Near fixation of 374l allele frequencies of the skin pigmentation gene SLC45A2 in Africa.

The L374F polymorphism of the SLC45A2 gene, encoding the membrane-associated transporter protein that plays an important role in melanin synthesis, has been suggested to be associated with skin color in human populations. In this study, the detailed distribution of the 374f and 374l alleles has been investigated in 2,581 unrelated subjects from 36 North, East, West, and Central African populations. We found once more the highly significant (p < 0.001) correlation coefficient (r = 0.957) cline of 374f frequencies with degrees of latitude in European and North African populations. Almost all the African populations located below 16° of latitude are fixed for the 374l allele. Peul, Toucouleur, and Soninké populations have 374l allele frequencies of 0.06, 0.03, and 0.03, respectively.

A rare variant of the mtDNA HVS1 sequence in the hairs of Napoléon's family.

This paper describes the finding of a rare variant in the sequence of the hypervariable segment (HVS1) of mitochondrial (mtDNA) extracted from two preserved hairs, authenticated as belonging to the French Emperor Napoléon I (Napoléon Bonaparte). This rare variant is a mutation that changes the base C to T at position 16,184 (16184C→T), and it constitutes the only mutation found in this HVS1 sequence. This mutation is rare, because it was not found in a reference database (P < 0.05). In a personal database (M. Pala) comprising 37,000 different sequences, the 16184C→T mutation was found in only three samples, thus in this database the mutation frequency was 0.00008%. This mutation 16184C→T was also the only variant found subsequently in the HVS1 sequences of mtDNAs extracted from Napoléon's mother (Letizia) and from his youngest sister (Caroline), confirming that this mutation is maternally inherited. This 16184C→T variant could be used for genetic verification to authenticate any doubtful material and determine whether it should indeed be attributed to Napoléon.

A decreasing gradient of 374F allele frequencies in the skin pigmentation gene SLC45A2, from the north of West Europe to North Africa.

The 374F mutation in the SLC45A2 gene, encoding the membrane-associated transporter protein (MATP) that plays an important role in melanin synthesis, has been suggested to be associated with skin color in Caucasians. In this study, the detailed distribution of the 374F allele has been investigated in 2063 unrelated subjects from 18 European and three North African populations. The highest allele frequency is observed in Denmark (0.980), and the lowest frequencies are observed in Tunisia (0.610) and in Morocco (0.691). A significant latitudinal cline in 374F allele frequencies was observed, ranging from the north of West Europe to North Africa (r = 0.869). The results confirm that the distribution of the 374F allele may reflect the ultraviolet radiation level and can be associated with skin color variation in these regions.

Molecular basis of complement factor I (CFI) polymorphism: one of two polymorphic suballeles responsible for CFI A is Japanese-specific.

Isoelectric focusing has revealed that human complement factor I (CFI) is controlled by two polymorphic alleles, CFI(*)A and CFI(*)B, and a few rare variant alleles. In this study the molecular basis of the CFI polymorphism was investigated in 174 Japanese. The CFI(*)A was divided into two suballeles, CFI(*)As (R201S) and CFI(*)Ah (R406H). CFI(*)Aj, a rare variant allele originating from CFI(*)Ah, had an additional mutation (R502L). The distribution of these three mutations and two registered SNPs was investigated in a total of 2,471 individuals in 20 populations from various areas, and six haplotypes were observed. Haplotype H3, which is characterized by CFI(*)As, was found only in Far East populations: the frequencies were about 0.03 in the main island of Japan and lower than 0.01 in Okinawa and Korea. Haplotype H5, characterized by CFI(*)Ah, prevailed almost exclusively in East Asians and was observed at the highest frequencies in southern Chinese Han and Thais. CFI(*)Ah must have arisen in a southeastern part of Asia and thereafter have spread to neighboring populations.

Population distribution of the methionine allele at the PRNP codon 129 polymorphism in Europe and the Middle East.

Methionine homozygosity at codon 129 of the prion protein gene is a risk factor for Creutzfeldt-Jakob disease. Knowledge of M129V polymorphism in normal populations may contribute to a better understanding of prion diseases. M129V polymorphism was studied in 2201 normal subjects, originating from 15 populations from Europe and the Middle East. Mean heterozygosity in these populations is 38.9%, and there is some significant geographic heterogeneity between them. A comparison of M129 allele frequencies in these 15 populations to those already published for 8 European countries plus Turkey shows significant correlations with both latitude (r = -0.77) and longitude (r = 0.69). The geographic map of methionine allele frequencies indicates an east-west gradient of decreasing methionine allele values from the Middle East to Western Europe.

Genetic screening of the G2019S mutation of the LRRK2 gene in Southwest European, North African, and Sephardic Jewish subjects.

The G2019S mutation in exon 41 of the leucine-rich repeat kinase 2 (LRRK2) gene accounts for 3-6% of familial dominant Parkinson's disease (PD) and for 1-2% of sporadic PD. It seems that there is a north-south gradient of G2019S frequency in Europe in PD patients, and the frequency of the mutation is up to 41% in North African cases. To obtain a precise estimate of G2019S frequency in populations with relatively elevated incidence of mutation carriers, we have tested for the presence of the G2019S in the south Mediterranean countries. Three thousand one hundred healthy European subjects were compared for the G2019S incidence with 597 healthy Arab subjects originating from five populations in North Africa and with 361 healthy Sephardi Jews from five other populations. The main incidence of G2019S carriers is 1/46 in our sample of North African Arabs, the most elevated carrier incidence (1/30) being found in Moroccan Berbers. An elevated incidence (1/72) is also found in our sample of Sephardi Jews. These results contrast with the ones we found (1/1550) in a sample of 3100 healthy subjects originating from 15 populations of southern Europe. Six microsatellite markers were used in the 20 G2019S carriers we found, to conduct a haplotype analysis. Our finding on the elevated incidence of the G2019S mutation in North African Arabs and in Sephardi Jews, Berbers being the people where the mutation probably originates from, has some important consequences for future genetic diagnosis and counseling for PD in these populations.

OCA2 481Thr, a hypofunctional allele in pigmentation, is characteristic of northeastern Asian populations.

Asians as well as Europeans have light skin, for which no genes to date are known to be responsible. A mutation, Ala481Thr (c.G1559A), in the oculocutaneous albinism type II (OCA2) gene has approximately 70% function of the wild type allele in melanogenesis. In this study, the distribution of the mutation was investigated in a total of 2,615 individuals in 20 populations from various areas. OCA2 481Thr prevailed almost exclusively in a northeastern part of Asia. The allele frequency was highest in Buryat (0.24) in Mongolia and showed a north-south downward geographical gradient. These findings suggest that OCA2 481Thr arose in a region of low ultraviolet radiation and thereafter spread to neighboring populations.

High prevalences of carriers of the 35delG mutation of connexin 26 in the Mediterranean area.

OBJECTIVE: Mutation 35delG in the connexin 26 gene is the main cause of recessive deafness in Europe. The prevalence of carriers varies, with a mean value proportion of 1/31 in Mediterranean countries. The aim of this study is to determinate the percentage of carriers in seven populations of the Mediterranean area and to compare prevalence of the mutation in seventeen other published populations in the same area. METHODS: This study has been carried out on the genomic DNAs out of a total of 886 healthy subjects, originating from Sevilla (Spain), Genoa, Sicily (Italy), Alexandria (Egypt), Libya, Algier (Algeria) and Tangier (Morocco), genotyped by Taqman assay. RESULTS: The approximate proportions of the 35delG mutation are <1/149 in Sevilla, 1/129 in Genoa, 1/34 in Sicily, 1/54 in Alexandria, 1/41 in Libya, 1/141 in Algier and 1/123 in Tangier. When compared to other Mediterranean populations, the mean prevalence of the mutation is 1/49. One of the most elevated values of 35delG prevalence corresponds to Greece (1/28); the pattern of various 35delG prevalences is interpretated in the present meta-analysis as the result of Ancient Greek colonizations of the "Magna Grecia" in historical times.

A functional variant of the dopamine D3 receptor is associated with risk and age-at-onset of essential tremor.

Familial essential tremor (ET), the most common inherited movement disorder, is generally transmitted as an autosomal dominant trait. A genome-wide scan for ET revealed one major locus on chromosome 3q13. Here, we report that the Ser9Gly variant in the dopamine D(3) receptor gene (DRD3), localized on 3q13.3, is associated and cosegregates with familial ET in 23 out of 30 French families. Sequencing revealed no other nonsynonymous variants in the DRD3-coding sequence and in the first 871 bp of the 5' flanking region. Moreover, Gly-9 homozygous patients presented with more severe and/or earlier onset forms of the disease than heterozygotes. A replication study comparing 276 patients with ET and 184 normal controls confirmed the association of the Gly-9 variant with risk and age-at-onset of ET. In human embryonic kidney (HEK) 293-transfected cells, the Gly-9 variant did not differ from the Ser-9 variant with respect to glycosylation and to anterograde and retrograde trafficking, but dopamine had an affinity that was four to five times higher. With the Gly-9 variant, the dopamine-mediated cAMP response was increased, and the mitogen-associated protein kinase (MAPK) signal was prolonged, as compared with the Ser-9 variant. The gain-of-function produced by the Gly-9 variant may explain why drugs active against tremor in Parkinson's disease (PD) are usually not effective in the treatment of ET and suggests that DRD3 partial agonists or antagonists should be considered as novel therapeutic options for patients with ET.

North African Berber and Arab influences in the western Mediterranean revealed by Y-chromosome DNA haplotypes.

We have analyzed Y-chromosome diversity in the western Mediterranean area, examining p49a,f TaqI haplotype V and subhaplotypes Vb (Berber) and Va (Arab). A total of 2,196 unrelated DNA samples, belonging to 22 populations from North Africa and the southern Mediterranean coast of occidental Europe, have been typed. Subhaplotype Vb, predominant in a Berber population of Morocco (63.5%), was also found at high frequencies in southern Portugal (35.9%) and Andalusia (25.4%). The Arab subhaplotype Va, predominant in Algeria (53.9%) and Tunisia (50.6%), was also found at a relatively high frequency in Sicily (23.1%) and Naples (16.4%); its highest frequency in Iberia was in northern Portugal (22.8%) and Andalusia (15.5%). In Iberia there is a gradient of decreasing frequencies in latitude for both subhaplotypes Va and Vb, related to eight centuries of Muslim domination (8th to 15th centuries) in southern Iberia.

Genetic screening for two LRRK2 mutations in French patients with idiopathic Parkinson's disease.

Several pathogenic mutations in the LRRK2 gene have been implicated in familial and sporadic cases of Parkinson's disease (PD). We screened 103 sporadic French PD patients for the presence of the LRRK2 R1441G and G2019S mutations. The R1441G mutation was absent in our PD sporadic cases, but the G2019S mutation was present in 2 of them (1.9%). Clinical features in our 2 patients were not different from classic PD. One of our patients was of Berberian (North Africa) origin. Our 2 patients displayed genetic profiles consistent with the same ancestral haplotype as previously reported for carriers of the LRRK2 G2019S mutation.

Haplotype XV of the Y-chromosome is the main haplotype in West-Europe.

We have analyzed Y-chromosome variation in a large sample of males from Western Europe by surveying p49a,f TaqI polymorphisms. Haplotype XV (A3, Cl, D2, Fl, Il) is the main Y-chromosome haplotype in West Europe, with a Basque focus in Southwestern Europe. This study demonstrates that the geographic distribution of Y-chromosome variation for p49a,f TaqI haplotype XV reveals an important genetic identity for populations that live in the Occidental part of Europe.

Connexin 26 mutation 35delG: prevalence of carriers in various regions in France.

OBJECTIVE: Mutation 35delG in the connexin 26 gene is the main cause of recessive deafness in Europe. The prevalence of carriers varies, with a mean value proportion of 1/30 in Mediterranean countries. The aim of this study is to determinate the percentage of carriers in several regions of the Mediterranean coast in France. METHODS: This study has been carried out on the genomic DNAs out of a total of 1584 healthy subjects, originating from five French towns or regions, genotyped by Taqman assays. RESULTS: the approximate carrier proportions of the 35delG mutation are 1/50 in Perpignan, 1/65 in Montpellier, 1/66 in Toulon, 1/53 in Grasse. This carrier proportion is 1/31 for the region of Marseilles, a value near the maximal value already obtained in France for Corsica.

The 35delG mutation in the connexin 26 gene (GJB2) associated with congenital deafness: European carrier frequencies and evidence for its origin in ancient Greece.

The 35delG mutation in the connexin 26 gene (GJB2) at the DFNB1 locus represents the most common mutation in Caucasian patients with genetic sensorineural deafness. This new meta-analysis concerns published carrier frequencies of the 35delG mutation in 27 populations for 6,628 unrelated individuals in Europe and in the Middle East; the mean carrier frequency of the mutation is 1.9%. Compared on a regional basis, the most elevated carrier frequency value is of 1 individual carrier in 31 in southern Europe. It is probable that the 35delG mutation originated in ancient Greece and was subsequently propagated in other Mediterranean countries (especially in Italy) during recent historical times.

The population distribution of the Met allele at the PRNP129 polymorphism (a high risk factor for Creutzfeldt-Jakob disease) in various regions of France and in West Europe.

The present study has been conducted to ascertain the level of allelic variation at codon 129 of the prion protein gene in France. Six French populations have been studied (Paris, Lille, Rennes, Chambéry, Grasse and Perpignan), totalling 1374 normal subjects. Mean heterozygosity in France is 46.5%, and the mean Met 129 allele (a high risk susceptibility factor for Creutzfeldt-Jakob disease) is 0.674. There is a genetic heterogeneity (chi(2)=38.44, p<0.001) between the six populations compared, and Met allele frequencies are inversely correlated with latitude (r=-0.93, p<0.01). Such an inverse correlation with latitude (r=-0.78, p=0.01) is also found when Met allele frequencies in France are compared to those already published in five other European countries and in Turkey. We hypothesise that high Met 129 frequencies populations may be at higher risk for Creutzfeldt-Jakob disease.

The endogenous retroviral locus ERVWE1 is a bona fide gene involved in hominoid placental physiology.

The definitive demonstration of a role for a recently acquired gene is a difficult task, requiring exhaustive genetic investigations and functional analysis. The situation is indeed much more complicated when facing multicopy gene families, because most or portions of the gene are conserved among the hundred copies of the family. This is the case for the ERVWE1 locus of the human endogenous retrovirus W family (HERV-W), which encodes an envelope glycoprotein (syncytin) likely involved in trophoblast differentiation. Here we describe, in 155 individuals, the positional conservation of this locus and the preservation of the envelope ORF. Sequencing of the critical elements of the ERVWE1 provirus showed a striking conservation among the 48 alleles of 24 individuals, including the LTR elements involved in the transcriptional machinery, the splice sites involved in the maturation of subgenomic Env mRNA, and the Env ORF. The functionality and tissue specificity of the 5' LTR were demonstrated, as well as the fusogenic activity of the envelope polymorphic variants. Such functions were also shown to be preserved in the orthologous loci isolated from chimpanzee, gorilla, orangutan, and gibbon. This functional preservation among humans and during evolution strongly argued for the involvement of this recently acquired retroviral envelope glycoprotein in hominoid placental physiology.

More about the Viking hypothesis of origin of the delta32 mutation in the CCR5 gene conferring resistance to HIV-1 infection.

The chemokine receptor CCR5 constitutes the major coreceptor for the HIV-1, because a mutant allele of the CCR5 gene named delta32 was shown to provide to homozygotes a strong resistance against infection. In the present study the frequency of the delta32 allele was collected in 36 European populations and in Cyprus, and the highest allele frequencies were found in Nordic countries. We constructed an allele map of delta32 frequencies in Europe; the map is in accordance to the Vikings hypothesis of the origin of the mutation and his dissemination during the eighth to the tenth centuries.

Y-chromosome DNA haplotype XI in Eastern Europe.

Haplotype XI frequencies at the Y-chromosome-specific DNA polymorphism (p49-TaqI) were reported in 639 males originating from 13 different geographic locations in Eastern Europe, where haplotype XI represents the major haplotype. The highest frequencies were obtained from Ukraine (44%), Russia (43.9%), and Hungary (40.7%). Percentages of haplotype XI geographic distribution show a gradient of decreasing frequency from these areas of higher percentages toward southeastern and more western countries in Europe.

A European allele map of the C282Y mutation of hemochromatosis: Celtic versus Viking origin of the mutation?

The aim of this new meta-analysis (to the end of 2002) is to compile the Y allele frequencies of the C282Y mutation of hereditary hemochromatosis (HFE gene) for 63 European populations, representing a total of 10,708 unrelated people concerning control samples. A new allele map of C282Y frequencies in Europe was constructed. The highest European frequencies are observed in the Celtic populations in Ireland, in the United Kingdom, and in France, but elevated frequencies are also observed in Scandinavia.