mini Review article (500 words)

Gene 592 (2016) 239–243

Contents lists available at ScienceDirect

Gene

journal homepage: www.elsevier.com/locate/gene

Review

The Arab genome: Health and wealth

Hatem Zayed College of Health and Sciences, Biomedical Sciences Department, Qatar University, PO Box 2713, Doha, Qatar

E-mail address: [email protected].

http://dx.doi.org/10.1016/j.gene.2016.07.007 0378-1119/© 2016 Published by Elsevier B.V.

a b s t r a c t

a r t i c l e i n f o

Article history: Received 21 June 2016 Accepted 3 July 2016 Available online 5 July 2016

The 22 Arab nations have a unique genetic structure, which reflects both conserved and diverse gene pools due to the prevalent endogamous and consanguineous marriage culture and the long history of admixture among dif- ferent ethnic subcultures descended from the Asian, European, and African continents. Human genome sequenc- ing has enabled large-scale genomic studies of different populations and has become a powerful tool for studying disease predictions and diagnosis. Despite the importance of the Arab genome for better understanding the dy- namics of the human genome, discovering rare genetic variations, and studying early human migration out of Africa, it is poorly represented in human genome databases, such as HapMap and the 1000 Genomes Project. In this review, I demonstrate the significance of sequencing the Arab genome and setting an Arab genome reference(s) for better understanding the molecular pathogenesis of genetic diseases, discovering novel/rare var- iants, and identifying a meaningful genotype-phenotype correlation for complex diseases.

© 2016 Published by Elsevier B.V.

Keywords: Arab countries Human genome sequencing Whole exome sequencing Consanguinity Endogamous marriage Novel genes Novel variants

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 239 2. The Arab world. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 240

2.1. Inbred Arab communities and rare variants discovery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 240 3. The Arab genome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241

3.1. Discovery of novel disease-causing genes and the Arab genome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241 3.2. Arab efforts in genome sequencing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241 3.3. The Arab genome and the “Out of Africa” theory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 242 3.4. Benefits of sequencing the Arab genome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 242

4. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 242 Disclosure declaration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 242 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 242

1. Introduction

The completion of the Human Genome Project (HGP) in April 2003 provided a wealth of information to scientists and clinicians. Subse- quently, the world has witnessed rapid evolution in the field of human genetics and genomics (Lander et al., 2001; Venter et al., 2001). Initially, the focus of the HGP was to catalog the protein- expressing genes, which are now estimated to include approximately 20,000 to 25,000 coding genes (International Human Genome Sequencing Consortium, 2004). However, the hard work of decoding

the function of many genes and their precise genotype-phenotype cor- relation in disease development remains.

From the publication of the first draft of the human genome, there has been fierce competition to develop sequencing technologies that are faster, more efficient and cheaper and to make the price of human genome sequencing more affordable. Thus far, whole genome/exome sequencing has provided outstanding insights into the frequency and incidence of novel variants in the human genome that are associated with disease phenotypes. This information provides opportunities to different populations in the world to be able to map the sequence vari- ants that might be unique to their own individuals and that might be re- sponsible for genetic disorders in their specific populations. For this purpose, the HapMap (human haplotype mapping) Project was

240 H. Zayed / Gene 592 (2016) 239–243

launched in 2002 (International HapMap Consortium, 2003); this pro- ject has identified a considerable number of genetic variants, providing extensive catalogs for genetic variation. The HapMap Project has also served as the basis for genome-wide association studies (GWAS). In particular, the HapMap Project has contributed to the successful map- ping of more than 100 genomic regions that are associated with genetic diseases (International HapMap Consortium, 2003).

As an extension of the HapMap Project, the 1000 Genomes Project was launched in 2008 through international concerted efforts (Buchanan et al., 2012). This project aims to sequence the whole ge- nomes of 1000 unidentified individuals from Europe, America, Africa, and Asia, and will add information to the single-nucleotide polymor- phism (SNP) database already cataloged by the HapMap Project and provide a rich resource for both SNPs and structural variant haplotypes. Although this information will allow researchers to learn more about many genetic variants and genetic diseases, unfortunately, the Arab ge- nome is greatly under-represented in the international efforts of such genomic studies; specifically, it is not included in the HGP, HapMap Pro- ject, or 1000 Genomes Project. There is no doubt that the importance of the Arab genome sequencing is significant and that this genome thus should not be omitted from the diverse collections of genomes that have already been sequenced. Therefore, I am focusing this review on elaborating upon the importance of the Arab genome and the potential contribution of the Arab genome to the genomic sciences.

2. The Arab world

The Arab world includes 22 Arabic-speaking countries (Fig. 1). Ac- cording to the World Bank latest classification for 2015 (http://data. worldbank.org), the Arab countries include high-income countries (HICs) such as Bahrain, Kuwait, Oman, Saudi Arabia, Qatar, and the United Arab Emirates; middle-income countries (MICs) such as Algeria, Egypt, Iraq, Jordan, Lebanon, Libya, Morocco, Palestine, Sudan, Syria, and Tunisia; and low-income countries (LICs) such as Comoros, Djibouti, Mauritania, Somalia, and Yemen. These countries occupy a

Fig. 1. Arabic speaking countries accordi (Source: http://www.arabic-keyboard.o

large area that extends from the Atlantic Ocean in the west to the Arabi- an Sea in the east, and the Arab population is approaching 0.5 billion. This region has been extensively exposed to many successive invaders from Turkey, Rome, and Europe as well as to traders and immigrants, thus contributing to mixing of the ethnic demographics of the popula- tion. However, the HICs, which include countries with the highest Gross Domestic Product (GDP) per capita worldwide (http://data. worldbank.org), spend less than 0.2% of their GDP on scientific develop- ment (Giles, 2006). This phenomenon has led to the immigration of many Arab scientists into the West to look for better opportunities. However, recently, biomedical disease-based research has received spe- cial attention from Arab governments, with the aim of improving the understanding and treatment of common diseases afflicting the Arab population. Various attempts have been made by Saudi Arabia and Qatar in particular to establish a research infrastructure, but the prog- ress has been significantly slow relative to the amount of capital infused into such programs, and the benefits of such investments might take significant time to yield results. In this manuscript I will refer to the “Arab genome” as the genome of the 22 Arab countries.

2.1. Inbred Arab communities and rare variants discovery

There are 955 genetic diseases that have been identified in Arabs, of which 586 (60%) are reported to be recessive diseases (http://www. cags.org.ae). Arabs have one of the highest rates of consanguineous marriage worldwide, reaching up to ~70%, with an extreme prevalence of first-cousin marriage (Tadmouri et al., 2009), These factors, together with the endogamous marriage culture and large family sizes, are re- sponsible for the spread of genetic diseases in Arab countries, with a high prevalence of rare diseases (Teebi and Teebi, 2005). Endogamous marriages approach 100% in many Arab countries, and especially the Gulf States (i.e., Bahrain, Kuwait, Oman, Qatar, Saudi Arabia and the United Arab Emirates). For example, women in Saudi Arabia are prohibited from marrying men other than Arab men from the Gulf countries without special dispensation from the king (http://web.

ng to the latest WHO classification. rg/arabic).

241H. Zayed / Gene 592 (2016) 239–243

archive.org/web/20120614045804/http://travel.state.gov/travel/cis_ pa_tw/tw/tw_931.html), and men must acquire a government permit to marry a foreign woman. This law is applicable to the six Gulf States and is due to deeply entrenched, centuries-old traditions that strongly favor marriage within the same Arab subcultures. In addition, this mar- riage culture is still on the rise; for example, consanguineous marriage rates in Qatar increased from 41.8% to 54.5% in just one generation (Bener and Alali, 2006).

Although a large number of rare variants still have unknown clinical significance because of the limitations of current technologies, which can be attributed to the need of large number of individuals harboring these variants that are largely untested by high-density SNP arrays. Therefore, studying inbred communities such as Arab communities is an ideal scenario to understand the effect of genetic variants on the human genome. In this regard, genetic analysis of the Arab genome is considered to be a goldmine for genomic scientists who are looking for a more discernible correlation between the genotype and the pheno- type of genetic diseases, and particularly complex disorders and rare ge- netic disorders. The inbreeding nature of many Arab communities and the commonness of the conservative marriage culture might predict a wide class of complex disorders, especially if the causative variants are rare and the most identified genetic variants causing the complex dis- eases in humans are partially recessive (Bittles and Black, 2010; Rudan et al., 2003). In this regard, Arabs represent an ideal population for bet- ter understanding the pathogenesis and prognosis of recessive diseases, which are yet to be elucidated. Although the consanguineous, endoga- mous Arab culture seems to predict a conserved pool of genes among Arabs, the structure of the Arab genome became diversified over time, mainly due to admixing of the genome with those of different ethnic groups descended from Africa, Asia, and Europe (Teebi and Teebi, 2005), which provide another opportunity for understanding the dy- namic of the Arab genome and the “out of Africa” migration theory.

3. The Arab genome

Although the Arab region is considered to be a hot spot for medical and clinical genetic studies, (Nat. Genet., 2006) Arabs have been slow to explore their own genome. This reticence might be due to the follow- ing reasons: (1) in most Arab countries, it is not yet affordable to se- quence a genome, even for clinical diagnostic reasons, despite the continual diminishing costs of next-generation sequencing technolo- gies; (2) research is not considered to be a necessity in most Arab coun- tries, mainly due to economic reasons; and (3) there is a dearth of well- trained scientists in genomics. As a consequence, there is a lack of infor- mation related to molecular pathogenesis and poor knowledge of both the genotype-phenotype correlation of genetic diseases and the gene variants that are responsible for the spread of these diseases that are segregating in the Arab genome. This is the case even for the most dev- astating diseases, such as diabetes and cardiovascular disorders, which compromises the level of the health care provided to the Arab popula- tion. Therefore, Arab governments must prioritize seeking the means to understand the complexity and dynamics of the Arab genome, espe- cially in countries that are able to afford the costs of genome sequencing. Consistent with this concept, a genomic revolution has been ignited in the Arabian Peninsula, especially in the Gulf States of Saudi Arabia, Kuwait, and Qatar, as the US Encyclopedia of DNA Elements (ENCODE) project and the Arab genome initiatives, represented by the Saudi Human Genome Project (SHGP) (http://shgp.kacst.edu.sa/site), the Qatar Genome Project (QGP) (Al-Mulla, 2014), and the Kuwaiti Genome Project (KGP) (Thareja et al., 2015), aim to systematically and compre- hensively analyze and catalog the genetic variants and haplotypes that are associated with health and disease. These efforts are expected to help in the identification of novel disease associated gene variants. The initiatives also aim to derive reference genome(s) sequence for dif- ferent subpopulations of different ancestries in Kuwait. Although Arab scientists are a decade late in sequencing the Arab genome, this

sequencing is expected to contribute to knowledge related to migration genome ancestry, genome evolution, genome dynamics, mapping of rare disease-associated variants, and novel disease associated gene discovery.

3.1. Discovery of novel disease-causing genes and the Arab genome

Inbreeding is associated with an increased disease risk based on in- creased homozygosity at many genetic loci (Rudan et al., 2003) and leads to a high probability of shared ancestry between randomly select- ed Arab individuals and longer runs of homozygosity, this is an ideal way to map rare disease susceptibility loci among highly consanguine- ous families in inbred Arab communities. A representative example was provided by Verge et al. (1998), who analyzed an inbred Bedouin Arab community who has a long history of first-cousin marriage, they analyzed a large Arab family of 248 individuals living in Israel that had 19 relatives affected with type 1 diabetes who carried rare predisposing haplotypes to type 1 diabetes that were not found in other families. In- terestingly, the researchers discovered a novel susceptibility locus (IDDM17; MIM#603266) for type 1 diabetes, which was mapped to chromosome 10 (10q25.1). Another example is the identification of a novel locus that was defined by the TMEM107 mutation through se- quencing 25 families with the rare, ciliopathic Meckel-Gruber syndrome (Shaheen et al., 2015), and another study that successfully led to the discovery of six novel candidate genes which found to be associated with embryonic lethality in Saudi Arabian consanguineous families (Shamseldin et al., 2015).

The whole exome sequencing (WES) was also successful to reveal a long list of novel candidate genes among consanguineous Arab families, including, but not limited to, identifying 69 genes which are linked to recessive diseases in 143 multiplex Saudi fami- lies, which was not previously associated with genetic diseases (Alazami et al., 2015). Diagnostic WES has also been able to identify several novel disease-associated genes among 149 probands that be- long to highly consanguineous population in Qatar, with various Mendelian phenotypes but mainly neurocognitive (Yavarna et al., 2015). In a study of 18 consanguineous Arab families with Meckel– Gruber syndrome (MKS), WES revealed a likely pathogenic mutation in three novel candidate MKS disease-causing genes (C5orf42, EVC2, and SEC8) (Shaheen et al., 2013). The ARL6IP6 gene was identified as a novel candidate gene for a syndromic form of CMTC in a Saudi con- sanguineous family (Abumansour et al., 2015). Therefore, the Arab genome carries significant potential in advancing the fields of clinical and medical genetics.

3.2. Arab efforts in genome sequencing

The SHGP is a 5-year project launched in December 2013 that in- volves a partnership between the SHGP and Life Technologies (http:// shgp.kacst.edu.sa/site). The aim of the project is to sequence 100,000 Saudi genomes that represent both normal and disease conditions to identify Saudi-specific genetic variants that are linked to high- incidence genetic diseases in Saudi Arabia, such as diabetes, deafness, cardiovascular disorders, cancer, and neurodegenerative diseases (Abu-Elmagd et al., 2015). The SHGP's specific mission is to establish a genotype-phenotype correlation for genetic disease and to create a foundation for personalized medicine, in which treatment will be devel- oped based on the DNA blueprint of each Saudi individual. This ap- proach will reduce the cost of health care, as the health care expenses related to human genetic disease are greater than $30 billion annually in Saudi Arabia (http://shgp.kacst.edu.sa/site).

A few days after the SHGP announcement, Qatar announced its in- tention to launch the QGP and a plan to sequence the genomes of all Qatari citizens (~300,000) (Al-Mulla, 2014). Similarly to the SHGP, the QGP seeks the future protection of Qatari citizens from the spread of ge- netic diseases due to the deep-entrenched culture of endogamous and

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consanguineous marriage by understanding the genomic make-up of the Qatari population, and integrating the sequencing information into clinical care for Qatari individuals. The data collected from the genome sequencing will be used as a platform for developing customized molec- ular diagnostics approaches to Arabs (Zayed and Ouhtit, 2016), help to create the foundation of personalized medicine in the Arabian Peninsu- la, and are expected to advance prenatal screening, genetic counseling for disease-carrying individuals in Qatar. QGP has already started its pilot phase by sequencing 3000 Qatari citizens (http://www.qatar- tribune.com/viewnews.aspx?d=20151214&cat=nation2&pge=5). Computational analyses aimed to decode the Qatari genome and map the genetic variants which are unique to the Qatari individuals, are sup- ported by generous competitive funding from Qatar Foundation (https://www.qf.org.qa). These sequencing data are kept in electronic medical records which will be an integral part of the Qatari National Health Service.

The KGP is an initiative to determine the genetic diversity of the main ethnic groups that constitute the Kuwaiti population, namely, Saudi Arabians, Bedouins, and Persians, ascribing their origin to dif- ferent regions of the Arabian Peninsula and West Asia (modern Iranians). Thus, this project is the first to report a reference genome resource for the population of Persian ancestry in Kuwait (Thareja et al., 2015).

3.3. The Arab genome and the “Out of Africa” theory

The modern Arab gene pool exhibits a very interesting genetic structure: it has numerous pockets of inbred communities due to the prevalence of consanguineous unions, conserved pools of ge- nomes due to widespread endogamous marriage, and a mixed gene pool due to the history of Arab nations and the admixture of the ge- nomes of different ethnic groups with those of people from Europe, Africa, and Asia. This diversity is important in terms of understand- ing genome evolution and dynamics, answering the “Out of Africa” human migration question, and providing insights into the migra- tion routes of early modern humans from Africa to Eurasia. The pri- mary African origin of all modern human populations is well known, but the routes of human migration out of Africa are still un- certain. One potential route is through Levant. Although the North African background is mainly stemmed from Near East/Arabian Pen- insula, the genomic ancestry of the Arabs of North Africa supports an African genome background due to the historical mixing with sub- Saharan African genome (Henn et al., 2012). Another potential route is to the South, across the Arabian Peninsula, which is a nexus of Asia, Africa, and Europe (Kopp et al., 2014). Interestingly, Fernandes et al. (Fernandes et al., 2012) focused in disentangling be- tween the impact of several waves of migration into Arabian Penin- sula in terms of contribution of African input and provided a proof that Arabian Peninsula could be the first staging post in the spread of modern humans from Africa to the rest of the world.

Interestingly, sequencing of just 13 exomes and 2 full genomes in Kuwait revealed ancestral genomic signature traces stemming from Asia, Europe and Africa (Alsmadi et al., 2014; Alsmadi et al., 2013). Egypt is an Afro-Asian Arab country that shares the Mediterranean Sea with European countries (Fig. 1), and it has been proposed as a potential source of the exodus of the African genome to Eurasia (Pagani et al., 2015) according to geographical, archaeological, and genetic evidence. African genomic components have been mapped (Pagani et al., 2015); however, most of the analyzed Egyptian haplotypes were genetically similar to those of modern non-Africans. The study concluded that Egypt was a potential gateway for the migration of the African genome to the rest of the world. Therefore, comparing the Egyptian genomes with European ones supports the exit route, where Ethiopian genomes compared with Arab genomes addresses southern route of the out-of- Africa migration.

3.4. Benefits of sequencing the Arab genome

Given the frequent spread of genetic diseases in Arab countries, reaching reference genome(s) reflecting the diversity and population structure of Arab countries will serve as an example for other communi- ties with comparable population structures and will have many bene- fits, including, but not limited to, (1) serving as a vital tool for the identification of novel variants; (2) serving as a baseline for further ge- nomic epidemiological studies in Arab nations; (3) serving as a useful foundation for cohort and case-control genetic studies that aim to char- acterize the genetic etiology of genetic diseases; (4) improving genetic counseling for individuals with genetic disorders; (5) serving as a plat- form for future GWAS; (6) advancing translational medicine in the fields of personalized medicine and pharmacogenomics, allowing med- ications to be individualized to Arab patients and Arab responses to drugs to become well understood; (7) allowing the study of inbred Arab communities, and specifically the Bedouin population, thus serv- ing as a valuable tool to facilitate the discovery of rare and novel gene variants and novel genes; this information is very important to better understand the molecular pathology of complex diseases/traits and is expected to shed light on other genetic risk factors related to gene- environment interactions and epistasis as well as many other genetic risk factors with major importance in genetic disease development, and (8) serve as a historical tracing tool for population migration.

The ultimate goal of the Arab genome is to create a database of the DNA variation in the Arab population and to make it available to clini- cians and researchers in Arab countries who seek to increase the power of disease prediction, to understand gene drug interactions, to study the Arab population substructures, to improve understanding of the nature of Arab genetic diversity, and to trace population migration. All of these endeavors will contribute to one major aim, which is to im- prove patients' quality of life by improving overall health care and sav- ing lives. However, translating the outcome of the results of the Arab genome into effective clinical practice is a challenging task that will re- quire concerted efforts by both policymakers and scientists to imple- ment effective strategies in the health care sector and to make funding available to allow such programs to continue.

4. Conclusion

Arabs are an ideal population for genetic studies, with a diverse genet- ic structure, ranging from inbred communities to a diverse gene pool that includes elements from Europe, Asia, and Africa. This feature renders the Arab population a rich source of information that would be of global benefit. This emphasizes the value of a consensus Arab genome reference(s) which will positively impact the future directions of person- alized medicine. Using genomic sequencing technologies, numerous rare variants and novel genes have been identified in Arab families, mainly with consanguineous marriage history. The outcome of the SHGP and QGP are soon to be released, which will pave the way of a future consen- sus Arab genome reference(s). Therefore, there is an urgent need for data sharing, both locally and internationally, which dictates the need for the development of mechanisms and standards to facilitate this sharing.

Disclosure declaration

Hatem Zayed declares no conflict of interest.

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