Evolutionary relationships between HLA‐B alleles as indicated by an analysis of intron sequences

Abstract

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.

Generation of HLA-B*1516/B*1567/B*1595 and B*1517 alleles (B15 specific group) by transpecies evolution

“…Serologically distinct molecules, B71 and B72 (subtypes of B70), are also encoded by alleles in the B15 family. Although B15/70 is found at high frequencies in all ethnic groups, alleles encoding these specificities and their frequencies are apt to be different in distinct populations [5][6][7]. [8].…”

“…[8]. The corresponding sequences from HLAB*1504, 1515, 1539, 4901 were obtained from Gomez Casado et al [5,6] and HLA-B*15170102, 151702, 1566, 4504, 47010101, 5001, 5401, and 5512 allele sequences were taken from IMGT-HLA database (www.ebi.ac.uk/imgt/hla) [1]. The intron compilation by Cereb et al [9] was also used.…”

HLA class I and II alleles may influence susceptibility to adult dermatomyositis in a Mexican mestizo population

“…Alleles HLA-A*01:01 and HLA-B*07:02 are reported as part of the polymorphism of some groups of healthy Mexican mestizos with a frequency of 9-14%. In the case of HLA-A*03:01, it was documented with a frequency lower than the previous (0.024%) [32,33].…”

The nature of introns 4–6 suggests reduced lineage specificity in HLA-B alleles

“…[5][6][7][8] Studies on intronic sequences revealed that intron 1 sequences present remarkably specific characteristics that help to identify the different HLA-B serological families and also confer upon them a phylogenetic support. 9 By contrast, introns 2 and 3 are characterized by a greater level of discordance among topologies. 10 In contrast to the 5 0 part of the HLA-B gene, which in this work is defined as the part that comprises exons 1-3, and introns 1-3, only limited sequence data 11,12 exist about its 3 0 part (exons 4-7, introns 4-6), the latter encoding the a3, transmembrane and cytoplasmatic domains.…”