Population genetic analysis of the genes APOE, APOB(3'VNTR) and ACE in some black and Amerindian communities from Colombia.

A population genetic study was carried out with the APOE, APOB and ACE loci in 17 Colombian human populations. Ten of them were Amerindian communities coming from the northeastern part of Colombia, Pacific region, Eastern Plains and Amazonia. Six were black populations from Providence Island, Caribbean and Pacific coasts. Finally, the Mestizo population of Bogota was studied as well. The APOE and ACE loci were in Hardy-Weinberg equilibrium, whereas the APOB locus was not studied in all populations. The genetic heterogeneity was substantially greater among the Amerindian populations (G(ST) = 0.059) than in the Afrocolombian populations (G(ST) = 0.009). Also the gene flow population pair estimates were so much higher among the Afrocolombian populations (Nm = 49.08 +/- 43.07) than among Amerindian populations (Nm = 9.66 +/- 18.04). Different phylogenetic and multivariant analyses showed that the Amerindian populations analyzed were clustered in three different arrays: one constituted by the Colombian northeastern and Pacific populations, the second one by the two Amazon populations (Coreguaje and Nukak) and the last one by the Yuco (the unique Caribbe-speaking population among those studied). The latter population was highly divergent from a genetic point of view from the remainder Amerindian populations studied. By using the Mantel test, the existence of a positive and significant correlation between the genetic and geographical distances found among Amerindian populations was demonstrated. This fact was not observed among the Afrocolombian populations. Nevertheless, an isolation-by-distance Slatkin analysis test did not show a significant clear structure of this special pattern among the Indian tribes studied.

Results of Expedicion Humana. I. Analysis of HLA class II (DRB1-DQA1-DPB1) alleles and DR-DQ haplotypes in nine Amerindian populations from Colombia.

HLA class II variation was analyzed in nine Native American populations of Colombia using PCR/SSOP typing methods. Under the auspices of the Expedition Humana, approximately 30 unrelated native Colombia Indian samples each from the Tule (NW Pacific Coast), Kogui (Sierra Nevada). Ijka (Sierra Nevada), Ingano (Amazonas), Coreguaje (Amazonas), Nukak (Amazonas), Waunana (Pacific), Embera (Pacific) and Sikuani (Northeastern Plains) were collected and analyzed at the DRBI, DQA1, DQB1 and DPB1 loci. The number of different DRB1, DQA1, DQB1 and DPB1 alleles in the Colombian Indians is markedly reduced in comparison with neighboring African Colombian populations, which exhibit a very high degree of class II variability, as discussed in an accompanying paper. In the Colombian Amerindian groups, DR2 (DRB1*1602), DR4 (DRB1*0407, *0404, *0403 AND *0411), DR6 (DRB1*1402) and DR8 (DRB1*0802) comprise > 95% of all DRB1 alleles. We also found an absence of DR3 in all populations, and DR1, DR7 and DR9 allelic groups were either very rare or absent. Each Colombian Amerindian population has a predominant DRB1 allele (f = approximately 0.22-0.65) and DRB1-DQA1-DQB1 haplotype. Several novel DR-DQ haplotypes were also found. At the DPB1 locus, DPB1*0402 (f = 0.28-0.82), *1401 (f = 0.03-0.45), and *3501 (f = 0.03-0.27), were the three most prevalent alleles, each population maintaining one of these three alleles as the predominant (f > 0.26) DPB1 allele. The reduction of diversity for the HLA class II alleles in the Colombian Indians is suggestive of a population bottleneck during the colonization of the Americans, with little to no subsequent admixture with neighboring African Colombian populations in the last approximately 300 years.

Results of Expedicion Humana. II. Analysis of HLA class II alleles in three African American populations from Colombia using the PCR/SSOP: identification of a novel DQB1*02 (*0203) allele.

PCR/SSOP typing methods were used to analyze the HLA Class II DRB1, DQA1, DQB1 and DPB1 loci of samples from three African American populations of Colombia. Forty samples from the Cauca (Pacific), and twenty samples each from the Choco (North Pacific Coast) and the Providencia (Caribbean island) populations, were collected and the Class II loci analyzed under the auspices of the Expedicion Humana. Despite the limited number of samples analyzed, the African Colombian populations exhibit a very high degree of class II polymorphism. A great diversity of DRB1 alleles was found, with representatives from all serological classes, including 19 DRB1 alleles in the Providencia, 16 in the Cauca and 14 in the Choco groups. In addition, a novel DQB1*02 allele (*0203) was found in two individuals from the Cauca population of the Pacific Coast. The sequence of the DQB1*0203 allele, associated with DR3, differs from DQB1*0201 by only one nucleotide substitution (C-->A) in the second position of codon 57, resulting in an Ala to Asp change. The addition of DQB1*0203 brings the total number of DQB1 alleles identified to date to 26. HLA class II diversity is much greater in these African Colombian populations than that seen in nearby Amerindian populations. Analysis of regional Colombian African American HLA population genetics is discussed with respect to the Colombian Amerindian HLA genetics described in an accompanying paper.

New allele variants of the immunoglobulin switch (Salpha) regions.

In this report we define ten Salpha1 IGHA1 (*S5-*S14) and nine Salpha2 IGHA2 (*S10-*S18) newly found alleles of the human immunoglobulin switch alpha 1 and switch alpha 2 regions, respectively, in Colombian Indian, Black and Mestizo populations, and a complete list of the SacI and PvuII alleles so far identified as given.

Distal trisomy 14q. I. Clinical and cytogenetical studies.

Two cases of de novo duplication of the distal part of the long arm of chromosome 14 are reported. In one case, the partial trisomy of 14q is due to translocation of a segment (14q24 to 14qter) at the end of the satellite stalk of chromosome 14. The clinical picture is very severe. In the second case, a tandem duplication in 14 (q23----q32) is present with only minor malformations and mild mental retardation.

Distal trisomy 14q. II. Molecular study of the 14q32 locus in two cases of chromosome 14 rearrangements with partial duplication.

Two cases of chromosome 14 rearrangements with partial duplication which occurred de novo were analyzed by Southern blot analysis using IGH, D14S1 and PI probes. In the first case, with a 46,XX,14p+ karyotype, our study confirms that the additional material on chromosome 14p+ results from a duplication of the 14q region containing the IGH, D14S1 and PI loci. In the second case, our study reveals only one 14q32 locus per chromosome 14 indicating that the extra material does not contain the 14q32 region. Our results demonstrate that molecular probes of the 14q32 region are valuable tools for the characterisation of chromosome 14 abnormalities appearing de novo.

Association between acute lymphoblastic leukemia and partial IgA deficiency in a young man--a family study.

We report on an unusual association between partial IgA deficiency and acute lymphoblastic leukemia in a young man. We also report results of the family study of immunoglobulin levels, sIgA B cells, in vitro IgA synthesis and molecular analysis of the structural C alpha genes. The IgA deficiency was present at diagnosis of leukemia prior to any therapy. The indirect arguments for a preexisting IgA deficiency are the absence of improvement of the IgA level during complete remission and especially the finding of a similar partial IgA deficiency in a sister who shared the same HLA haplotype, had a low percentage of sIgA B cells and decreased in vitro IgA production. The mother, who had a normal IgA serum level also had decreased in vitro IgA synthesis. No major structural C alpha gene defect was found. The relationship between acute lymphoblastic leukemia and IgA deficiency remains to be elucidated.

Molecular analysis of the IGHA and MHC class III region genes in one family with IgA and C4 deficiencies.

We report molecular studies in 2 IgA-deficient persons. One of them had an unusual association with an acute lymphoblastic leukaemia; his sister was also IgA deficient and shared an HLA haplotype and a complotype known to be associated to IgA deficiencies. The 2 IgA-deficient siblings also had low C4 serum levels due to C4A*Q0 allele. We showed that both defects were transmitted independently in the family. Molecular analysis revealed no major structural defects of the IGHA coding and switch regions, whereas a broad C4A-21-OHA deletion was responsible for the C4A*Q0 phenotype. These results confirm previous data showing that IgA deficiencies seem to be, in most cases, a regulatory defect rather than a structural defect of the coding IGHA region itself. These data were further supported by another molecular study in a patient with a recurrent Landry-Guillain-Barre syndrome who showed total absence of serum IgA and sIgA+B cells with no major structural defect of the IGHA region.

A multigene deletion in the human IGH constant region locus involves highly homologous hot spots of recombination.

A simultaneous absence of the IgG1, IgG2, IgG4, and IgA1 immunoglobulins (Ig) was unambiguously demonstrated in six healthy individuals of two different families (family HASS and family TOU). These individuals were shown to be homozygous for a large deletion in the immunoglobulin heavy chain constant region locus. This deletion, which encompasses the G1-EP1-A1-GP-G2-G4 genes, allowed us to predict an order for the IgCH genes and to localize GP between A1 and G2. In this paper, we study the deletion-recombination point in the IGH locus of individual EZZ from the TOU family. We show that the distance between the G3 and the E genes on the EZZ recombinant chromosome is 24.7 kb and that the multigene deletion in the IgCH locus involves two highly homologous regions (hsg3 and hsg4) which are hot spots of recombination, outside of the switch sequences.

Molecular characterization of a ring chromosome 14 showing that the PI locus is centromeric to the D14S1 and IGH loci.

Molecular characterization of a ring chromosome 14 was carried out in a patient with the 46,XX,r(14) karyotype. The breakpoints shown by chromosome banding were within bands p11 and q32. Using molecular probes for the immunoglobulin heavy chain (IGH), D14S1 and PI loci located at 14q32, we showed that the IGH and D14S1 loci, located at 14q32.3 and 14q32.2 respectively, were deleted on the ring chromosome 14, but that the PI locus was not. Therefore, the chromosomal break lies between PI and D14S1. These results show that the order of these chromosome 14 markers is cen-PI-D14S1-IGH, in keeping with multipoint linkage data. Further molecular characterization of ring 14 chromosomes should lead to a detailed understanding of the molecular events and clinical consequences of the gene deletion associated with such chromosomal aberrations.

A gamma 3 hinge region probe: first specific human immunoglobulin subclass probe.

We report the first specific human immunoglobulin subclass probe which was obtained by subcloning the gamma 3 hinge region. This specific gamma 3 probe allowed us to identify with certainty the C gamma 3 gene on Southern genomic blots, to describe the first C gamma 3 restriction fragment length polymorphism (EZZ gamma 3 RF) and to show that an IgG3 selective deficiency, previously described serologically, was not due to a deletion of the C gamma 3 gene. Such a probe should be particularly useful for screening libraries from individuals with IgG3 immunodeficiencies or presenting unusual C gamma 3 genes and, consequently, for studying the C gamma gene evolution.

Complement polymorphism in Colombia.

The polymorphism of complement component C3, BF and C4 was studied in an urban population of Bogota, Colombia and for C3 and BF, genetic heterogeneity was further examined among the five villages of the Colombian Andes. For both C3 and BF systems there is considerable variation of allele frequencies among the five villages and overall there is significant heterogeneity among the six population groups studied.