The LAMC3 gene – involved in cell adhesion that plays a key role in embryonic development – may be crucial to the process.
An analysis of the gene shows that it is expressed during the embryonic period that is vital to the formation of dendrites, which form synapses or connections between brain cells. "Although the same gene is present in lower organisms with smooth brains such as mice, somehow over time, it has evolved to gain novel functions that are fundamental for human occipital cortex formation and its mutation leads to the loss of surface convolutions, a hallmark of the human brain," Gunel said.
Major funding for the study was provided by National Institute of Neurological Disorders and Stroke through the Recovery Act. Several institutions from Turkey contributed to the paper. Co-lead authors of the paper were Tanyeri Barak and Kenneth Y Kwan of Yale. Other Yale authors include Angeliki Louvi, Murim Choi, Ying Zhu, Saliha Yilma, Mehmet Bakircioglu, Ahmet Okay Çaglayan, Ali Kemal Öztürk, Katsuhito Yasuno, Richard A Bronen, Shrikant Mane, Richard P Lifton, Nenad Šestan and Kaya Bilgüvar.
One Gene Can Spur Huge Changes in the Human Brain, Yale Researchers Find
Mutations in a single gene critical to the development of the human cerebral cortex can cause a host of brain deformities previously thought to be unrelated, Yale researchers report online August 22 in the journal Nature.
The surprising findings describe how a single gene can regulate the production of cortical neurons, their migration to proper sites within the brain, the folding of brain tissue that marks the human cortex and even the size of the human brain compared to its primate cousins.
"Mechanistically, we know little about how the human cerebral cortex develops and the genes involved in this process. Cutting-edge molecular genetic approaches now allow us to dissect this complex process. Understanding the normal function of molecules like WDR62 will get us a step closer to solving this amazing puzzle," said Murat Gunel, the Nixdorff-German Professor of Neurosurgery, Genetics and Neurobiology at Yale and senior author of the paper.
As part of a long-term collaboration between Gunel and Turkish scientists, the Yale team studied two cousins from Turkey born with extremely underdeveloped cerebral cortices resulting in significantly smaller brains. The cousins also showed evidence of an abnormality in the migration of cortical neurons to their normal destinations and abnormalities in the normal folding of the cortex. These deformities were previously believed to be separate disorders, but finding all these features in two related subjects suggested there might be a single underlying cause, noted the researchers.
To test this theory, the investigators used whole exome sequencing, a technology pioneered at Yale that enables the rapid and relatively inexpensive sequencing of all the protein coding genes in the human genome. The investigators identified mutations in both copies of the gene encoding the protein WDR62. Upon sequencing this gene in additional subjects with malformations of cerebral cortical development, the scientists identified six additional families with mutations in both copies of WDR62.
"Because patients with mutations in this gene were only a fraction of the total cohort, this gene would have been very difficult to map and identify using traditional genetic approaches," said Richard Lifton, Sterling Professor and Chair of Genetics at Yale, whose lab developed the exome sequencing and analysis methods used for this study.
The results offer surprising insights into the diverse roles that a single gene can play in brain development, noted the scientists.
"The study of disorders of the human brain is undergoing a revolution as a result of new sequencing technologies," said Matthew W. State, the Donald J. Cohen Associate Professor of Child Psychiatry, Psychiatry and Genetics, who designed the study along with Gunel and Lifton. "The approaches used in this study promise to unlock many of the mysteries regarding the genetics of developmental disorders ranging from cortical malformations to autism to mental retardation," he added.
Kaya Bilguvar and Ali Ozturk from Yale are the co-first authors of the study. A dozen other researchers from Yale contributed to the study, as did several Turkish clinicians and scientists. Major funding for the study was provided by a stimulus grant from the National Institutes of Health, National Institute for Neurological Disorders and Stroke.
"The ongoing collaboration with our Turkish colleagues along with the technology development at Yale combined with the timely NIH funding allowed us to achieve these results," said Gunel. "It would not have been possible without the stimulus funding," he added, noting that additional funding was provided by Yale University and the Howard Hughes Medical Institute.