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HLA-G is a class Ib (nonclassical) major histocompatibility complex (MHC) protein expressed at the materno-fetal interface that may inhibit natural killer (NK) cell-mediated lysis in an allotype-independent manner. The human MHC-G transcript is differentially spliced, giving rise to at least six different forms. In order to study the evolutionary importance of this phenomenon, the presence of alternative splicing in MHC-G mRNA molecules from Pongidae (Chimpanzee, Gorilla, and Orangutan) has been investigated in the present work, and three alternative spliced isoforms (i.e.: G1, G2, and G3) have been found, but not the G4 and the soluble G5 and G6 ones. In addition, a novel MHC-G isoform is described in Gorilla, “G2 short.” This molecule is similar to the G2 isoform, but it lacks 29 amino acids normally encoded by exon 4. Our findings suggest that soluble isoforms are not necessary for MHC-G function(s) in Pongidae or that MHC-G is not a functional protein, because G1 is not necessary for survival in humans and Cercopithecinae bear stop codons in MHC-G exon 3.

The HLA allele frequency distribution of the Mexican Mazatecan Indians (Olmec culture) has been studied and compared with those of other First American Natives and worldwide populations (a total of 12,100 chromosomes; 6,050 individuals from 59 different populations). The main conclusions are: 1) An indirect evidence of Olmec and Mayan relatedness is suggested, further supporting the notion that Olmecs may have been the precursors of Mayans; 2) Language and genetics do not completely correlate in microenvironmental studies; and 3) Peopling of the Americas was probably more complex than postulated by Greenberg and others (three peopling waves). Significant genetic input from outside is not noticed in Meso and South American Amerindians according to the phylogenetic 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 Neighbor-Joining, correspondence and plane genetic distance analyses.

The gene profile of Arabic-speaking Moroccans has been compared with those of other Mediterranean populations in order to provide additional information about the history of their origins. Our HLA data suggest that most Moroccans are of a Berber (Imazighen) origin and that Arabs who invaded North Africa and Spain in the 7th century A.D. did not substantially contributed to the gene pool; however, they imposed their advanced culture and their religion. Present-day Egyptians are also related to Moroccan Berbers and this supports an ancient Saharan origin for part of the present-day Mediterraneans, particularly for the Arabic-speaking ones (also Algerians) and also for the older substratum of Mediterranean people.

The Cretan HLA gene profile has been compared with those of other Mediterranean populations in order to provide additional information regarding the history of their origins. The allele frequencies, genetic distances between populations, relatedness dendrograms and correspondence analyses were calculated. Our results indicate that the Indoeuropean Greeks may be considered as a Mediterranean population of a more recent origin (after 2000 B.C.), while all other studied Mediterraneans (including Cretans) belong to an older substratum which was present in the area since pre-Neolithic times. A significant Turkish gene flow has not been detected in the Greek or Cretan populations, although Greeks and Turks have two high frequency HLA-DRB-DQB haplotypes in common. It is proposed that Imazighen (Caucasoid Berbers living at present in the North African coast and Saharan areas) are the remains of pre-Neolithic Saharan populations which could emigrate northwards between about 8000-6000 B.C., when desert desiccation began. They also could be part of the stock that gave rise to Sumerians, Cretans and Iberians; this is supported by both linguistic and HLA genetic data.

The HLA-B locus is the most polymorphic of the class I genes encoded within the human major histocompatibility complex. This polymorphism is mainly located in exons 2 and 3, which code for the molecule's alpha1 and alpha2 domains and includes the antigenic peptide binding site. However, information about adjacent non-coding regions (introns 1 and 2) has not been extensively reported but could be very important in establishing an understanding of the evolutionary mechanisms involved in the polymorphism generation of HLA-B and the Mhc loci. In the present work, introns 1 and 2 of 14 HLA-B alleles are studied and their significance is discussed; 10 have been sequenced in our own laboratory and the other 4 have been previously reported by others. Different serological families share the complete intron 1 sequence; at this region, 12 out of 14 HLA-B alleles could be included in four groups with the same intron 1 sequence: a) B*0702, B*4201, B*4801; b) B*27052, B*4002, B*4011; c) B*40012, B*4101, including B*4501, B*5001 (these latter two alleles have specific characteristics in both introns 1 and 2, which may reflect a common evolutionary pathway); and d) B*44031, B*44032. The other alleles, B*1402, and B*1801, do not have identical intron 1 sequences compared to any of the described groups, but share many similarities with them. The B*1801 evolutionary pathway seems to be very specific since it branches separately from other alleles both in intron 1 and intron 2 dendrograms. On the other hand, HLA-B allelic group distribution and similarities according to intron 1 sequences were not confirmed when using intron 2, especially in the cases of B*4002, B*4101 and B*4801. This would suggest that both point mutations fixed by genetic drift and gene conversion events are involved in HLA-B diversification. The latter events could be supported by the strong homology between intron 1 and, to a lesser extent, intron 2, and also the CG content within them. Finally, the precise knowledge of these non-coding regions could be important for developing DNA base typing strategies for the HLA-B alleles.

MHC-G is a class Ib (non-classical) major histocompatibility complex (MHC) whose functional and evolutionary characteristics are still under scrutiny. The study of noncoding sequences in the MHC genes may provide important phylogenetic information. In this work we have sequenced the MHC-G exon 8, which encodes for the 3′UT region, in different species of primates. It has been shown that: (1) a previously described 14 base pair (bp) deletion polymorphism is human-specific and the HLA-G alleles may be classified according to its absence or presence; (2) another newly described 3 bp deletion/insertion polymorphism is also human-specific; and (3) another newly described 51 bp deletion polymorphism is common to Pongidae and humans, but is not found in other primates belonging to the Cercopithecinae family. A hypothesis on the evolutionary pathway of this gene is put forward in the light of these findings.

The high HLA (Human Leukocyte Antigens) polymorphism has been proven to be useful for singling out individuals and populations. The discovery of new loci and the presently available DNA typing and sequencing of new alleles have dramatically increased the variety of HLA allelism (Tsuji et al. 1992). Certain HLA alleles are frequent only in specific populations (i.e., A36, A43 in African Americans) and the strong linkage disequilibrium between HLA neighboring loci demonstrates that certain combinations of contiguous alleles (HLA haplotypes) show a characteristic frequency or are distinctive in particular living populations (Imanishi et al. 1992a, b; Hors et al. 1997; Piazza et al. 1997). HLA is a unique tool for studying the origins of human groups, as the characteristic HLA allele frequencies of founder populations have not been completely lost with time in certain cases.

Background and Aims: It has been postulated that the HFE C282Y mutation (linked to human leukocyte antigen [HLA]-A3-B7 haplotype) is not only responsible for hereditary hemochromatosis; HLA class I alleles would also contribute to the disease pathogenesis. In addition, H63D mutation linked to HLA-A29-B44 would also be pathogenetic, particularly in the Mediterranean Basin and throughout the world. However, sporadic porphyria cutanea tarda (s-PCT) has also been linked to these HFE mutations. In the present work, we have studied HFE mutations and HLA genes to test these hypotheses. Methods: C282Y and H63D mutations together with HLA genetic typing have been performed in Spanish hereditary hemochromatosis (n = 98) and PCT (n = 63) patients. The etiologic fraction (δ) has been used to determine the absolute strongest gene linkage to both diseases. Results: The Spanish frequent HLA-A29-B44 haplotype is not significantly associated to the H63D mutations in hereditary hemochromatosis patients (although it is found more frequently in patients than in controls). Sporadic porphyria cutanea tarda patients do not show a significant association to H63D mutations, although it is also more frequent than in controls; however, compound H63D/C282Y subjects seem to bear a significant risk to s-PCT. Allelic C282Y (and not H63D) frequencies show a significant association with s-PCT. Conclusions: The postulated additional risk of hereditary hemochromatosis given by class I HLA antigens may be secondary to the HFE gene linkage disequilibrium with certain class I alleles or to the existence of other neighboring genetic pathogenetic factors in our Spanish sample.