North African-Mediterranean HLA genetic contribution in a population of the kidney transplant waiting list patients of Canary origin (Gran Canaria).

The peopling of the Canary Islands has been widely debated. The mitochondrial DNA and Y-chromosome data support the idea of a Berber genetic origin coming from the North of Africa (maternal) and a later contribution of the Spanish invaders (paternal). The frequencies of the HLA class II alleles from the Tenerife Island (another Canary Island) have previously been published, postulating a Berber and Atlantic/Iberian contributions to the current population. The HLA class I and class II allele frequencies, haplotype frequencies and phylogenetic comparisons were performed in 215 unrelated individuals from Gran Canaria Island (belonging to the kidney transplant waiting list), with at least three generations of ancestors from Canary Islands, in order to study the different ethnical HLA contributions to the genetic background of the Canary Islanders. Results showed the presence of a compound HLA haplotype of putative Phoenician-Berber origin, A*33:01-C*08:02-B*14:02-DRB1*03:01-DQB1*02:01, likely coming from the combination of haplotypes A*30:02-C*05:01-B*18:01-DRB1*03:01-DQB1*02:01 and A*33:01-C*08:02-B*14:02-DRB1*01:02-DQB1*05:01 of North African (probably Berber) and West Asian Mediterranean (probably Phoenician) origins, respectively. The latter haplotypes and others from the same origin (Berber/Phoenician) are also present in the population studied. Besides, other contributions from the North of Europe, North England-Iberian (Atlantic contribution), and Western Europe/Mediterraneans (Spanish colonization) are also discussed. These data conclude that the current genetic background of the Canary Islands inhabitants has been generated over the years by different ways with an original Phoenician-Berber substrate and several genetic contributions generated in different invasions.

Description of the novel HLA-DQB1*02:02:01:02 allele in a Spanish individual.

HLA-DQB1*02:02:01:02 has an intron sequences coming from a combination of DQB1*02:01:01 and DQB1*02:02:01:01.

Description of the novel HLA-DQB1*02:02:01:02 allele in a Spanish individual.

HLA-DQB1*02:02:01:02 has an intron sequences coming from a combination of DQB1*02:01:01 and DQB1*02:02:01:01.

Identification of the novel HLA-DQB1*03:03:02:04 allele in a Spanish individual.

HLA-DQB1*03:03:02:04 and DQB1*03:03:02:02 alleles differ by a single point mutation in intron 2.

Different patterns of A*80:01:01:01 allele generation based on exon or intron sequences.

Generation of the HLA-A*80:01:01:01 allele has been analysed using its complete sequence. Direct comparison of the sequences and phylogenetic trees using the human leukocyte antigen (HLA)-A representative alleles and the major histocompatibility complex (MHC)-A sequences of non-human primates has been made. Results based on exon sequences confirm previously published, but considering only the sequences of the introns, two distinct regions can be differentiated. The first one comprises from the 5' untranslated region region to the first part of intron 3 sequence (shared with A2 family), and the second one includes the sequence from the end of intron 3 to intron 7 (shared with A1/A3/A11/A36/A30 family). Each of them clusters with Gorilla and Chimpanzee MHC-A sequences, respectively, suggesting an origin coming from a common ancestor to Gorilla and Chimpanzee.

Promoter sequences confirm the three different evolutionary lineages described for HLA-G.

HLA-G alleles follow a different pattern of polymorphism generation that those of the HLA classical I alleles. However, this polymorphism maintenance could have an evolutionary specific pathways based on non coding regions as introns, 14 bp deletion/insertion (exon 8) or promoter regions. For this reason, a systematic sequencing study of HLA-G promoter region was done in 36 individuals with a total of 15 different alleles. From the 12 sequences obtained, 7 were new sequences and not previously described. Results show that the sequences have three different patterns of evolution confirming the results obtained in the rest of the sequence regions (exons, introns and 3'UTR) where three different lineages were established. Only one of these lineages includes the non-human primate promoter sequences suggesting the possibility of this lineage could come directly from non-human primates while the other two could be generated after the speciation. More non-human primates MHC-G promoter sequences must be obtained to confirm this hypothesis. Expression and functional assays could be done considering the differences obtained in the promoter regions involving the HLA-G function (mRNA expression, isoforms).

The novel HLA-G*01:03:01:02 allele differs from G*01:03:01:01 by a possible inversion event in intron 3.

HLA-G*01:03:01:02 and G*01:03:01:01 differ by a two nucleotide changes in intron 3.

The HLA-B*83:01 allele is generated by a gene conversion event including whole of exon 2 and partial introns 1 and 2 between B*44 and B*56 alleles.

Several studies have indicated the gene conversion as the most important mechanism about the MHC polymorphism generation when intron sequences are studied. The data obtained confirm that the B*83:01 allele is generated by gene conversion event including exon 2 and partial intron 1 and 2 between B*44 and B*56 alleles.

HLA in Jaidukama: an Amerindian secluded Colombian population with new haplotypes and Asian and Pacific-shared alleles.

America first inhabitants and peopling are still debated. In order to increase knowledge about these questions, we have aimed to detect HLA genes of an Amerindian secluded community: Jaidukama, who lives in North Colombia Equatorial forest. HLA genotyping and extended haplotype calculations were carried out in 39 healthy individuals belonging to 13 families. HLA frequencies were compared to other Amerindians and worldwide populations by calculating genetic distances, relatedness dendrograms and correspondence analyses. Only four DRB1 alleles were found (*0404, *0407, *1402 and *1602); however a total of 17 Amerindian different extended class I-class II HLA haplotypes were directly counted from the family studies, nine of them were specific of Jaidukamas. Some of the alleles or group of alleles within an extended haplotype (i.e. DQB1-DRB1) were also found in Asians and Pacific Islanders, further supporting existence of Asian and Pacific gene flow with Amerindians or a common founder effect. It is further supported that HLA extended haplotypes vary faster than alleles in populations. It is concluded that this unique model of Amerindian secluded families study suggests that rapid HLA haplotype variation may be more important than allele variation for survival (starting immune responses). This work may also be useful for future transplant programs in the area.

A new allele, HLA-G*010120, is generated by a recombination event between HLA-G*01010101/02 and HLA-G*01010201.

Recombination between HLA-G*01010101/02 and HLA-G*01010201 generates HLA-G*010120.

The novel HLA-G*01010302 allele differs from G*01010301 by a single nucleotide change in intron 5.

HLA-G*01010301 and G*01010302 differ by a single point mutation in intron 5.

A new allele, HLA-G*01010106, with changes in intron 2.

Three nucleotide changes and one insertion in intron 2 upon human leucocyte antigen (HLA)-G*01010105 generate HLA-G*01010106.

HLA-E polymorphism in Amerindians from Mexico (Mazatecans), Colombia (Wayu) and Chile (Mapuches): evolution of MHC-E gene.

Human leukocyte antigen (HLA)-E is a nonclassical class I (Ib) gene with a restricted polymorphism. Only eight DNA alleles and three proteins of this gene have been described and their frequencies analyzed in Caucasian, Oriental, Asian Indian, and Negroid populations. In the present study, HLA-E polymorphism has been analyzed in six Amerindian and Mestizo populations from North and South America and compared with previously described populations. HLA-E*0101 is the most frequent allele found in all populations except in Afrocolombian and Wayu Amerindians, in which blood group analyses show a high admixture with Caucasian and African populations. Mazatecan and Mapuche (two Amerindian groups from North and South America, respectively) presented similar HLA-E frequencies, whereas Wayu Indians are more similar to the Afrocolombian population. The Mexican and Colombian Mestizo show similar allele frequencies to Amerindians with high frequencies of HLA-E*0101 and HLA-E*010302 alleles. Also, frequencies in Negroids and Asian Indians present a similar distribution of HLA-E alleles. These data are in agreement with worldwide restricted polymorphism of HLA-E because no new allele was detected in the six populations studied. The allelic frequencies show differences among Caucasian, Oriental, Mestizo and Indian populations. Ape major histocompatibility complex-E allelism is also very restricted: common chimpanzee (one allele); bonobo (two alleles); gorilla (two alleles); orangutan (one allele); rhesus monkey (eight alleles); cynomolgus monkey (two alleles); and green monkey (two alleles).

HLA-G polymorphism and evolution.

Six proteins, one null allele and 22 human leukocyte antigen (HLA)-G alleles were found in humans. Bonobo, chimpanzee and gorilla only show one allele and orangutan shows five alleles. All Cercopithecus alleles show stop codons at position 164 (Macaca mulatta with seven DNA alleles, Macaca fascicularis with seven DNA alleles and Cercopithecus aethiops with three DNA alleles). Cotton-top tamarin New World monkeys showed 20 DNA and protein alleles; the major histocompatibility complex (MHC)-G New World sequences seem to be closer to MHC-E and lack typical MHC-G primates intron 2-specific deletion. This seems to suggest that MHC-G genes in New World primates are not orthologous and that their function may be similar to that of classical presenting MHC genes.

Generation of the B*41 group of alleles as indicated by intron sequences.

The generation of the B*41 alleles has been analysed using exon 1, intron 1, exon 2, intron 2 and exon 3 sequences. Results showed that B*4102 may have been generated as the first B*41 allele by a recombination mechanism between B*400102 and B*0801 or B*4201 involving intron 2. B*4101, B*4104 and B*4107 alleles could have been generated from B*4102 by a gene conversion event taking three different fragments from sequences belonging to intron 2/exon 3 of B*45, B*50 or B*49 alleles. B*4105 and B*4106 could be generated from B*4101 allele by point mutations, and B*4103 generation is unclear due to the lack of intron 2. The importance of introns in HLA-B allele polymorphism generation is stressed.

MHC-F DNA sequences in bonobo, gorilla and orangutan.

The major histocompatibility complex (MHC)-F class Ib locus shows a limited polymorphism, and the function of its mainly intracellular protein is not clear. We have identified human leucocyte antigen (HLA)-F orthologous DNA sequences in Pongidae in order to study the MHC-F gene evolution and its products' function. HLA-F orthologous cDNA transcripts are found in chimpanzee and in the new primate species studied (bonobo, gorilla and orangutan). Analyses of the predicted amino acid sequences and their comparison with other primate MHC-F proteins show that MHC-F may be a protein with a typical class I structure and that the key residues of the peptide-binding region (PBR) are highly conserved in MHC-F in all studied primates species. Thus, MHC-F conservation along the primate evolution suggests an important role in cellular physiology. It is possible that the MHC-F protein could be involved, together with MHC-G and MHC-E, in the natural killer (NK) cell activity regulation, although rhesus macaque does not express MHC-G and MHC-E orthologues. The evolutionary pathway of the six-base-pair deletion at exon 2 existing in some primates is put forward.

Origin of Aymaras from Bolivia and their relationship with other Amerindians according to HLA genes.

Aymara Amerindians from the Titicaca Lake Andean highlands are studied for HLA-A, HLA-B, HLA-DRB1 and HLA-DQB1 gene frequencies. Genetic distances, neighbour-joining and correspondence analyses are performed by using other Amerindian and worldwide populations (15384 chromosomes are studied). The HLA genetic profile of Aymaras is different from neighbouring and language-related Quechuas (Incas). Both Quechuas and Aymaras seem to present an HLA-DRB1*0901 high frequency, which is present in a very low frequency or absent in Mesoamericans (Mazatecans, Mayans) and most studied Amerindians. Moreover, it is observed a closer relatedness of Aymaras with Amerindians from the Amazon Basin and Chaco lowlands, compared to Quechuans.

Origin of Mayans according to HLA genes and the uniqueness of Amerindians.

The HLA allele frequency distribution of the Mayans from Guatemala was studied and compared with those of other First American Natives and worldwide populations (a total of 12,364 chromosomes and 6182 individuals from 60 different populations). The main conclusions were (1): the closest Amerindian group to Mayans is the Arhuacs, who were the first recorded Caribbean Islands' inhabitants (2). Mayans are not so close to Mesoamerican Zapotec, Mixe and Mixtec Amerindians, who genetically cluster together. Mixe had been related to Mayans only on linguistic bases (3). DRB1*0407 and DRB1*0802 alleles are found in 50% of Mayans; these alleles are also found in other Amerindians, but the Mayans' high frequencies may be showing a founder effect for this Mesoamerican-Caribbean population (4). Extended Mayan specific HLA haplotypes are described for the first time (5). Language and genes do not completely correlate in microgeographical studies (6). Significant genetic input from outside is not noticed in Meso and South American Amerindians according to the genetic analyses; while all world populations (including Africans, Europeans, Asians, Australians, Polynesians, North American Na-Dene Indians and Eskimos) are genetically related. Meso and South American Amerindians tend to remain isolated in the neighbour joining analyses.

HLA alleles in isolated populations from North Spain: origin of the Basques and the ancient Iberians.

HLA-A, -B, -DRB1, -DQA1 and -DQB1 alleles have been studied in three relatively isolated populations of northern Spain from Cantabria ( Pas Valleys inhabitants or Pasiegos and Cabuernigos) and from the Basque Country (Arratia Valley inhabitants). These populations have been compared with neighbouring ones and other Mediterraneans by using neighbour-joining dendrograms and plane genetic distances.