Medical genetics and genomic medicine in Turkey: a bright future at a new era in life sciences

Medical genetics and genomic medicine in Turkey: a bright future at a new era in life sciences.

historian who lived in the fifth century BCE in Halicarnassus (present day Bodrum, Turkey), and Pomponius Mela, the earliest Roman geographer who lived in Tingentera (present day Algeciras, Spain) during the first century CE. They refer to the "Turcae" or "Tyrcae" in the forests north of the Sea of Azov in Crimea. In Chinese sources, reference to Turks appeared during the 600s CE as nomadic traders in the south of the Altai Mountains. The term "T€ urk" or "T€ ur€ uk" was first documented circa eighth century in Central Asia in the earliest surviving Old Turkic Orkhon inscriptions of G€ okt€ urks (Celestial Turks). Turkey is derived from Medieval Latin Turchia. Byzantine emperor and scholar Constantine VII also used the name Tourkia, but this was a referral to Magyars. Arabs referred to the Mamluk Sultanate as al-Dawla al-Turkiyya (State of Turkey). European contemporaries sometimes referred to the Ottoman Empire as Turkey or the Turkish Empire.
Seljuk Turks entered into Anatolia in 1071 following the Battle of Manzikert against the Byzantine Empire and ruled the land until the Mongols' Conquest of Anatolia in the 11th century. Following a short-lived period of Beyliks (Turkish lords of Karasi, Saruhan, Aydin, Mentes ße, Teke, Hamid, and Germiyan), a group of Oghuz Turks calling themselves Ottomans took control of Anatolia, first crossing the Dardanelles and then conquering Constantinople in 1453 under Sultan Mehmed II. The Ottoman Empire reached at the height of its power during the 16th and 17th centuries, under Suleiman the Magnificent, as a multinational and multilingual entity controlling much of Southeast Europe, parts of Central Europe, Western Asia, the Caucasus, North Africa, and the Horn of Africa.
Konstantiniyyealso referred to as Stamboul or Islambol or Der-i Sa'ãdet (Abode of Felicity) or Bãb-i Alî (The Sublime Port) or Pâyitaht (The Seat of the Throne)as its capital, the Ottoman Empire ruled in the Mediterranean basin for six centuries until its decline in the late 18th and early 19th centuries mainly due to the weakening of the military system and falling behind that of their European rivals, the Habsburg and Russian Empires. At the end of World War I, the Empire lost most of its Balkan and Middle Eastern territories leading to the creation of Balkan and modern Arab countries, and the Republic of Turkey. Mustafa Kemal Atat€ urk and his colleagues founded modern Turkey in 1923 after the Turkish War of Independence (1919Independence ( -1922. The country has borders with Greece, Bulgaria, Georgia, Armenia, Azerbaijan, Iran, Iraq, and Syria. Turkey is a charter member of the UN, an early member of NATO, and a founding member of the OECD, OSCE, OIC, and G-20. Turkish Science in the Wake of World War II In order to understand the journey of life sciences and genetics in Turkey, it is necessary to take a look at the key events that shaped the Turkish medical establishment and research community during the Ottoman modernization of Tanzimat in the 19th century and the early days of the Republic. Dar€ ulf€ unun, the predecessor of Istanbul University, is linked to Emperor Justinian's sixth century codification of Roman law, the Corpus Iuris Civilis, marking the commencement of teaching and paving the way to the establishment of medieval universities such as Bologna (1088), Paris (c.1150), and Oxford (1167). With the conquest of Constantinople, scholarship continued at the Fatih Medrese, and expanded to Mekteb-i Tıbbiye-i S ßahane (Magnificent School of Medicine) in the 19th century. M€ uhendishane-i Bahr-i H€ umayun (School of Naval Engineering) of the 18th century evolved to Istanbul Technical University. There is then the first Turkish Academy of Sciences, Enc€ umen-i Danis ß, established in 1860s to live only for a decade and reemerge approximately one century later with the establishment of T € UB _ ITAK (The Scientific and Technological Research Council of Turkey) and T € UBA (Turkish Academy of Sciences).
In 1933, Einstein wrote a letter to Atat€ urk asking for his permission to accept scientists (mainly but not restricted to physicians) who were oppressed under the Third Reich (Fig. 2). Atat€ urk and _ In€ on€ u, the Prime Minister and the second President of Turkey, welcomed this request and initiated the far-reaching "University Reform of 1933," which resulted in the re-establishment of Istanbul University followed by Ankara, Istanbul Technical, Ege, Hacettepe, Middle East Technical, Bilkent, and now more than 100 institutions of higher education. The University Reform of 1933 marks the beginning of modern university establishments in Turkey.
More than 80 professors and doctors of medicine arrived during the next decade including Erich Frank (surgery), Phillip Schwartz (medicine), Ernst Eduard Hirsch (law), Fritz Neumark (economy), Hans Winterstein (physiology), Leo Brauner (botanics), Hans Willebrandt (agriculture), Rosa Maria R€ ossler (pathology), Fritz Arndt (chemistry), Albert Eckstein (pediatrics), Ernst Reuter (urban planning, later the German mayor of West Berlin during the cold war), Werner Laquer (obstetrics and gynecology), Friedrich Reimann (genetics), Clemens Holzmeister (architect, planned the Grand National Assembly of Turkey), Felix Michael Haurowitz (biochemistry), Hugo Braun (microbiology), Siegfried Oberndorfer (pathology), Rudolf Nissen (surgery), and others. At one point, nearly 35% (85/237) of the entire faculty of Istanbul University was composed of foreign scientists. We can now trace these names to the nominators from Turkey at the Nobel Nomination Database.

Beginnings: Clinical Observations that Lead the Way to Basic Research
Human genetics first flourished through clinical description of genetic syndromes followed by gene identification studies mainly in consanguineous families. Examples include Say syndrome (181180) (Editorial, 2009(Editorial, , 2010. But it is _ Ihsan Do gramacı's remarkable tenure as an architect of higher education and child health, and Aziz Sancar's relentless commitment to scientific inquiry that have the farthest reaching effects on the human genetics community in Turkey (Fig. 3).
_ Ihsan Do gramacı was born during World War I to an affluent Turkmen family in the Ottoman Empire province of Erbil (present day Iraq). He was one of the founders of WHO, the longest serving Executive Board member of UNICEF and a tireless campaigner for world peace. Through his long tenure first as a scientist-physician (Dogramaci 1946;Gocmen et al. 1986) then as a statesman (http://www.bilkent.edu.tr/hocabey/indexeng.html), he established several major universities and centers of excellence, and laid the foundations for the advancement of human genetics and genomics in Turkey.
Aziz Sancar was born in the southeastern town of Savur, Mardin shortly after the end of World War II. His chief mentor at Istanbul Medical School was Muzaffer Aksoy, who established the link between benzene exposure and risk of leukemia. He also defined several hemoglobin mutations including the one named "Istanbul." His other mentors include Mutahhar Yenson (biochemist), Sevim B€ uy€ ukdevrim (diabetologist), Nuran G€ okhan (physiologist), T€ urkan Erbengi (histologist), M€ ufide K€ uley (one of the first Turkish female internists), Remzi € Ozcan (cardiologist) who were among the first generation of scientists trained by scholars who had fled Nazism (Aksoy 1955(Aksoy , 1962Aksoy and Lehmann 1957;Devrim and Recant 1966;Erdem et al. 1966;Aksoy et al. 1972).
It was in the mid-90s that Aziz Sancar reunited with the Turkish academia after going to the United States in the early 70s to pursue a career in science. He was already established as a leading figure in DNA repair. And a real breakthrough came in 1996 during a transatlantic flight when Dr. Sancar was returning from his annual pilgrimage to Turkey. Sleepless, he stumbled on an article in the airline magazine on transcontinental journeys, its health effects, and jetlag. He began reading through and learned for the first time the Latin origins of the term circadian rhythm (circa: about and dies: days). Humans have it, animals have it, and plants have ita more or less 24-  hour inner clock that regulates all cellular functions. Could this be the answer to a more than a decade-old mystery, the true biological function of one of the first ever identified components of DNA repair, photolyase? This enzyme, cloned by Dr. Sancar during his Ph.D. studies in the early 70s, repairs UV-damaged DNA in bacteria. It was the first player identified in the quest to solve the mechanistic properties of nucleotide excision repair. Ironically, photolyase is found in many organisms including marsupials but not placental mammals; so, what was this photolyase homolog doing in humans and mice? Dr. Sancar, after reading the flight magazine article, suspected that it might function in the circadian clock that he later described as one of the most exciting eureka moments of his career (Zagorski 2005). Photolyase is one of the critical components in the regulation of circadian rhythm. The rest is history (Hsu et al. 1996;Miyamoto and Sancar 1998). The genetics community in Turkey eagerly waited to hear the name of Aziz Sancar every year that the Nobel prizes were announced. But the grand dame of the Turkish academic institutions, Istanbul University, was resourceful and the first ever Nobel laureate from Turkey proved to be another of her graduates, Orhan Pamuk. This was 2006 and it was in the field of literature. And the climax of the Turkish science was reached on October 8, 2015 when the Royal Swedish Academy of Sciences decided to award the Nobel Prize in Chemistry for 2015 to Tomas Lindahl, Paul Modrich, and Aziz Sancar "for mechanistic studies of DNA repair."

A Nobel Medal at Anıtkabir: the Nation's Most Important Memorial and Museum
Aziz Sancar's 2015 Nobel Prize in Chemistry medal and diploma is permanently displayed at Anıtkabir in Ankara, Turkeythe Nation's most important memorial and museum. Inside The Atat€ urk and Independence War Museum, there is a special corner for Aziz Sancar's Nobel medal, diploma, and the story of his scientific journey along with the 20th century history of science in Turkey to inspire the present and future generations (Fig. 4): "Atat€ urk and the Turkish Republic revolutionized education in Turkey by opening schools throughout the country including remote areas like Savur and appointed very idealist teachers who provided first-rate primary and secondary education. Atat€ urk and the Republic also modernized higher education, free to all citizens. Aziz Sancar is the product of those visionary educational reforms. Indeed, Aziz thinks that the Nobel Prize in Chemistry 2015 is not to himself but to Atat€ urk and the Republic, both providing him with an outstanding education and self-confidence that have enabled him to do the research on DNA Repair that benefits all mankind." Looking into the Future: Fact I Medical genetics in Turkey should be viewed in the context of the rich migration history of the Middle East, the Balkans, and the Mediterranean basin. The region is home to approximately 10% of the world's population today and has been a central hub of human migration and population admixture. In a study published in the September 2016 issue of Nature Genetics (Scott et al. 2016), the genomic landscape of the region is revealed providing a comprehensive view of genetic variation for enhanced discovery of disease-associated genes and comparisons with global ancestry populations. With the participation of research groups from Algeria, Egypt, France, Morocco, Iran, Iraq, Israel, Jordan, Lebanon, Libya, Pakistan, Qatar, Saudi Arabia, Syria, Tunisia, Turkey, United Arab Emirates, and United States, scientists first collected whole-exome data and compared these with data from 1000 Genomes Project Populations. They detected tight clusters of European and Asian populations, and high levels of divergence among the Middle Eastern regions. While populations from northwest Africa, the Arabian Peninsula, Persia, and Pakistan were found to be the least admixed, Turkish Peninsula and Syrian Desert population data were consistent with higher levels of European admixture.

Looking Into the Future: Fact II
Medical genetics studies since the early 1980s consistently indicated that consanguineous populations such as the ones from the Middle East facilitate Mendelian disease gene identification significantly ( € Ozc ßelik et al. 2010). Highest levels of consanguinity in the world are observed on the southern and eastern rims of the Mediterranean basin, Middle East, Mesopotamia, the Gulf, and the Indian subcontinent to southeast Asia. The reasons for preferring consanguineous marriages lie in historical and contemporary cultural preferences such as maintenance of family structure and property, and financial advantages relating to dowry. Additional factors include better relations with in-laws and the perception that intrafamilial marriages are more stable. Although there are regional differences even among single countries, the overall rate of first cousin marriages are around 25% in the region. When multiple layers of consanguinity originating from endogamy is considered, homozygosity rates increase beyond the predictions that are based on kinship alone, ultimately raising the levels of inbreeding coefficiency. The direct consequence of such a genetic structure is increase in the number of recessive diseases.
Importantly, beginning from the 1980s the genomic resources of the region significantly contributed to the global efforts centered on identification of disease-associated genes. For example, genes associated with neurodevelopmental disorders (ALS2, ATP8A2, FA2H, FGD4, HTRA2, SNAP29, VLDLR, VRK1, WDR81) and rare diseases (ALX1, BBS10, CHST14, DDR2, SLC34A2, TAC3, TACR3) have been identified in Mediterranean and Middle Eastern families. This is coupled with excellent clinical medicine services and functional biobanks funded by regional and EU resources. For example, every major medical school in Turkey has a medical genetics department now. Several referral centers carry out exome sequencing for research and diagnostic purposes.
The exome-wide view of the Mediterranean basin and the Middle East shows that estimated inbreeding coefficients are around 10-to 20-fold higher than those in European, African, and East Asian 1000 Genomes Project populations. This translates to an impressive four-to sevenfold increase in the identification of potential diseasecausing variants for unsolved recessive conditions (Scott et al. 2016; € Ozc ßelik and Onat 2016).

Reverse Phenotyping for Complex Diseases
In the years following the adoption of next-generation sequencing, an extreme degree of allelic, locus, and phenotypic heterogeneity has emerged for commonly observed diseases such as diabetes, extreme forms of obesity, hypertension, or neurodegeneration, making it notoriously difficult to resolve their molecular determinants at the genomic level. A scheme called "reverse phenotyping" offers an opportunity to facilitate the way forward in clinical delivery and informatics in the age of precision medicine ( € Ozc ßelik and Onat 2016). Briefly, it consists of selection of candidate genes, prioritization of candidate variants from a cohort by filtering through prediction programs, phenotyping of individuals with candidate variants, establishment of causality by Mendelian segregation in large consanguineous families, and population screening (Fig. 5).
A successful application of reverse phenotyping recently occurred when the circadian rhythm gene cryptochrome 1 (CRY1) was found mutated in humans with delayed sleep phase disorder (DSPD) (Patke et al. 2017). Sleep disturbances is a common medical problem that affects nearly 10% of the population. Circadian disruption is known to predispose individuals to metabolic, cardiovascular, and psychiatric diseases, and lead to obesity and cancer.
The Future is Now: The Turkish Genome Project During the past decade, Turkey achieved universal health coverage and significant improvements in outcomes and equity, thus transforming the country's health system. This achievement is a good example that with commitment at the political level, middle-income countries can simultaneously improve public health, financial risk protection, and user satisfaction (Atun 2015).
Armed with this experience, Turkey is now in the planning phase of an ambitious genome project that is centered on the identification of inherited gene mutations in rare as well as common diseases and cancer. The Turkish NIH, T € USEB (Health Institutes of Turkey) initiated The Turkish Genome Project, which is planned in two phases: the first targeting 100,000 genomes in the next 3 years, and then reaching to 1,000,000 genomes before the 100th anniversary of the Republic in 2023. A major component of the project will be on complex phenotypes with high heritability index such as obesity, diabetes, cardiovascular, neuropsychiatric, endocrine, and rheumatologic diseases. A parallel-executed component will focus on rare diseases, an area that Turkey has contributed significantly over the years. And yet another major component of the project is on cancer with particular emphasis on familial forms of these diseases.