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VOL - University of Vermont Libraries InfoTrac OneFile Plus Human Biology, Oct 2005 v77 i5 p619(19) The Basques: review of population genetics and Mendelian disorders. Frederic Bauduer; Josue Feingold; Didier Lacombe. Author's Abstract: COPYRIGHT 2005 Wayne State University Press The Basques live at the western end of the Pyrenees along the Atlantic Ocean and are thought to represent the descendants of a pre-neolithic people. They demonstrate marked specificities regarding language and genetics among the European populations. We review the published data on the population genetics and Mendelian disorders of the Basques. An atypical distribution in some blood group polymorphisms (ABO, Rhesus, and Duffy) was first found in this population. Subsequently, additional characteristics have been described with regard to proteins (enzymes and immunoglobulins) and the HLA system. The advent of molecular biology methods in the 1990s allowed further insights into Basque population genetics based mainly on Y-chromosome and mitochondrial DNA. In addition, the Basques demonstrate peculiarities regarding the distribution of various inherited diseases (i.e., unusual frequencies or founding effects). Taken together, these data support the idea of an ancient and still relatively unmixed population subjected to genetic drift. KEY WORDS: BASQUES, MITOCHONDRIAL DNA HAPLOGROUPS, Y-CHROMOSOME HAPLOTYPES, FACTOR XI DEFICIENCY, BLOOD GROUPS, FACTOR V LEIDEN, INHERITED DISEASES, ABO BLOOD GROUPS, RH, KELL, DUFFY, HLA, DF508 ([DELTA] F508), CYSTIC FIBROSIS, THROMBOSIS, HEREDITARY HEMOCHROMATOSIS. Full Text: COPYRIGHT 2005 Wayne State University Press The Basques The present-day Basque population (about 3 million people) is located on both sides of the western Pyrenees. The corresponding area is divided into seven provinces, four in Spain (Guipuzcoa, Biscay, Alava, and Navarre) (Hegoalde) and three in the French departement known as Pyrenees-Atlantiques (Labourd, Basse-Navarre, and Soule) (Iparralde) (Figure 1). Toponymic data would suggest a larger territory occupied by the ancient Basques, stretching from the Garonne River in the north to the Ebro River in the south. The Basque language (Euskara) is agglutinative and of non-indo-european origin. It is described as an file:///f /Human Genetics/Papers/Bauduer et al.htm (1 of 24)9/6/2006 4:31:38 PM

isolate with no living relatives (Ruhlen 1991) and is currently spoken by about 25% of the population. The language is not homogeneous and can be divided into several dialects, as described more than 140 years ago (Bonaparte 1863). On the basis of historical and toponymic sources, Euskara may be a relict from ancient times that has played an important role in maintaining a high degree of genetic isolation (Collins 1986; Cavalli-Sforza 1988). In the Basque area much archeological data (such as cave paintings) support the view of human occupation during the Paleolithic age (de la Rua 1990). Analyses of the classical markers (protein and immunologic polymorphisms) have supported the Basques' distinctive and ancient origin within the European human groups. As discussed later in this review, there are now various genetic arguments for considering the Basques as the most homogeneous relict population of the pre-neolithic inhabitants of Europe (Lucotte and Hazout 1996; Torroni et al. 1998; Semino et al. 2000; Richards et al. 2000; Torroni et al. 2001; Chikhi et al. 2002). The results of a principal-components analysis are in favor of a local differentiation of this people within their present-day territory at about the last glacial maximum, that is, 18,000 years ago (Calafell and Bertranpetit 1994). The Pyreneo-Cantabric zone could have constituted a "refuge" during the last glacial maximum for a population subsequently subjected to the expansion and recolonization process of Europe (Straus 1991). This theory is in agreement with studies on mitochondrial DNA (Torroni et al. 1998, 2001). The Neolithic period, corresponding to the introduction of agriculture, appeared about 5,000 years later in the western Pyrenean zone than in other European regions (Ammerman and Cavalli-Sforza 1984). This phenomenon took place more as a cultural diffusion process than as a demic expansion (Arias 1991). Similarly, records of cattle domestication before the Iron Age are rare (Piazza et al. 1988). The low population density in the hunter-gatherer societies accounts for the major role of genetic drift in the proto-basque population (Bertranpetit and Cavalli-Sforza 1991). For instance, the Sardinians [an isolated Mediterranean population of pre-neolithic individualization (Cavalli-Sforza et al. 1994)] have also conserved a high proportion of "Paleolithic" genes, but major differences exist between Sardinians and Basques because of genetic drift (Chikhi et al. 2002). Similarly, physical anthropology supports the persistence in the modern Basques of some ancient characteristics related to upper Paleolithic morphology (Cro-Magnon type) (de la Rua 1990), in contrast to changes observed from the Neolithic to the present day in other areas of the Iberian peninsula (Bertranpetit and Cavalli-Sforza 1991). Because of its cultural uniqueness, the Basque population seems to have conserved a significant level of endogamy through the ages. The region was relatively protected from incomers by the Pyrenees but, more important, by cultural factors (language, ancient food economy, and customs). Contacts with the Celts and Iberians have been scarce (Ammerman and Cavalli-Sforza 1984; Piazza et al. 1988). Limited signs of Roman occupation are encountered within the Basque area (except in Navarre and Alava) in contrast to neighboring zones. Thus the genetic structure of the Basque population did not receive any significant new contribution until the beginning of the 20th century, with the influx of migrants from various neighboring regions (Collins 1986; Cavalli-Sforza et al. 1994). Basques can be easily differentiated from Spanish and French with respect to genetic distances (Nei and Roychoudhury 1982; Piazza et al. 1988). Overall, the main points explaining the genetic file:///f /Human Genetics/Papers/Bauduer et al.htm (2 of 24)9/6/2006 4:31:38 PM

differentiation of Basques are (1) an initial population of limited size, (2) reduced genetic admixture (Cavalli-Sforza 1988), and (3) length of time. All these characteristics optimize the role of drift. However, the Basques do not constitute a single population regarding many genetic markers. The determinants explaining this relative heterogeneity remain a subject of debate. The first hypothesis is to consider that the Basque population is composed of genetically differentiated subentities according to geographic structure (valleys, river basins, coastal versus inland populations), dialectal zones, or social organization with some degree of isolation (Aguirre et al. 1991; Iriondo et al. 2003). Some data have underlined the role of the main travel routes, the watershed, the ancient tribal distribution, and dialectal subdivisions. One can also hypothesize that this spatial genetic pattern could reflect different degrees of admixture with surrounding populations in relation to cultural or linguistic barriers to random mating (Calderon et al. 1998; Perez-Miranda et al. 2003). This view is supported by a study demonstrating parallelism between genetic distances and distribution of the Basque language among the subpopulations from Spain (Calderon et al. 1998). Interestingly, the HLA-DQA1*02 allele shows its highest frequency in two zones exhibiting a limited level of admixture, Guipuzcoa and northern Navarre (Perez-Miranda et al. 2003). Overall, this genetic heterogeneity could be the consequence of a gradual differentiation in subentities from a founding population (Calderon et al. 2000). file:///f /Human Genetics/Papers/Bauduer et al.htm (3 of 24)9/6/2006 4:31:38 PM

The main point to address in this kind of review is the mode of selection of individuals as autochthonous Basques in the various studies found in the literature. In most of the recent papers the most common criterion was a two-generation ancestry (i.e., four grandparents of Basque origin). However, in older publications only the place of residence was sometimes considered. Obviously, such an important methodological issue must be taken into account when interpreting data. Analyses of several genetic markers, which are discussed in this review, place the Basques as outliers in Europe. Analyses from Classical Markers Before the Molecular Genetics Era Blood Groups. An overview of the distribution of blood groups in the Basques is given in Table 1. The high frequency of ABO blood group O and the quasi-absence of blood group B in the Basques came to light in the 1930s in a study performed on 229 individuals from the region of San Sebastian (Guipuzcoa) (Boyd and Boyd 1937). The same features were subsequently described in the French Basques and, to a lesser extent, in the adjacent regions of the "Aquitaine perimeter" (Vallois 1944). Interestingly, a parallel was noted between toponymy (place names of pre-indo-european origin) and the isogenic curve of 0.70 ABO*O allele frequency (Cavalli-Sforza et al. 1994). Blood group O could have been advantageous for resistance to infectious challenges thought to be prevalent during the pre- Neolithic period, such as bacterial or parasitic intestinal infections, because of the synthesis of both anti-a and anti-b antibodies (Mourant et al. 1978). The frequency of blood group B (thought to originate in Asia) is among the lowest in the world (2-3%) (Moulinier 1949; Levine et al. 1977). A high frequency of Rh-negative Basques was found in a pivotal study of Basque emigrants in Argentina at the end of World War II (35.6% of Rh-negative subjects; allele frequency 0.59) (Etcheverry 1945). This finding was confirmed later, albeit with less significant values and heterogeneity according to province and selection criteria with respect to the choice of autochthonous subjects. Hence Rh allele d frequency seems to vary between 0.45 (French Basques) (Nijenhuis 1956) and 0.54 (Chalmers et al. 1949). For the scholars of the 1950s the Basques showed the highest Rhnegative frequency in the world (Etcheverry 1945; Mourant 1947; Chalmers et al. 1949). It was once thought that the modern Basques were the remnants of a proto-european population that was mostly or entirely Rh-negative, in contrast to later Rh-positive migration waves (Mourant 1947). In any respect, the Basques represent one of the rare populations on earth in which the frequency of gene d (Rh-negative) is superior to that of gene D (Rh-positive). Furthermore, gene E is uncommon. The high frequencies of blood group O and Rh cde may represent the genetic characteristics of the Europeans from the Paleolithics (Cavalli-Sforza et al. 1994) and have been described to a lesser extent in neighboring areas (Bernard and Ruffie 1976). Besides the ABO and Rh groups, the Duffy (FY) and Kell (K) systems have peculiar frequencies in the Basques. Fy (a) and K+ have the lowest prevalence among all European peoples (Levine et al. file:///f /Human Genetics/Papers/Bauduer et al.htm (4 of 24)9/6/2006 4:31:38 PM

1977). The heterogeneity of distribution of FY*A among Basque provinces is also to be noted (Bauduer, Touinssi et al. 2004), as is the case for other biological markers (Aguirre et al. 1991; Manzano et al. 1996, 2002). The highest FY*A prevalence was described in a district of Guipuzcoa (0.40) (Manzano et al. 2002), and the lowest prevalence of FY*A was described in Biscay (0.27) (Iturrioz et al. 1983). Red Blood Cell Enzymes and Plasma Proteins. Analyses of red blood cell enzymes and plasma proteins place the Basques in a unique position among the neighboring populations (Aguirre et al. 1989). For instance, regarding esterase D (ESD) polymorphisms established by isoelectric focusing, the lowest European values of allele ESD*5 have been observed in Biscay and Guipuzcoa. On the other hand, Alava demonstrated some less "pure" Basque characteristics that were in accordance with archeological and historical data (Manzano et al. 1993). HLA System. HLA analysis greatly contributed to the development of population genetics at the end of the 20th century. Detailed data on the Basque HLA profile, which are not within the scope of this paper, will not be reviewed here; only papers relevant for Basque population genetics are briefly presented. HLA class I loci have been more intensively studied than class II genes and/or microsatellites (Pena et al. 2002). HLA-A1-B8, one of the most frequent HLA-class I profiles in Europeans, is also commonly observed in the Basques (Comas et al. 1998b). Considering seven class I and II loci (A, B, C, DRB1, DQA1, DPA1, and DPB1) typed by molecular methods, the most frequent haplotypes observed in the Basques are A*29-Cw*1601, B*44-DRB1*0701, DQA1*0201- DPA1*0103, and DPB1*0401. This profile resembles that of Catalans living at the eastern end of the Pyrenees and appears to lie within the genetic European variation (Comas et al. 1998b). Conversely, no close relationship has been observed with North African populations (Comas et al. 1998b; Perez- Miranda et al. 2003), as previously suggested on the basis of serological assays (Arnaiz-Villena et al. 1997). The distinction between Basques and the neighboring populations of France and Spain seems to be clear-cut when considering the HLA-A1 and HLA-B35 loci. Similarly, differences between Spanish and French Basques are noted especially for HLA-A28, HLA-A29, HLA-A30, and HLA-A31 and for HLA-B17 and HLA-B18 (Calderon et al. 1993). However, there is evidence of a significant degree of homogeneity within the various Basque subpopulations (Comas et al. 1998a). The distributions of D6S105, D6S125, and TNFa, three microsatellite DNA markers from the HLA region, seem markedly different in the Basques compared to other European populations, especially regarding the TNFA*1 allele (Pena et al. 2002). Similarly, analysis of HLA-DPA1 and HLA-DPB1 loci on samples from file:///f /Human Genetics/Papers/Bauduer et al.htm (5 of 24)9/6/2006 4:31:38 PM

northern Navarre and Guipuzcoa revealed a high degree of similarity between these two Basque groups, contrasting with their marked genetic distance from the remaining European populations (Perez-Miranda et al. 2004). Drift, gene flow, and/or natural selection probably are the main forces at the origin of this peculiar HLA profile. Y Chromosome. The nonrecombining portion of the Y chromosome represents a polymorphic system inherited from father to son and is an interesting model for population genetics. A DNA polymorphism specific to the Y chromosome (haplotype XV, p49/taqi) is extremely prevalent in the Basques (72,2%) compared to other Western European populations (mean value, 41%), whereas the haplotypes originating from Southern Europe or the Middle East (haplotypes XII, VII, and VIII) are quasi-absent. This profile supports the hypothesis of an ancient European population (haplotype XV is ancestral) having had little contact with Neolithic migrants (Lucotte and Hazout 1996). Furthermore, a study of haplotype p49a, f/taqi has shown that this peculiar genetic position among the Europeans is correlated with linguistic data (isolation from the Indo-European family) (Poloni et al. 1997). Table 2 presents an overview of the Y-chromosome markers in the Basques. The Y-chromosome haplogroups of the Basques and Celtic populations of the British Isles (Welsh and Irish) share striking similarities, especially haplotype 1.15 (Atlantic modal haplotype; see Table 2) (Wilson et al. 2001). This fact is more likely explained by the relatively low Neolithic component in these two populations (Wilson et al. 2001) than by common ancestors, as previously thought (Cavalli-Sforza et al. 1994). Compared to the other European populations, the Basques have the highest frequency of haplotype M173 (a marker that dates back 30,000 years, that is, to the upper Paleolithic). Haplotype M173, which probably originated in Central Asia, marks the Aurignacian settlement in Europe about 30,000 years ago or, less precisely, before the last glacial maximum (Semino et al. 2000). In addition, the extreme frequency of haplotype M173 in the Basques and to a lesser extent in the British Isles is probably enhanced by genetic drift that occurred within the context of a small population size (bottleneck effect) during the last glacial maximum (Wells et al. 2001). Analysis of 22 binary markers from the nonrecombining region of the Y chromosome in 17 European countries indicates that present-day Basques are an unbiased representation of pre-neolithic huntergatherer populations (Chikhi et al. 2002). The distribution of other Y-chromosome haplotypes suggests an ancient origin for the Basque population and limited genetic exchanges with Neolithic migrants (Lucotte and Hazout 1996). The worldwide distribution of the T/C transition at SRY-2627 (haplotype 22) has been studied. Haplotype 22 is rare or absent except in populations of Iberian origin. The Basques and the Catalans, who belong to different linguistic families, demonstrate the highest haplotype 22 prevalence. Moreover, there is evidence of possible gene flow through male individuals between these two peoples during the past few thousand years (Hurles et al. 1999). Interestingly, this resemblance is not found when mitochondrial DNA (Corte Real 1996) or HLA (Comas et al. 1998b) profiles are compared. The high predominance of the DYS19*11 allele and the file:///f /Human Genetics/Papers/Bauduer et al.htm (6 of 24)9/6/2006 4:31:38 PM

absence of the Y-Alu insertion found in the Basques compared to various populations from Europe, northern Africa, and western Asia constitute interesting markers for a better understanding of the peopling of Europe (Calderon 2003). Mitochondrial DNA. The control region of the mitochondrial DNA (mtdna) is interesting to study, given its high mutation rate, maternal inheritance, and lack of recombination. A sample analysis of mtdna from all of Europe showed that the Neolithic fraction is the lowest in the Basques (7%; European range, 9-21%) (Richards et al. 2000). Hence Basque individualization is thought to have occurred during the Mesolithic or earlier, during the upper Paleolithic (Solutrean). Haplogroup V, an autochthonous European haplogroup, has been shown to have originated from the current Basque area about 10,000-15,000 years ago (see Table 2). Its prevalence in modern Basques is one of the highest in Europe (Torroni et al. 2001). Haplogroup H, which originated in the Near East about 25,000-30,000 years ago and expanded into Europe before the last glacial maximum, reaches its highest frequency among the Basques (Torroni et al. 1998). On the basis of mtdna, there is no genetic proximity between Celts and Basques, as shown by Y- chromosome analyses, and the Celtic populations are situated among other European peoples. This suggests a genetic flow in the Neolithic populations by means of Celtic women, whereas the Basques did not mix with the migrants from the east (Wilson et al. 2001). Analysis of hypervariable segment I (positions 16024-16383) showed that among the populations compared, the Basques have the lowest average pairwise difference between individuals (see Table 2). That study also reported the in situ differentiation of the Basques from a low number of original upper Paleolithic founding settlers (Bertranpetit et al. 1995), as previously proposed (Rogers and Harpending 1992). The expansion of this population is dated from 14,500 to 42,000 years ago and was probably associated with the last glacial maximum, 18,000 years ago, in view of the resources of the region (Straus 1991). Paleoanthropological studies conducted on mtdna from prehistoric dental samples also argue in favor of this Paleolithic expansion model (Izagirre and de la Rua 1999). Other Chromosomal Markers. World frequencies of haplotypes within a polymorphic region close to the MX1 gene of chromosome 21 show that, together with the peoples of sub-saharan Africa, the Basques share the highest proportion of the haplotype Ht1, which is becoming extinct and is thought to represent the original human haplotype (Jin et al. 1999) (see Table 2). Recently, a large study assessed the distribution of 6 microsatellite polymorphisms in 797 autochthonous individuals from 17 districts of the 4 Spanish Basque provinces. It seems that since the last glacial maximum, the population has settled in three major groups (west, central, and east Basques), perhaps reflecting the distribution of ancient tribes and dialects and the influence of rivers. This settlement pattern represents a new map of Spanish Basque heterogeneity and further underlines the role of genetic drift within this people and the low degree of gene mixing with allochthonous populations (Iriondo et al. 2003). file:///f /Human Genetics/Papers/Bauduer et al.htm (7 of 24)9/6/2006 4:31:38 PM

Similarly, the lack of homogeneity within the Spanish Basque region has been demonstrated by studying six autosomal polymorphic Alu loci (de Pancorbo et al. 2001). According to the distribution file:///f /Human Genetics/Papers/Bauduer et al.htm (8 of 24)9/6/2006 4:31:38 PM

of the autosomal minisatellite MS205, the Basques seem to cluster with other Northern European populations. However, a significant proportion of apparently Basque-specific alleles can be dated back to the post-aurignacian period. This finding supports a certain level of continuity of this population since the Upper Paleolithic (Alonso and Armour 1998), a fact more likely explained by a certain degree of isolation than by drift. The distribution of GM and KM immunoglobulin allotypes has been tested in samples from the seven Basque provinces (Calderon et al. 1998, 2000). Inherited Disorders An overview of inherited disorders among the Basques is presented in Table 3. Coagulation Deficiencies. Factor XI deficiency is an autosomal recessive disorder conferring a variable increased risk of injury- or surgery-related bleeding. It represents a rare condition in the general population (about 1 case in 1 million), except for Ashkenazi Jews, in whom two peculiar mutations predominate (Seligsohn 1993). Factor XI deficiency is about 200 times more prevalent in the French Basques than in non-ashkenazi European populations (Bauduer, Ducout et al. 2004). After the Jews and the Arabs, the Basques constitute the third largest population in the world presenting with an ancestral mutation causing severe factor XI deficiency. This Cys38Arg substitution does not appear to generate any significant hemorrhagic tendency (Zivelin et al. 2002). The mutation has not been dated, and its pattern of distribution within the different provinces is still unknown and to our knowledge has not been described among any other populations so far. Overall, the prevalence of autosomal recessive factor deficiencies seems increased in the Basque population, because it is generally pointed out in endogamous human groups (Bauduer, Ducout et al. 2004). It is likely that other, still unknown founding mutations are implicated in some of these cases. Prothrombotic Genetic Polymorphisms. Until now, activated protein C resistance has been the most frequently encountered genetic abnormality in patients with venous thrombosis (20-30% of cases) (Dahlback et al. 1993). In more than 90% of cases the condition is due to a single mutation (G1691A) in the factor V gene: factor V Leiden (Bertina et al. 1994). The transmission is autosomal dominant (1q21) and is found in up to 50% of familial thromboses among Europeans (Bertina et al. 1994). The relative risk for thrombosis is about 5 to 10 for heterozygotes and 50 to 100 for homozygotes (Rosendaal et al. 1995). Factor V Leiden is highly frequent in Europeans but variable according to geographic distribution [allele frequencies range from 1.4% (Italy) to 7% (Greece)]; conversely, factor V Leiden seems absent among sub-saharan Africans, East Asians, the indigenous peoples of the Americas and Australasia (Rees 1996), and Inuit Eskimos (De Maat et al. 1996). A possible evolutionary advantage in relation to improved hemoglobin status and reduced blood loss has been hypothesized for female carriers (Lindqvist et al. 2001). file:///f /Human Genetics/Papers/Bauduer et al.htm (9 of 24)9/6/2006 4:31:38 PM

Several studies have shown that factor V Leiden is almost absent in the Basques (Rees 1996; Lucotte and Mercier 1997; Zabalegui et al. 1998; Soria et al. 2001; Bauduer, Zivelin et al. 2004), who thus constitute the "European exception" regarding this mutation. The distribution of prothrombin G20210A and methylene tetrahydrofolate reductase (MTHFR) C677T, representing other populationdependent genetic prothrombotic factors, is unremarkable in the Basques compared to neighboring European countries (Soria et al. 2001; Bauduer, Zivelin et al. 2004). Hereditary Hemochromatosis. Hereditary hemochromatosis (HH) (HFE-related or type 1 genetic hemochromatosis) is an autosomal recessive disorder characterized by a progressive iron overload that induces tissue deterioration, especially in the liver, pancreas, or heart. Cirrhosis, diabetes mellitus, cardiac failure, polyarthropathy, endocrinopathies, and skin pigmentation are the main possible clinical manifestations. Two main missense mutations, C282Y and H63D, are found in the majority of HH patients. These mutations impair the normal role of HFE protein in the duodenal cells, consisting in the uptake modulation of transferrin-bound iron according to the level of body iron stores (Bacon et al. 1999). Interestingly, the frequency of these mutations varies significantly among populations, and HH is more common in subjects of Celtic or Northern European descent (Lucotte 1998; Bacon et al. 1999). The C282Y mutation is estimated to have occurred during the past 2,000 years (Rochette et al. 1999), about 60 (Ajioka et al. 1997; Thomas et al. 1998) to 100 (Lonjou et al. 1998) generations ago, according to haplotype analyses. Conversely, the H63D mutation is considered older and is not limited to Europe (Rochette et al. 1999). HH seems rarer in the Basques than in other European populations (Bauduer et al. 2001). In addition, the percentage of C282Y homozygosity is significantly lower in Basque patients with HH than in the majority of patients with other European origins (Bauduer et al. 2005), a finding common to both French and Spanish Basques (de Juan et al. 2001; Bauduer et al. 2005). The highest European prevalence of the H63D allele has been described in the Basques (Merryweather-Clarke et al. 1997; de Juan et al. 2001; Bauduer et al. 2005). Of note, the clinical significance of the H63D polymorphism remains less clear (Merryweather-Clarke et al. 1997; Bacon et al. 1999). The high H63D allele frequency in Basques contrasts with the low prevalence of symptomatic HH seen in this people (Bauduer et al. 2001), as already noted in other populations (Merryweather-Clarke et al. 1997). Hence the severe HH phenotype is exceptional in Basque patients (Bauduer et al. 2001, 2005). Given the ancient origin, limited population, and marked endogamy of the Basque people, one may hypothesize that the high prevalence of the H63D polymorphism results from genetic drift. However, the HFE gene has probably been involved in the process of selection pressure, and HH-related mutations could represent balanced polymorphisms regarding infectious diseases, environmental conditions, or other genetic disorders (Rochette et al. 1999). For instance, HH could have been advantageous for protecting women from anemia induced by menstruation or pregnancy (Thomas et al. 1998). The low frequency of the C282Y polymorphism among Basques could be correlated to the Basques' file:///f /Human Genetics/Papers/Bauduer et al.htm (10 of 24)9/6/2006 4:31:38 PM

late conversion to agriculture [about 5,000 years after the beginning of this revolution in the Middle East (Ammerman and Cavalli-Sforza 1984)] and therefore to the maintenance of the hunter-gatherer diet, which includes a high content of meat, the most important nutritional source of absorbable iron (Eaton and Konner 1985). This could explain the absence of selective pressure regarding iron deficiency in the Basques. S65C, an additional HFE mutation (Mura et al. 1999), appears as relatively frequent in a sample of Spanish Basques (de Juan et al. 2001), but it has not been largely investigated in French Basques. Furthermore, if one accepts the hypothesis postulating a Celtic origin for C282Y HH (Lucotte 1998), the Basque profile supports the idea of a limited admixture with this ethnic group. No significant degree of genetic heterogeneity has been described among the Basque subpopulations for HH. To our knowledge, there are no data concerning the distribution among the Basques of the more recently described polymorphisms implicated in genetic hemochromatosis. Neurological and Muscular Diseases. A new nonsyndromic X-chromosome-linked mental retardation locus (MRX82) has been mapped to chromosome Xq24-q25 in a Basque family (Martinez et al. 2004). A Spanish-English collaborative study found novel mutations segregating with PARK8, the common genetic cause of familial Parkinson disease. Some of the explored families were of Basque descent, and the mutated protein was named dardarin, the Basque term for tremor (Paisan-Ruiz et al. 2004). A large pedigree with autosomal dominant lateral temporal epilepsy linked to the 10q region has been described in the Guipuzcoa province (Poza et al. 1999). An association between dopamine D3 receptor gene polymorphisms (excess of allele 7685-C) and schizophrenia has been observed in a human isolate from Navarre (Staddon et al. 2005). The frequency of the JT mtdna haplogroup seems lower in Basque multiple sclerosis patients than in patients from other Spanish regions. That fact could indicate a protective effect from optic neuritis, which is one of the major manifestations of multiple sclerosis (Otaegui et al. 2004). A very high prevalence of carriers of the myotonic dystrophy gene (26.5 cases per 100,000) was reported in 1993 in Guipuzcoa province (Lopez de Munain et al. 1993). Such a peculiar distribution, probably related to genetic drift, has also been found in Quebec (Mathieu et al. 1990). More recently, limb-girdle muscular dystrophy type 2A, a rare autosomal recessive disorder, has been described with the highest prevalence rate described so far (69 per 1 million) in Guipuzcoa. Most of these cases are due to a single calpain-3 gene file:///f /Human Genetics/Papers/Bauduer et al.htm (11 of 24)9/6/2006 4:31:38 PM

mutation (exon 22, 2362AG [right arrow] TCATCT) and could be related to a founder effect. Interestingly, this mutation has been found in North America, Brazil, and Reunion Island (a French possession in the Indian Ocean), where it could have moved by Basque migration (Urtasun et al. 1998). Mutation [DELTA]F508 of the Cystic Fibrosis Gene. Cystic fibrosis, which is related to numerous mutations (more than 1,000) within the cystic transmembrane conductance regulator (CFTR) gene (7q31.2), is the most frequent severe recessive disease in Caucasians (1 in 2,500 affected newborns). The main mutation, [DELTA]F508, demonstrates its highest European frequency in the Basques: 87% (Casals et al. 1992), similar to the frequency in Denmark (Estivill et al. 1997). This percentage is significantly different from that of neighboring Southern European peoples, especially the Spanish (50%), where the fraction of the other mutations is high (Casals et al. 1992). The lack of genetic heterogeneity and the quasi-exclusive presence of [DELTA]F508 in the Basques may be due to the genetic isolation of this people, thus obviating the appearance of the other mutations brought with the waves of immigrants to Europe. The reason for this is unclear, although the increased protection against some bacteria-related digestive tract infections conferred by heterozygosity is the most likely reason (balanced polymorphism). Nevertheless, data from haplotype analysis suggest that the [DELTA]F508 mutation was present in Europe during the Paleolithic period (Casals et al. 1992) and appeared more than 52,000 years ago (Morral et al. 1994). This latter finding contradicts previous results, which propose an age of about 3,000 to 6,000 years (Serre et al. 1990). [DELTA]F508 was diluted (not disseminated) in Europe by Neolithic migrants. Interestingly, the incidence of cystic fibrosis in the Basque provinces is not markedly high (1 in 4,500 newborns) (Casals et al. 1992). Other Inherited Disease-Related Peculiarities. Besides HLA-B*27, HLA-A*2402 and the microsatellite D6S248 are additional independent susceptibility markers to ankylosing spondylitis in file:///f /Human Genetics/Papers/Bauduer et al.htm (12 of 24)9/6/2006 4:31:38 PM

Basque patients (de Juan et al. 2004). Celiac disease is not associated here with the classical CTLA4 gene (Martin-Pagola et al. 2003). The maximum genetic susceptibility to type 1 diabetes mellitus in Basques is conferred by the extended HLA haplotype F1C30-DR3-DQ2-DPB1*0202 (Ramon-Bilbao et al. 2002). The [DELTA]CCR5 mutation, which protects against HIV-1 in Caucasian populations and which has a single and recent (about 3,500 years B.P.) origin in northeastern Europe, has one of its lowest frequency in the Basques (Libert et al. 1998). Preliminary investigations have suggested that Spanish Basques are less prone to develop fragile X syndrome, given the stability of the FMR1 gene (lower frequency of large alleles) (Arrieta et al. 1999). However, the same team has recently analyzed the CGG repeats within this gene using a different sample and have found that the prevalence of potentially unstable alleles is comparable to that of other European populations (Penagarikano et al. 2004). Conclusion The Basques constitute a peculiar genetic group among the European peoples. Most of the data argue in favor of their pre-neolithic individualization in their present-day area, the major influence of drift on an initially small population, their contribution to the gene pool of modern Central and Northern Europeans, and the relative absence of mixing with the different human groups who migrated to Southern and Western Europe through the ages. Hence the genetic study of the Basques contributes to improving our knowledge about the settlement of Europe. To reconstruct the history of the Basque population, one must compare genetic data with archeological, historical, linguistic, physical anthropological, and demographic findings. However, the Basque population should probably not be considered genetically as a whole because it demonstrates a significant degree of heterogeneity. It is tempting to speculate about possible interactions between genetic characteristics and cultural traits, that is, considering the role of language as a barrier to admixture (Calderon et al. 1998; Perez-Miranda et al. 2003) or the parallelism between some genetic polymorphisms and dialects or ancient tribe distribution (Iriondo et al. 2003). Thus the Basques could constitute a paradigm with respect to interrelation between genes, culture, and language. The genetic profile of the Basques is also interesting to study in terms of public health. In particular, they demonstrate a favorable antithrombotic genetic profile, including the absence of factor V Leiden, increased factor XI deficiency, and elevated prevalence of blood group O. However, it is not yet clear whether these biological characteristics are associated with a decreased thrombotic tendency. Acknowledgments This study was sponsored by the association Sang 64. Received 31 March 2005; revision received 15 July 2005. file:///f /Human Genetics/Papers/Bauduer et al.htm (13 of 24)9/6/2006 4:31:38 PM

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