Mediterranean Founder Mutation Database (MFMD): Taking Advantage from Founder Mutations in Genetics Diagnosis, Genetic Diversity and Migration History of the Mediterranean Population

HUMAN MUTATION

DATABASE IN BRIEF

HUMAN MUTATION Database in Brief #____ (2015) Online

© 2015 WILEY-LISS, INC.

Received 23 April 2015; accepted revised manuscript 26 June 2015.

Mediterranean Founder Mutation Database (MFMD):

Taking Advantage from Founder Mutations in

Genetics Diagnosis, Genetic Diversity and Migration

History of the Mediterranean Population

Hicham Charoute1,2, Amina Bakhchane1, Houda Benrahma1, Lilia Romdhane3, Khalid Gabi1, Hassan Rouba1, Malika Fakiri2, Sonia Abdelhak3, Guy Lenaers4 and Abdelhamid Barakat1,*

1 Laboratoire de Génétique Moléculaire Humaine, Institut Pasteur du Maroc, 1 Place Louis Pasteur, 20360 Casablanca, Morocco; 2 Laboratory of Agri-food and Health, Faculty of Sciences and Techniques, Hassan 1st University, BP 577, 26000, Settat, Morocco; 3 Laboratory of Biomedical Genomics and Oncogenetics LR11IPT05, Institut Pasteur de Tunis, 1002 Tunis, Tunisia; 4 Pôle de Recherche et d’Enseignement en Médecine Mitochondriale (PREMMi), Université d'Angers, CHU Bât IRIS/IBS, Rue des Capucins, 49933 Angers cedex 9, France

*Correspondence to Abdelhamid Barakat, Laboratoire de Génétique Moléculaire Humaine, Département de Recherche Scientifique, Institut Pasteur du Maroc. 1 Place Louis Pasteur, 20360 Casablanca, Morocco. E-mail: [email protected]. Communicated by Alastair F. Brown

ABSTRACT: The Mediterranean basin has been the theater of migration crossroads followed by settlement of several societies and cultures in prehistoric and historical times, with important consequences on genetic and genomic determinisms. Here, we present the Mediterranean Founder Mutation Database (MFMD), established to offer web-based access to founder mutation information in the Mediterranean population. Mutation data were collected from the literature and other online resources and systematically reviewed and assembled into this database. The information provided for each founder mutation includes DNA change, amino-acid change, mutation type and mutation effect, as well as mutation frequency and coalescence time when available. Currently, the database contains 383 founder mutations found in 210 genes related to 219 diseases. We believe that MFMD will help scientists and physicians to design more rapid and less expensive genetic diagnostic tests. Moreover, the coalescence time of founder mutations gives an overview about the migration history of the Mediterranean population. MFMD can be publicly accessed from http://mfmd.pasteur.ma. ©2015 Wiley Periodicals, Inc.

KEY WORDS: Database, Founder Mutation, Mediterranean population, human genetics, mutation screening

INTRODUCTION

The Mediterranean Basin is the region of lands that surround the Mediterranean Sea at the intersection between

three different continents: Africa, Asia and Europe. Since the original diaspora of peoples from the African

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continent (Capelli et al. 2006), its population history witnessed many civilization movements both in prehistorical

and historical times, as it was and still is an important route of transport, trade and interaction. The Neolithic

period is marked by the transition from hunter-gathering to the spread of agriculture, that led to a demographic

transition, by increasing the population growth rate (Bocquet-Appel and Bar-Yosef 2008). In addition, the

Neolithic period is marked by the development of trading between different civilizations and by several migratory

movements. Ancient civilizations were located around the Basin, including, the Phoenician, the Greek, the Roman

and the Arab ones. The Phoenicians used their maritime expertise to become the principal traders in the

Mediterranean Sea, as they spread throughout the Mediterranean basin and establish important colonies and

centers of trade (Zalloua et al. 2008). Indeed, starting from Carthage, the most important Phoenician colony, this

population spread to settle throughout the western Mediterranean regions of the North African coast and the

Iberian Peninsula (Abulafia 2011). The Greeks had multiple colonies along the western Mediterranean and Black

Sea coasts, many of these being in Italy. They contested with the Phoenicians over control of colonies and trading

posts in Sicily and the western Mediterranean (Sacks and Murray 2009). After the Third Punic War between the

Romans and Phoenicians, the Roman Empire became the most powerful force in the Mediterranean region

(Abulafia 2011). Then, in the early part of the middle ages, the Arabs conquered a large region of the

Mediterranean Sea, unifying the Arabian Peninsula with a vast part of the Byzantine Empire, the whole Persian

lands, North Africa and the Iberian Peninsula (Hitti 1948).

All these demographic events, population interactions and migratory movements that occurred along the

Mediterranean Sea, had a crucial impact on the genetic structure of the Mediterranean population, which have

already been studied using Mitochondrial DNA (mtDNA), Y chromosome and Autosomal molecular markers and

sequencing. The population history and diversity have important medical genetic implications (Laberge et al.

2005). In particular populations, many disease-causing mutations can be traced to a founder individual, in whom

the mutation first appeared. Founder effect occurs when a new group is established by a small number of

individuals that are separated from a larger population. The new population represents only a restricted sample of

the genetic variability that was present in the original population (Neuhausen 2000) and further endogamy led to

modifications in DNA variation frequencies. Therefore, founder effects explain the high prevalence of some

disease-causing mutations in a particular population, and haplotype analysis can demonstrate that a common

mutation is due to a founder effect with linkage disequilibrium to the adjacent genetic markers. The size of the

linkage disequilibrium intervals helps to estimate the age of the original mutation spreading into a given

population (Zeegers et al. 2004). Identification of founder mutations in a particular population has been useful for

the improvement of molecular diagnosis and genetic counseling. Screening for few prevalent founder mutations is

quicker and cheaper than testing many rare mutations (Ferla et al. 2007). Moreover, determining founder

mutations and their regional distribution in different ethnic groups can help scientists to study the genetic diversity

and migration history of these populations (Ostrer 2001).

There are a lot of published findings that highlight the importance of founder mutations in medical genetics. For

instance, various ancient founder mutations transmitted across tens or hundreds of generations, tend to migrate

over long distances and spread widely around the Mediterranean Sea. This case is illustrated by the c.35delG

common founder mutation in the GJB2 gene that causes deafness, and appears to have arisen in the Middle East

about 500 generations ago (10000 years) and spread across Europe and around the Mediterranean basin (Van Laer

et al. 2001). Furthermore, several genetic disorders have a wide geographical presence along the Mediterranean

region, with multiple disease-causing founder mutations. This situation is observed for the familial Mediterranean

fever disease; multiple founder mutations affecting the MEFV gene were shared between different Mediterranean

populations. Phylogenetic analyses based on allele frequencies of the most common MEFV founder mutations

(M694V, V726A, M680I, M694I, and E148Q) in 14 Mediterranean populations, suggested three major possible

gene flows between populations (Papadopoulos et al. 2008). The current distribution pattern of MEFV mutations

may be influenced by several historical events: the Byzantine Empire, the Arab conquests, the Ottoman

dominance, the dispersal of the Armenian nation and the Jewish Diaspora (Papadopoulos et al. 2008). Screening

frequent founder mutations in a particular population as the first step in molecular genetic diagnosis is a cost-

effective methodology before considering alternative approaches such as Next Generation Sequencing (Ponti et al.

2015).

In this paper, we describe the Mediterranean Founder Mutation Database (MFMD), a comprehensive online

database established to collect and document human founder mutations reported in the Mediterranean population.

We believe that this is the first database for founder mutations in the Mediterranean region. The database will help

Mediterranean Founder Mutation Database e3

scientists and physicians in having an overview about the spectrum of founder mutations found in the

Mediterranean population, and will be beneficial to understand the history, demography and migration flows of the

Mediterranean populations. Furthermore, MFMD provides useful information for the diagnosis and prevention of

genetic diseases. The MFMD can be publicly accessed from http://mfmd.pasteur.ma.

METHODS

Software design and implementation

The MFMD was implemented using a three-tier model (client, application server and database). The web

interface was designed following the Model-View-Controller (MVC) design pattern, and developed using HTML

(HyperText Markup Language), CSS (Cascading Style Sheets) and Javascript programming languages. The PHP

(version 5.4) scripting language was used for all data retrieval and output. The data were managed with MySQL

(version 5.5) database management system. The PHPlot 6.1.0 tool (http://phplot.sourceforge.net/) was used to

generate graphs in the statistics page of the MFMD web interface. The R statistical programming language was

used to draw Bar charts and to perform Heatmap Analysis.

Literature search and data extraction

We conducted a literature search using the PubMed database for articles, published before March, 1st 2015. The

search strategy to identify all relevant studies was based on a combination of the following keywords: (“founder”

OR “common”) AND (“effect” OR “mutation” OR “allele” OR “variation” OR “variant” OR “loci” OR “locus”

OR “haplotype” OR “microsatellite” OR “polymorphism”), without any restriction on language. In addition, to

determine articles conducted in subjects of Mediterranean origin, we used a list of Mediterranean country names to

filter out non relevant studies. Remaining abstracts were downloaded in XML-format from PubMed and stored in

the database. Data were extracted from abstracts by independent reviewers and validated by the database editor in

chief. Genes, diseases and mutations were identified and highlighted in abstracts using the PubTator text mining

tool, to facilitate data extraction. Eligible studies were selected if they were conducted in subjects of Mediterranean

origin, and reported a founder mutation. We collected both founder mutations proved by haplotype analysis and

mutations with suggested founder effect. Moreover, we also checked all references cited in the identified articles

for any additional literature. The following data were extracted from the eligible studies: publication information,

subject information (population of origin, geographical region and ethnic group) and mutation information (DNA

change, amino acid change, prevalence of mutation among affected individuals and coalescence time) (Figure 1A).

The Mutalyzer 2.0.6 software (Wildeman et al. 2008) was used to check mutation nomenclature according to the

HGVS recommendations. Gene symbol follows the HUGO gene nomenclature (Gray et al. 2014). Genetic diseases

registered in the database have been classified using the World Health Organization (WHO) International

Statistical Classification of Diseases and Related Health Problems 10th Revision (ICD-10) Version 2010

(http://apps.who.int/classifications/icd10/browse/2010/en).

The current version of the database registered founder mutation data from the following Mediterranean

countries: Albania, Algeria, Bosnia and Herzegovina, Croatia, Cyprus, Egypt, France, Greece, Israel, Italy,

Lebanon, Libya, Malta, Monaco, Morocco, Palestine, Slovenia, Spain, Syria, Tunisia and Turkey. All patients are

classified according to their population of origin before emigration.

e4 Charoute et al.

RESULTS

Data included in the database

The flowchart of the study selection is shown in Figure 1B. The literature search yielded 1397 publications. A

total of 1006 studies did not meet the inclusion criteria and were rejected based on the title, abstract or the full text

screening. Three hundred and eighty-one studies met the inclusion criteria and were included in the database.

Moreover, 28 additional articles were obtained from reviewing references from the eligible studies. Finally, a total

of 419 studies were included in the database. These relevant articles dated from 1989 to 2015 and the distribution

of number of articles per year showed an increasing trend (Figure 2).

Figure 1. Database curation steps and data extraction form literature. (A) Workflow for the retrieval of articles and

extraction of founder mutation information from literature. (B) Flowchart of study identification, inclusion, and

exclusion.

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Figure 2. The distribution of papers included in the database by year of publication.

The MFMD web interface organization and functionality

The web interface allows several query options to search mutation data cataloged in the MFMD database. To

retrieve the corresponding information of the founder mutation of interest, the website provides two ways to query

the database (Figure 3). Users can use the search box to explore the content of the database by keywords related to

disease name, gene symbol, OMIM ID and patient origin. In addition, the single letter search option arranges

diseases and genes in alphabetical order. Clicking on any letter will provide all available diseases and genes

starting with this letter. When the user selects a disease or gene of interest from the search result, the related

mutation data will be displayed. For each mutation, a summary of information is provided including DNA change,

protein change, location, reference sequence ID, mutation type and effect. In addition, mutation frequency among

affected individuals and mutation coalescence time are provided when available. The gene record includes: gene

symbol, gene full name and chromosome location. For each disease entry, details such as phenotype name, disease

classification according to the World Health Organization International Classification of Disease (WHO-ICD) and

the mode of inheritance are provided. Moreover, links to online resources are available to get further detailed

information about a specific disease or gene, including OMIM, Orphanet, Genetic testing registry, ClinicalTrials,

Genome Browser, Ensembl, UniProt GeneCards, Kyoto Encyclopedia, BioGPS, HGNC and HPRD.

e6 Charoute et al.

Figure 3. The home page of the MFMD website.

Characteristics of disease and gene data

A total of 219 Mendelian diseases are registered in MFMD. Data analysis reveals that 67.1% of all the inherited

diseases follow autosomal recessive mode of inheritance, while autosomal dominant transmission represents

21.9% of all cases. In addition, 2.3% are X-linked and 8.7% of genetic diseases have multiple modes of

transmission (Figure 4A). According to the WHO-ICD-10 disease classification, the main disease categories in the

database include endocrine, nutritional and metabolic diseases (26.5%), followed by nervous system diseases

(20.5%) and congenital malformations and chromosomal abnormalities (17.4%). Diseases of blood and immune

mechanism (11%), neoplasms (7.3%), diseases of the eye and adnexa (5.5%) are also prevalent (Figure 4B).

Mediterranean Founder Mutation Database e7

Figure 4. Summary statistics about genetic diseases registered in the database. (A) Distribution of genetic diseases

according to the mode of inheritance. (B) Classification of genetic diseases using the WHO ICD-10 system.

Comparison of founder mutation spectrum between Mediterranean populations

At the time of its first online release, the MFMD database contained 383 founder mutations. At present, the

disease with the highest number of founder mutations is Breast-ovarian cancer, with 21 mutations in the BRCA1

gene and 13 mutations in the BRCA2 gene, the majority of them being found in Spanish, Italian and Greek

populations. Founder mutations are also prevalent in Ataxia-telangiectasia disease, with 15 out of 18 mutations in

the ATM gene reported in the Italian population. The 35delG mutation in GJB2 gene is the most common

mutation, detected in 8 Mediterranean countries from Europe (Greece, Italy and Spain), Asia (Lebanon and

Turkey), and Africa (Egypt, Morocco and Tunisia). More than one founder mutation is responsible for the Beta

thalassemia in the Mediterranean population. The most recurrent mutation c.118C>T (also known as Codon 39,

C>T) in HBB gene has been reported in 3 populations. Five founder mutations responsible for Familial

Mediterranean fever widely spread around the Mediterranean Sea, were described in 4 populations (Egypt,

Lebanon, Syria and Tunisia). On the other hand, current data showed that 270 mutations were reported in only one

population.

We clustered Mediterranean populations, using the number of shared mutations as a linkage criterion which

indicates the similarity between populations. The results are presented as a heatmap in Figure 5. Each colored cell

of the Heat Map indicates the number of founder mutations shared between two countries, and the diagonal cells

show the total number of mutations in a particular country. Current data indicate the presence of more than 117

founder mutations in the Italian population, which represents 30.55 % of all mutations included in the database.

Italy is followed by Tunisia, Spain and Morocco with 89, 71 and 54 mutations, respectively. Based on the resulting

pair wise comparisons between populations, we can define three clusters: the first is composed of 3 Arab

populations, including Egypt, Lebanon and Syria. The second is mainly composed of European populations

e8 Charoute et al.

(Albania, Bosnia-Herzegovina, Croatia, Cyprus and Greece, Malta, Monaco and Slovenia) and contains a small

number of founder mutations. The third group was composed of 4 European populations (France, Italy, Spain and

Turkey) and 3 North African populations (Algeria, Morocco and Tunisia).

Figure 5. Heat Map and clustering of Mediterranean countries according to the number of shared founder

mutations.

Coalescence times of several founder mutations have been determined in Mediterranean populations; they are

shown in Figure 6 together with the gene symbol and population in which the mutation occurred. There are 60

mutations in the database with known age, their coalescence time ranging from 30000 to 100 years ago. The three

Mediterranean Founder Mutation Database e9

oldest mutations were found in the MEFV gene with the following coalescence time: 30000, 23000 and 15000

years ago. The most recent founder effect was reported in the ACVRL1 gene and occurred 100 years ago.

Figure 6. Timing of founder mutations in Mediterranean populations.

DISCUSSION

The Mediterranean basin has been the point of intersection between several civilizations, and religions that

influenced each other (Abulafia 2011), thus providing an exceptional context to examine the impact of

demographic events and migration on the actual genetic landscape. The study of the genetic structure of

Mediterranean populations using Y-chromosome microsatellites (Quintana-Murci et al. 2003) and mtDNA

variations (Plaza et al. 2003), revealed a low genetic structure between the northern and southern shores of the

Mediterranean sea. In addition, Y-chromosome analysis failed to find any significant barrier to genetic exchange

between populations from the eastern part of the Mediterranean (Manni et al. 2002). On the basis of X-

chromosome polymorphisms, high overall genetic population homogeneity was found in the Mediterranean area,

except in north-west African populations (Morocco) (Tomas et al. 2008). In the western part of the Mediterranean

area, the Strait of Gibraltar has been suggested by several studies as a geographic barrier to gene flow between

north-west Africa and the Iberian Peninsula (Tomas et al. 2008)(Ennafaa et al. 2009). The Mediterranean Sea

might also act as a partial barrier to gene flow between the northern and southern shores (Athanasiadis et al. 2010).

On the other hand, the Arab region played an important role in shaping the current genetic structure of the

Mediterranean population. It was an important area for human population interactions and movements, as well as

an interesting bridge for gene flow between Africa, Asia, and Europe (Tadmouri et al. 2014).

MFMD is a carefully curated database extracted from the literature for all described founder mutations reported

in the Mediterranean population, providing detailed information for each one. A user-friendly web interface was

e10 Charoute et al.

designed to provide a flexible access to the database content. MFMD could be a useful resource for research

purposes in medical and population genetics studies on the Mediterranean population.

More than 30% of founder mutations registered in the database were reported in the Italian population; several

of them have been found in Sardinia and Sicily islands. Due to geographical and cultural barriers to gene flow,

some populations can be considered as genetic isolates which lack significant genetic sub-structures such as

Sardinian (Pardo et al. 2012; Di Gaetano et al. 2014) and Sicilian populations (Rickards et al. 1998; Sarno et al.

2014). The Italian Peninsula hosted various human migration events and cultural exchanges, due to its central

geographical location in the Mediterranean basin. Furthermore, numerous ethno-linguistic minorities inhabit Italy

and represent 5% of the total population (Capocasa et al. 2014). Consequently, the combination of linguistic and

geographic factors may have influenced the genetic isolation of Italian populations (Capocasa et al. 2014) in

combination with endogamy and genetic drift phenomena.

The database registered 60 mutations with known coalescence time, 24 older than 2000 years ago, and 36

mutations more recent. We observed that 13 out of 24 old mutations were reported in more than two populations;

in contrast only 6 out of 36 recent mutations were reported in different populations. Thus, we can hypothesize that

founder mutations reported in only one population, which is the case of 270 mutations, can be due to recent

founder effects.

The Heat Map constructed based on the number of shared mutations between Mediterranean populations,

revealed three main groups (labelled as Group 1, Group 2 and Group 3). The number of founder mutations

reported in populations belonging to Group 1 and Group 2 was relatively low. Both groups were mainly composed

of Eastern Mediterranean countries, for which insufficient amount of molecular data on genetic diseases has been

published. The interest for human genetics research in this part of the Mediterranean region is relatively recent and

there remains a clear need for more investments to build capacities in medical genetics. In contrast, remarkable

efforts in exploring the molecular bases of genetic disorders in western Mediterranean countries forming Group 3,

has led to a wide characterization of disease-causing mutations. Clinicians and researchers from North Africa

(Morocco, Tunisia and Algeria) benefit from collaboration with northern Mediterranean partners to bridge the gap

in healthcare infrastructures and to overcome the lack of molecular genetic technologies. The Heat Map showed

that western Mediterranean populations (Morocco, Algeria, Tunisia, France, Italy and Spain) hold the majority of

founder mutations and have several shared founder mutations. In particular, North African populations (Morocco,

Algeria and Tunisia) shared 15 founder mutations. This is in agreement with the analysis of mitochondrial DNA

(mtDNA) sequences performed in Western Mediterranean populations that showed multidirectional gene flow in

this region (Plaza et al. 2003). Moreover, recent migration events from North Africa have a significant contribution

to the genetic diversity in the southern European region, consequently North African disease risk alleles should be

taken in consideration when developing molecular diagnostic tests for genetic disorders in European populations

(Botigué et al. 2013).

Differences in the prevalence of many diseases and mutations have been observed in different populations and

ethnic groups, as a result of founder effects (Neuhausen 2000). For example, more than 30 inherited diseases are

more prevalent in the Finland than in other populations (Polvi et al. 2013). On the other hand, many mutations in

MFMD database are unique to a specific ethnicity, such as Jewish groups. Thus, patient ancestry can be used as a

criterion for diagnosis (Ostrer 2001).

To date, the database contains 219 genetic diseases; the majority of them follow an autosomal recessive mode

of inheritance (67.1%). The high rate of consanguinity in this region and especially in Arab countries may

contribute to this observation (Tadmouri et al. 2009). The disease classification reveals that the majority of

diseases in MFMD belong to three categories: endocrine, nutritional and metabolic diseases (26%),

neurodegenerative diseases (21%) and congenital malformations and chromosomal abnormalities (17%).

Similarly, endocrine and metabolic diseases are also prevalent in Morocco; they represent 24% of all genetic

disorders reported in the Moroccan Genetics Disease Database (MGDD), then followed by congenital

malformations and chromosomal abnormalities (22%) and nervous system diseases (19%) (Charoute et al. 2014).

In contrast, the classification of genetics disease registered in the “Catalogue of Transmission Genetics in Arabs"

(CTGA) database, showed that congenital malformations and chromosomal abnormalities are the most prevalent

category of genetic disorders in the Arab population (the United Arab Emirates, Bahrain, Oman and Qatar). They

represent 34% of all recorded diseases, followed by endocrine and metabolic disorders (19%) and nervous system

disorders (11%) (Tadmouri 2012). Moreover, the classification of genetic diseases reported in Tunisia is in

accordance with the data observed in the Arab population. Congenital malformations and chromosomal

Mediterranean Founder Mutation Database e11

abnormalities constitute 30% of all genetic disorders found in the Tunisian population, followed by endocrine and

metabolic disorders (19%) and nervous system disorders (11%) (Romdhane et al. 2011). Differences in the

classification of genetic disorders may be explained by the fact that genetic disorders are not equally distributed in

the Arab region, where some genetic diseases are presents in many countries, whereas almost half of diseases were

reported only in a single population (Tadmouri et al. 2014). In addition, the majority of MFMD data were collected

from European countries (Italy, France and Spain), consequently the heterogeneity between populations registered

in both databases (MFMD and CTGA) may be responsible for these differences in the classification diseases.

Founder mutation data were collected from 419 articles, the distribution of these studies against time shows an

increasing trend. The number of founder mutations discovered in the Mediterranean population is expected to keep

increasing in the coming years, due to the use of next-generation sequencing technology. In this respect,

identification of founder mutations facilitates the development of efficient molecular diagnostic assays. Testing

prevalent founder mutations would be cheaper and quicker than screening for various rare mutations. In addition,

the number of carriers of a given founder mutation, allows scientists to perform penetrance analyses of this

mutation among populations (Neuhausen 2000; Zeegers et al. 2004; Ferla et al. 2007; Romdhane et al. 2012).

In conclusion, we developed an online database of founder mutations in the Mediterranean population. It

provides relevant information to the research community, through a user-friendly interface. All efforts have been

made to construct a comprehensive database by conducting an exhaustive search for relevant studies reporting

founder mutations. However, the current version of the MFMD database might miss some mutation data. To

ensure the collection of the complete set of founder mutation data in the Mediterranean population, we will

develop new research strategies including more biomedical literature databases and text-mining tools. We will

continue collecting new founder mutation data from published literature, to keep MFMD updated. In addition, the

database supports new data submission from public users, using an online submission form. The MFMD database

will be beneficial to the improvement of disease diagnosis and better understanding the gene flow in the

Mediterranean population.

ACKNOWLEDGMENTS

This work was supported by Pasteur Institute of Morocco (IPM) and a collaborative project between the French

National Institute of Health and Medical Research (INSERM) and the Moroccan National Centre for Scientific and

Technical Research (CNRST).

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