Tissue Antigens ISSN 0001-2815
BRIEF COMMUNICATION
Different patterns of A*80:01:01:01 allele generation based on exon or intron sequences I. Cervera1 , M. A. Herraiz2 , J. Vidart2 , S. Ortega2 & J. Martínez-Laso1 1 Unidad de Inmunogenetica, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Madrid, Spain 2 Servicio de Ginecología del Hospital Clínico de San Carlos, Madrid, Spain
Key words evolution; human leukocyte antigen; HLA-A*80:01:01:01; introns; non-human primates Correspondence Jorge Martínez-Laso Unidad de Inmunogenetica Centro Nacional de Microbiología Instituto de Salud Carlos III Crta, Majadahonda-Pozuelo Km. 2,2. 28220 Majadahonda Madrid Spain Tel: +34 918223715 Fax: +34 918223423 e-mail: [email protected]
Abstract 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.
Received 14 July 2014; revised 24 November 2014; accepted 30 November 2014 doi: 10.1111/tan.12496
The name listed for the HLA-A*80:01:01:01 sequence has been officially assigned as a confirmatory by the World Health Organisation (WHO) Nomenclature Committee. This follows the agreed policy that, subjected to the conditions stated in the most recent Nomenclature report (1, 2), names will be assigned to new sequences as they are identified. List of such new names will be published in the following WHO Nomenclature Report. The nucleotide sequence data reported in this paper have been submitted to the GenBank nucleotide sequence database and have been assigned the following accession number: JX009131. In the present work, the complete sequence, including non-coding regions (first described in this manuscript), was determined in order to study the origin and the relationship of the HLA-A*80:01:01:01 allele with the rest of the other human leukocyte antigen (HLA)-A human evolutionary families and with the non-human primates major histocompatibility complex (MHC)-A alleles available taking into account exon and intron sequences. HLA-A alleles have been grouped into two evolutionary lineages with six different families (3–11). The A2 lineage comprises the A2 (A*02, A*68, and A*69 alleles), A10 (A*25, A*26, 58
A*34, A*43, and A*66 alleles), and A19 (A*29, A*31, A*32, A*33, and A*74 alleles) families, and the A3 lineage comprises the A9 (A*23 and A*24 alleles), A1/A3/A11/A30/A36 (also named as A3 family) (A*01, A*03, A*11, A*30, and A*36 alleles), and A80 (A*80 alleles) families based on nucleotide and protein analyses (3–11). Three of these families A2, A10, and A19 (A2 lineage) have been related with a Gorilla MHC-A ancestral lineage while Chimpanzee MHC-A locus alleles are related to the A1/A3/A11/A30/A36 family (5, 8, 9, 12–14). Thus, both lineages predate the separation of humans, Chimpanzees, and Gorillas and were present in the common ancestor of the three species, an example of trans-species evolution (15). HLA-A*80:01:01:01 exon sequences do not fit into any of the five families of HLA-A alleles (3). At positions which define family-specific substitutions (3), A*80:01:01:01 has a motif which does not correspond to any of those found in the A2, A3, A9, A10, or A19 families. The A*80:01:01:01 and A3 family motifs are identical in the 5′ half of the coding region (positions 1–671) which includes exons 2 and 3. In the 3′ part of the coding region (positions 672–1098), the A*80:01:01:01 motif bears no close relationship to the A3 © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Tissue Antigens, 2015, 85, 58–67
I. Cervera et al.
family motif and is divergent from all five family motifs. From these analyses, the A*80:01:01:01 allele appears as a sixth family of HLA-A alleles included in the A3 lineage (16). The distribution of this allele is mainly focused in Sub-Saharan Africa (Senegal, Ghana, Guinea, Zambia, and Cameroon with a frequency from 0.019 to 0.038) and North Africa (Morocco, frequency 0.027) and extended in low frequency to Spain and Switzerland (from 0.017 to 0.011), confirming its African origin (http://www.allelefrequencies.net) (17). HLA-A sequence comprising from 5′ untranslated region (UTR) to 3′ UTR of A*80:01:01:01 allele was sequenced in one unrelated healthy umbilical cord (UCB) sample obtained from full-term programmed caesarean of Caucasoid origin (Madrid, Spain), following ethical committee approval. Non-human primates (Pan troglodytes, P. paniscus, Gorilla gorilla, and Pongo pigmaeus) MHC-A sequences were taken from IPD-MHC Database (http://www.ebi.ac.uk/ ipd/mhc/nhp/index.html; 2, 18). The first representative alleles of the different HLA-A families, comprising the maximisation of the HLA-A variation, were taken as reference for the phylogenetic analyses from the IMGT/HLA database (www.ebi.ac.uk/imgt/hla; 1) (see Figure 1). Total DNA was extracted using the Mini Kit (Qiagen, Crawley, UK) according to the manufacturer’s instructions. HLA-A 5′ UTR, exon 1, intron 1, exon 2, intron 2, exon 3, and exon 4 sequences were obtained using the BDR-HLA-A SBT kit (Blackhills Diagnostic Resources, Zaragoza, Spain). Additional HLA-A generic sequencing primers HLA-E4-788F: 5′ -GAACCT TCCAGAAGTGGGCGG-3′ , HLA-E7-1052F: 5′ -ACAGTGC CCAGGGCTCTGATG-3′ , and HLA-E7-1092R: 5′ -TTTACA AGCTGTGAGAGACAC-3′ , and additional HLA-A*80:01:01: 01-specific sequencing primers HLA-E3-538F: 5′ -CTGAGAG CCTACCTGGAGGGCG-3′ and HLA-E5-947F: 5′ -TTCTCC TTGGAGCTGTGATCG-3′ were used. Primers HLA-E3-538F and HLA-E5-947F were designed in order to avoid the intron 3 and intron 5 deletions/insertions from the sequence of the other HLA-A allele (HLA-A*29:02:01:01) of the individual. Polymerase chain reaction products were purified using EXOSAP-IT® (USB Corporation, Cleveland, OH) methodology following standard protocols (19) and automatically sequenced in a 3730xl ABI sequencer (Applied Biosystems, Foster City, CA). Sequences obtained were analysed with the SEQin program (Applied Biosystems), and multiple-sequence alignment analyses were calculated by using the ClustalW algorithm (European Bioinformatics Institute; http://www.ebi.ac.uk/clustalw; 20). Phylogenetic and molecular evolutionary analyses were performed using MEGA version 6.0.6, and the neighbour-joining method with a 500 bootstrap test (21) was selected. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Tissue Antigens, 2015, 85, 58–67
HLA-A*80:01:01:01 allele generation
HLA-A exon sequence comparisons
HLA-A*80:01:01:01 exon 1 sequence is shared with the corresponding one of the A3 family from position 14 to 41 and presents a unique C nucleotide not found in any other HLA-A allele (Figure 1). Exon 2 is more complex with three different regions in the sequence: (1) from the beginning of exon 2 to position 253 is shared with the A*01, A*03, A*32, A*74, and A*36 group of alleles, (2) from nucleotide at position 233–387 with the A*23 and A*24 alleles, and (3) from position 400 to the end of exon 2 with the A*25 and A*26 group of alleles. This lack of specific HLA-A family pattern is probably due to the evolutionary pressure on this region because it constitutes part of the peptide binding region. Besides, this exon has a T nucleotide at position 293 that only belongs to A*80:01:01:01 allele and three positions more, a nucleotide at position 306, A-369, and A-422 that are shared with a few very specific and low frequency HLA-A alleles. Exon 3 shares the region comprised from the beginning of the exon to position 892 with the A*03 group of alleles and from this position to the 916 with A*30 group of alleles. The rest of the exon does not have a clear pattern of sharing with other HLA-A alleles. The nucleotides at positions 930 and 931 (G and G, respectively) are only found in specific and low frequency alleles (data not shown). HLA-A*80:01:01:01 exons 4 and 5 sequences show similarities with the corresponding ones of the A3 family. On the other hand, specific regions comprising from the beginning of exon 4 to position 1622 and from the beginning of exon 5 to position 1952 are shared with the corresponding ones of the A*23 and A*24 alleles. A common and independent event could be postulated for the generation of exon 4 and exon 5: a gene conversion event at the beginning of exons 4 and 5, respectively, between an ancestral A3 family allele as a receptor and some allele from the A*23 or A*24 group of alleles as a donor. The nucleotides at positions 1779 (A), 1785 (A), and 1824 (G) of exon 4 and positions 1976 (T) and 2053 (A) at exon 5 are unique in the A*80:01:01:01 allele and are not found in any other HLA-A alleles (Figure 1). Exon 6 nucleotide sequence is shared from position 2508 to the end of the exon with all HLA-A families except the A3 family; therefore, this exon probably comes from an ancestral HLA-A allele, common to these families, acting as a donor over the ancestor of the A*80:01:01:01. Exon 7 has a nucleotide sequence common to A3, A2, and A9 families (Figure 1). Phylogenetic trees of the exon sequences reflect the previously described results, although the statistically bootstrap numbers are low. Exon 1 sequence is more related with the A2, A9, and A10 family alleles, exons 2 and 3 with the A3 family alleles, and exons 4 and 5 with A3 and A9 families (Figure 2). HLA-A intron sequence comparisons
A simpler pattern is found when considering the intron sequences. The 5′ UTR region of the A*80:01:01:01 has a common sequence with the corresponding ones of the A2, A10, and A19 families and a specific A nucleotide at position 59
Figure 1 Variable nucleotide positions of the most representative HLA-A alleles from 5′ untranslated region (UTR) to intron 7 regions. Clear grey regions represent the higher homology DNA sequence between the considered alleles. Dark grey regions represent the nucleotides specific for the HLA-A*80:01:01:01 allele. Nucleotide agreement with the HLA-A*01:01:01:01 allele is indicated by a hyphen (−). Numbers of the positions are taken from IMGT/HLA database (http://www.ebi.ac.uk/imgt/hla).
HLA-A*80:01:01:01 allele generation
60
I. Cervera et al.
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Tissue Antigens, 2015, 85, 58–67
HLA-A*80:01:01:01 allele generation
Figure 1 Continued.
I. Cervera et al.
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Tissue Antigens, 2015, 85, 58–67
61
I. Cervera et al.
Figure 1 Continued.
HLA-A*80:01:01:01 allele generation
62
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Tissue Antigens, 2015, 85, 58–67
Figure 2 Phylogenetic trees of the most representative human leukocyte antigen (HLA)-A alleles from 5′ untranslated region (UTR) to intron 7. Neighbour-joining tree with 500 bootstrap methodology is used (bootstrap over 40% is shown). The same allelic composition for exons and introns has been made excluding the alleles with incomplete sequences except for the 5′ UTR phylogenetic tree.
I. Cervera et al.
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Tissue Antigens, 2015, 85, 58–67
HLA-A*80:01:01:01 allele generation
63
I. Cervera et al.
Figure 2 Continued
HLA-A*80:01:01:01 allele generation
64
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Tissue Antigens, 2015, 85, 58–67
I. Cervera et al.
HLA-A*80:01:01:01 allele generation
Figure 2 Continued
−104 is found (Figure 1). Intron 1 and intron 2 maintain a common sequence with the A2 and A10 families. In intron 2, there are three nucleotides only present in the A*80:01:01:01 allele (position 519-T, 619-G, and 660-G) (Figure 1). The nucleotide sequence from the beginning of intron 3 to position 1399 is shared with the corresponding ones of the A2, A10, and A19 families and from position 1401 to the end of the intron, the sequence is similar to the corresponding ones of the A3 family and in a lesser degree with the A9 family. Besides, there are 10 nucleotides only found in the A*80:01:01:01 allele: C-1101, T-1137, A-1197, G-1263, C-1299, A-1321, G-1489, A-1495, and G-1566 (Figure 1). Intron 4 follows the same A3 family pattern with 2 specific nucleotides of the A*80:01:01:01 allele (T-1910 and A-1920) (Figure 1). Intron 5 also follows the same A3 family pattern of the last introns with a characteristic A9 motif from position 2223 to 2265. This intron has five specific nucleotides (C-2151, C-2181, T-2399, G-2434, C-2438, and G-2481) (Figure 1). The nucleotide sequence of intron 6 is shared with the corresponding ones of the A2 and A3 families, probably because this intron comes from a common ancestor for the two families. Nucleotide G at position 2585 is exclusive to the A*80:01:01:01 allele (Figure 1). Intron 7 has the same A3 family pattern with similarities to the A9 family. Also, the G nucleotide at position 2769 is unique in the A*80:01:01:01 allele (Figure 1). Phylogenetic trees of the intron sequences yield two groups of evolution, one of them comprising the 5′ UTR, intron 1, and intron 2 related to the A2 and A10 families and in a lesser degree to the A19 and A9 families. The other includes the introns 3, 5, 6, and 7 and is related to the A3 family and in a lesser degree to A9 family (Figure 2). Intron 4 phylogenetic tree locates the A*80:01:01:01 as an outgroup of the rest of the HLA-A alleles and probably could reflect the age of the A*80:01:01:01 allele (Figure 2). In conclusion, when the exon sequences are only considered, a more complex pattern of evolution is found: exons 1, 4, and © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Tissue Antigens, 2015, 85, 58–67
6 share a pattern corresponding to the A3 family with some A9 family common characteristics and exon 7 includes A3, A9, and A2 family characteristics (Figure 1). However, exons 2 and 3 do not present similarities with any HLA-A family (Figure 1). Two clear patterns of evolution of the A*80:01:01:01 allele are found when the non-coding regions are considered. One comprising the 5′ UTR, intron 1, 2, and partial intron 3 whose sequences are common to those of the A2, A10 and in a lesser degree A19 family alleles, and another comprising partial intron 3 until intron 7 shared with the A3 family alleles. The latter has certain characteristics of the A9 (last part of introns 3, 5, and 7) and A2 family alleles (intron 6) (Figures 1 and 2). There are a lot of data supporting the idea that intron sequences give a more clear view of the evolutionary pathways of the HLA alleles generation than the exon sequences (22–24). These data confirm that intron sequences are coming from a recombination from to HLA-A ancestral sequences belonging to A2 and A3 families, respectively, followed by an evolutionary pressure mainly in exons 2 and 3 with point mutations, and other recombination events as cross-linking or gene conversion events with the surrounding alleles. The presence of specific A*80:01:01:01 allele nucleotides (some of them only present in non-human primates, see below) confirms the ancient origin of this allele.
HLA-A and non-human primates MHC-A sequence comparisons
There are 24 nucleotides in intron sequences and 14 in exon sequences only present in the A*80:01:01:01 allele (Figures 1 and 3). Five of 14 nucleotides appearing in exon sequences are present in a specific and low frequency HLA-A alleles (see above). Two of them appear in the A*30 group of alleles, probably due a gene conversion event between the A*30 ancestral alleles and the ancestral A*80:01:01:01 allele. Because of the lack of the intron sequences from the non-human primates MHC-A alleles, a study of the presence of the unique 65
HLA-A*80:01:01:01 allele generation
I. Cervera et al.
Figure 3 Characteristic HLA-A*80:01:01:01 nucleotides and its comparison with the corresponding ones of the non-human primates MHC-A alleles. Grey nucleotides represent the common nucleotides between HLA-A*80:01:01:01 and MHC-A non-human primates alleles. Patr: Pan troglodytes (Chimpazee); Papa: P. Paniscus (Bonobo); Gogo: Gorilla gorilla (Gorilla), Popy: Pongo Pygmaeus (Orangutan) between the considered alleles. E1, exon 1; E2, exon 2; E3, exon 3; E5, exon 5; E6, exon 6. Numbers of the positions are taken from ref. IMGT/HLA database (http://www.ebi.ac.uk/imgt/hla).
A*80:01:01:01 nucleotides of the exon sequences is only possible. From the 14 nucleotides found as unique, 9 appear in the non-human primates (Figure 3): C at position 13 in exon 1, shared with Patr and Papa MHC-A sequences; A-369 in exon 2 present only in Gogo MHC-A sequences; A-422 in exon 2 present in Patr, Papa, and Popy MHC-A sequences; G and A at positions 930 and 931, respectively, in exon 3 appearing in Gogo and Popy MHC-A alleles and are characteristic of the HLA-A*30 alleles; A-1779 in exon 4 shared with Gogo and Popy MHC-A alleles; G-1824 in exon 4 and present in Gogo and Popy MHC-A alleles; and A-2053 present only in Gogo MHC-A allele (Figure 3). From these comparisons, a possible ancestral origin for the A*80:01:01:01 allele could be postulated. The nucleotides T, A, C, A, and T at positions 293, 306, 897, 1785, and 2507, respectively, belonging to HLA-A*80:01:01:01 are not present in any MHC-A non-human primates alleles tested. These data support the notion that the A*80:01:01:01 allele is evolutionarily older than the other HLA-A alleles because these nucleotides are not shared with non-human primate MHC-A sequences (Figure 3). A phylogenetic analysis has been made with the exon sequences of human HLA-A alleles and non-human primate MHC-A alleles (data not shown), confirming the results previously described. The families of A3 and A9 appear to be nearest to the Chimpanzee MHC-A alleles while A2, A10, and A19 are more closely aligned with Gorilla MHC-A alleles. 66
In conclusion, the ancient origin of the A*80:01:01:01 is confirmed from the data obtained. The study of the intron sequences could give a better view of the origin of specific or rare alleles, because they do not support the evolutionary pressure of the exons (mainly exons 2 and 3). In this work, the use of intron sequences has led to the hypothesis of the generation of A*80:01:01:01 coming from a recombination event between an ancestral allele belonging to the A2/A10/A19 common family (shared with Gorilla) with an ancestral allele from the A3 family (shared with Chimpanzee). Therefore, this allele could have been generated before the speciation of the different non-human primates, although other hypotheses can not be discarded. Besides, A*80:01:01:01 has specific nucleotides belonging to Orangutans and has other nucleotides specific for this allele and not present in other HLA-A alleles. The available evidence raises the possibility that A*80:01:01:01 is an old allele of African origin that did not disseminate from Africa during the first colonisation of Europe and Asia by humans. It is of interest that it is defined as an old allele because age is usually associated with subtypic diversity (3, 17). The only explanation is that the A*80 alleles have been isolated in very specific conditions in Africa, and natural selection has deleted the possible variations that appear because these ancient proteins have unique properties that may have conferred evolutionary benefits (15, 25–27). It would be necessary to study the different populations in Africa to detect © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Tissue Antigens, 2015, 85, 58–67
I. Cervera et al.
HLA-A*80:01:01:01 allele generation
the presence/frequency of these alleles to establish a possible explanation. 13.
Acknowledgments
This work was supported, in part, by grant of the Ministerio de Ciencia e Innovación (PI-11/0333).
14.
Conflict of interest
15.
There is no conflict of interest in the present manuscript. 16.
References 1. Robinson J, Halliwell JA, McWiliam H, Lopez R, Parham P, Marsh SGE. The IMGT/HLA database. Nucleic Acid Res 2013: 41: D1222–7. 2. Robinson J, McWiliam H, Lopez R, Marsh SGE. IPD – the Immuno Polymorphism Database. Nuceic Acid Res 2013: 41: D1234–40. 3. Domena JD, Hildebrand WH, Bias WB, Parham P. A sixth family of HLA-A alleles defined by HLA-A*8001. Tissue Antigens 1993: 42: 156–9. 4. Kato K, Trapani JA, Allopenna J, Dupont B, Yang SY. Molecular analysis of the serologically defined HLA-Aw19 antigens. A genetically distinct family of HLA-A antigens comprising A29, A31, A32, and Aw33, but probably not A30. Immunology 1989: 143: 3371–8. 5. Adam EJ, Cooper S, Thomson G, Parham P. Common chimpanzees have greater diversity than humans at two of the three highly polymorphic MHC class I genes. Immunogenetics 2000: 51: 410–4. 6. Cowan EP, Jelachich ML, Biddison WE, Coligan JE. DNA sequence of HLA-A11: remarkable homology with HLA-A3 allows identification of residues involved in epitopes recognized by antibodies and T cells. Immunogenetics 1987: 25: 241–50. 7. Jakobsen IB, Gao X, Easteal S, Chelvanayagam G. Correlating sequence variation with HLA-A allelic families: implications for T cell receptor binding specificities. Immunol Cell Biol 1998: 76: 135–42. 8. Lawlor DA, Warren E, Ward FE, Parham P. Comparisons of class I MHC alleles in humans and apes. Immunol Rev 1990: 113: 147–85. 9. Lawlor DA, Warren E, Taylor P, Parham P. Gorilla class I major histocompatibility complex alleles: comparison to human and chimpanzee class I. J Exp Med 1991: 174: 1491–509. 10. Little AM, Madrigal JA, Parham P. Molecular definition of an elusive third HLA-A9 molecule: HLA-A9.3. Immunogenetics 1992: 35: 41–5. 11. Madrigal JA, Hildebrand WH, Belich MP et al. Structural diversity in the HLA-A10 family of alleles: correlations with serology. Tissue Antigens 1993: 41: 72–80. 12. Chen ZW, Hughes AL, Ghim SH, Letvin NL, Watkins DI. Two more chimpanzee Patr-A locus alleles related to the
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Tissue Antigens, 2015, 85, 58–67
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
HLA-A1/A3/A11 family. Immunogenetics 1993: 38: 238–40. Lawlor DA, Ward FE, Ennis PD, Jackson AP, Parham P. HLA-A and B polymorphisms predate the divergence of humans and chimpanzees. Nature 1988: 335: 268–71. Mayer WE, Jonker M, Klein D, Ivanyi P, van Seventer G, Klein J. Nucleotide sequences of chimpanzee MHC class I alleles: evidence for trans-species mode of evolution. EMBO J 1988: 7: 2765–74. Klein J. Origin of major histocompatibility complex polymorphism: the trans-species hypothesis. Hum Immunol 1987: 19: 155–62. Wagner AG, Hughes AL, Iandoli ML et al. HLA-A*8001 is a member of a newly discovered ancient family of HLA-A alleles. Tissue Antigens 1993: 42: 522–9. Starling GC, Witkowski JA, Speerbrecher LS, McKinney SK, Hansen JA, Choo SY. A novel HLA-A*8001 allele identified in an African-American population. Hum Immunol 1994: 39: 163–8. de Groot NG, Otting N, Robinson J et al. Nomenclature report on the major histocompatibility complex genes and alleles of Great Ape, Old and New World monkey species. Immunogenetics 2012: 64: 615–31. Martinez-Laso J, Moscoso J, Zamora J et al. Different evolutionary pathway of B*570101 and B*5801 (B17 group) alleles based in intron sequences. Immunogenetics 2004: 55: 866–72. Higgins D, Thompson J, Gibson T, Thompson JD, Higgins DG, Gibson TJ. CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. Nucleic Acids Res 1994: 22: 4673–80. Tamura K, Stecher G, Peterson D, Filipski A, Kumar S. MEGA6: Molecular Evolutionary Genetics Analysis version 6.0. Mol Biol Evol 2013: 30: 2725–9. Gomez-Casado E, Vargas-Alarcón G, Martínez-Laso J et al. Evolutionary relationship between HLA-B alleles as indicated by an analysis of intron sequences. Tissue Antigens 1999: 53: 153–60. Martínez-Laso J, Herraiz MA, Vidart JA et al. Polymorphism of the HLA-B*15 group of alleles is generated following 5 lineages of evolution. Hum Immunol 2011: 72: 412–21. Roman A, Cervera I, Head J, Rodríguez M, Martínez-Laso J. Generation of HLA-B*1516/B*1567/B*1595 and B*1517 alleles (B15 specific group) by transpecies evolution. Hum Immunol 2007: 68: 1001–8. Hughes AL, Nei M. Pattern of nucleotide substitution at major histocompatibility complex class I loci reveals over dominant selection. Nature 1988: 335: 167–70. Hughes AL, Nei M. Nucleotide substitution at major histocompatibility complex class II loci: evidence for overdominant selection. Proc Natl Acad Sci U S A 1989: 86: 958–62. Parham P, Arnett KL, Adams EJ et al. Episodic evolution and turnover of HLA-B in the indigenous human populations of the Americas. Tissue Antigens 1997: 50: 219–32.
67
Copyright of Tissue Antigens is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
BRIEF COMMUNICATION
Different patterns of A*80:01:01:01 allele generation based on exon or intron sequences I. Cervera1 , M. A. Herraiz2 , J. Vidart2 , S. Ortega2 & J. Martínez-Laso1 1 Unidad de Inmunogenetica, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Madrid, Spain 2 Servicio de Ginecología del Hospital Clínico de San Carlos, Madrid, Spain
Key words evolution; human leukocyte antigen; HLA-A*80:01:01:01; introns; non-human primates Correspondence Jorge Martínez-Laso Unidad de Inmunogenetica Centro Nacional de Microbiología Instituto de Salud Carlos III Crta, Majadahonda-Pozuelo Km. 2,2. 28220 Majadahonda Madrid Spain Tel: +34 918223715 Fax: +34 918223423 e-mail: [email protected]
Abstract 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.
Received 14 July 2014; revised 24 November 2014; accepted 30 November 2014 doi: 10.1111/tan.12496
The name listed for the HLA-A*80:01:01:01 sequence has been officially assigned as a confirmatory by the World Health Organisation (WHO) Nomenclature Committee. This follows the agreed policy that, subjected to the conditions stated in the most recent Nomenclature report (1, 2), names will be assigned to new sequences as they are identified. List of such new names will be published in the following WHO Nomenclature Report. The nucleotide sequence data reported in this paper have been submitted to the GenBank nucleotide sequence database and have been assigned the following accession number: JX009131. In the present work, the complete sequence, including non-coding regions (first described in this manuscript), was determined in order to study the origin and the relationship of the HLA-A*80:01:01:01 allele with the rest of the other human leukocyte antigen (HLA)-A human evolutionary families and with the non-human primates major histocompatibility complex (MHC)-A alleles available taking into account exon and intron sequences. HLA-A alleles have been grouped into two evolutionary lineages with six different families (3–11). The A2 lineage comprises the A2 (A*02, A*68, and A*69 alleles), A10 (A*25, A*26, 58
A*34, A*43, and A*66 alleles), and A19 (A*29, A*31, A*32, A*33, and A*74 alleles) families, and the A3 lineage comprises the A9 (A*23 and A*24 alleles), A1/A3/A11/A30/A36 (also named as A3 family) (A*01, A*03, A*11, A*30, and A*36 alleles), and A80 (A*80 alleles) families based on nucleotide and protein analyses (3–11). Three of these families A2, A10, and A19 (A2 lineage) have been related with a Gorilla MHC-A ancestral lineage while Chimpanzee MHC-A locus alleles are related to the A1/A3/A11/A30/A36 family (5, 8, 9, 12–14). Thus, both lineages predate the separation of humans, Chimpanzees, and Gorillas and were present in the common ancestor of the three species, an example of trans-species evolution (15). HLA-A*80:01:01:01 exon sequences do not fit into any of the five families of HLA-A alleles (3). At positions which define family-specific substitutions (3), A*80:01:01:01 has a motif which does not correspond to any of those found in the A2, A3, A9, A10, or A19 families. The A*80:01:01:01 and A3 family motifs are identical in the 5′ half of the coding region (positions 1–671) which includes exons 2 and 3. In the 3′ part of the coding region (positions 672–1098), the A*80:01:01:01 motif bears no close relationship to the A3 © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Tissue Antigens, 2015, 85, 58–67
I. Cervera et al.
family motif and is divergent from all five family motifs. From these analyses, the A*80:01:01:01 allele appears as a sixth family of HLA-A alleles included in the A3 lineage (16). The distribution of this allele is mainly focused in Sub-Saharan Africa (Senegal, Ghana, Guinea, Zambia, and Cameroon with a frequency from 0.019 to 0.038) and North Africa (Morocco, frequency 0.027) and extended in low frequency to Spain and Switzerland (from 0.017 to 0.011), confirming its African origin (http://www.allelefrequencies.net) (17). HLA-A sequence comprising from 5′ untranslated region (UTR) to 3′ UTR of A*80:01:01:01 allele was sequenced in one unrelated healthy umbilical cord (UCB) sample obtained from full-term programmed caesarean of Caucasoid origin (Madrid, Spain), following ethical committee approval. Non-human primates (Pan troglodytes, P. paniscus, Gorilla gorilla, and Pongo pigmaeus) MHC-A sequences were taken from IPD-MHC Database (http://www.ebi.ac.uk/ ipd/mhc/nhp/index.html; 2, 18). The first representative alleles of the different HLA-A families, comprising the maximisation of the HLA-A variation, were taken as reference for the phylogenetic analyses from the IMGT/HLA database (www.ebi.ac.uk/imgt/hla; 1) (see Figure 1). Total DNA was extracted using the Mini Kit (Qiagen, Crawley, UK) according to the manufacturer’s instructions. HLA-A 5′ UTR, exon 1, intron 1, exon 2, intron 2, exon 3, and exon 4 sequences were obtained using the BDR-HLA-A SBT kit (Blackhills Diagnostic Resources, Zaragoza, Spain). Additional HLA-A generic sequencing primers HLA-E4-788F: 5′ -GAACCT TCCAGAAGTGGGCGG-3′ , HLA-E7-1052F: 5′ -ACAGTGC CCAGGGCTCTGATG-3′ , and HLA-E7-1092R: 5′ -TTTACA AGCTGTGAGAGACAC-3′ , and additional HLA-A*80:01:01: 01-specific sequencing primers HLA-E3-538F: 5′ -CTGAGAG CCTACCTGGAGGGCG-3′ and HLA-E5-947F: 5′ -TTCTCC TTGGAGCTGTGATCG-3′ were used. Primers HLA-E3-538F and HLA-E5-947F were designed in order to avoid the intron 3 and intron 5 deletions/insertions from the sequence of the other HLA-A allele (HLA-A*29:02:01:01) of the individual. Polymerase chain reaction products were purified using EXOSAP-IT® (USB Corporation, Cleveland, OH) methodology following standard protocols (19) and automatically sequenced in a 3730xl ABI sequencer (Applied Biosystems, Foster City, CA). Sequences obtained were analysed with the SEQin program (Applied Biosystems), and multiple-sequence alignment analyses were calculated by using the ClustalW algorithm (European Bioinformatics Institute; http://www.ebi.ac.uk/clustalw; 20). Phylogenetic and molecular evolutionary analyses were performed using MEGA version 6.0.6, and the neighbour-joining method with a 500 bootstrap test (21) was selected. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Tissue Antigens, 2015, 85, 58–67
HLA-A*80:01:01:01 allele generation
HLA-A exon sequence comparisons
HLA-A*80:01:01:01 exon 1 sequence is shared with the corresponding one of the A3 family from position 14 to 41 and presents a unique C nucleotide not found in any other HLA-A allele (Figure 1). Exon 2 is more complex with three different regions in the sequence: (1) from the beginning of exon 2 to position 253 is shared with the A*01, A*03, A*32, A*74, and A*36 group of alleles, (2) from nucleotide at position 233–387 with the A*23 and A*24 alleles, and (3) from position 400 to the end of exon 2 with the A*25 and A*26 group of alleles. This lack of specific HLA-A family pattern is probably due to the evolutionary pressure on this region because it constitutes part of the peptide binding region. Besides, this exon has a T nucleotide at position 293 that only belongs to A*80:01:01:01 allele and three positions more, a nucleotide at position 306, A-369, and A-422 that are shared with a few very specific and low frequency HLA-A alleles. Exon 3 shares the region comprised from the beginning of the exon to position 892 with the A*03 group of alleles and from this position to the 916 with A*30 group of alleles. The rest of the exon does not have a clear pattern of sharing with other HLA-A alleles. The nucleotides at positions 930 and 931 (G and G, respectively) are only found in specific and low frequency alleles (data not shown). HLA-A*80:01:01:01 exons 4 and 5 sequences show similarities with the corresponding ones of the A3 family. On the other hand, specific regions comprising from the beginning of exon 4 to position 1622 and from the beginning of exon 5 to position 1952 are shared with the corresponding ones of the A*23 and A*24 alleles. A common and independent event could be postulated for the generation of exon 4 and exon 5: a gene conversion event at the beginning of exons 4 and 5, respectively, between an ancestral A3 family allele as a receptor and some allele from the A*23 or A*24 group of alleles as a donor. The nucleotides at positions 1779 (A), 1785 (A), and 1824 (G) of exon 4 and positions 1976 (T) and 2053 (A) at exon 5 are unique in the A*80:01:01:01 allele and are not found in any other HLA-A alleles (Figure 1). Exon 6 nucleotide sequence is shared from position 2508 to the end of the exon with all HLA-A families except the A3 family; therefore, this exon probably comes from an ancestral HLA-A allele, common to these families, acting as a donor over the ancestor of the A*80:01:01:01. Exon 7 has a nucleotide sequence common to A3, A2, and A9 families (Figure 1). Phylogenetic trees of the exon sequences reflect the previously described results, although the statistically bootstrap numbers are low. Exon 1 sequence is more related with the A2, A9, and A10 family alleles, exons 2 and 3 with the A3 family alleles, and exons 4 and 5 with A3 and A9 families (Figure 2). HLA-A intron sequence comparisons
A simpler pattern is found when considering the intron sequences. The 5′ UTR region of the A*80:01:01:01 has a common sequence with the corresponding ones of the A2, A10, and A19 families and a specific A nucleotide at position 59
Figure 1 Variable nucleotide positions of the most representative HLA-A alleles from 5′ untranslated region (UTR) to intron 7 regions. Clear grey regions represent the higher homology DNA sequence between the considered alleles. Dark grey regions represent the nucleotides specific for the HLA-A*80:01:01:01 allele. Nucleotide agreement with the HLA-A*01:01:01:01 allele is indicated by a hyphen (−). Numbers of the positions are taken from IMGT/HLA database (http://www.ebi.ac.uk/imgt/hla).
HLA-A*80:01:01:01 allele generation
60
I. Cervera et al.
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Tissue Antigens, 2015, 85, 58–67
HLA-A*80:01:01:01 allele generation
Figure 1 Continued.
I. Cervera et al.
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Tissue Antigens, 2015, 85, 58–67
61
I. Cervera et al.
Figure 1 Continued.
HLA-A*80:01:01:01 allele generation
62
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Tissue Antigens, 2015, 85, 58–67
Figure 2 Phylogenetic trees of the most representative human leukocyte antigen (HLA)-A alleles from 5′ untranslated region (UTR) to intron 7. Neighbour-joining tree with 500 bootstrap methodology is used (bootstrap over 40% is shown). The same allelic composition for exons and introns has been made excluding the alleles with incomplete sequences except for the 5′ UTR phylogenetic tree.
I. Cervera et al.
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Tissue Antigens, 2015, 85, 58–67
HLA-A*80:01:01:01 allele generation
63
I. Cervera et al.
Figure 2 Continued
HLA-A*80:01:01:01 allele generation
64
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Tissue Antigens, 2015, 85, 58–67
I. Cervera et al.
HLA-A*80:01:01:01 allele generation
Figure 2 Continued
−104 is found (Figure 1). Intron 1 and intron 2 maintain a common sequence with the A2 and A10 families. In intron 2, there are three nucleotides only present in the A*80:01:01:01 allele (position 519-T, 619-G, and 660-G) (Figure 1). The nucleotide sequence from the beginning of intron 3 to position 1399 is shared with the corresponding ones of the A2, A10, and A19 families and from position 1401 to the end of the intron, the sequence is similar to the corresponding ones of the A3 family and in a lesser degree with the A9 family. Besides, there are 10 nucleotides only found in the A*80:01:01:01 allele: C-1101, T-1137, A-1197, G-1263, C-1299, A-1321, G-1489, A-1495, and G-1566 (Figure 1). Intron 4 follows the same A3 family pattern with 2 specific nucleotides of the A*80:01:01:01 allele (T-1910 and A-1920) (Figure 1). Intron 5 also follows the same A3 family pattern of the last introns with a characteristic A9 motif from position 2223 to 2265. This intron has five specific nucleotides (C-2151, C-2181, T-2399, G-2434, C-2438, and G-2481) (Figure 1). The nucleotide sequence of intron 6 is shared with the corresponding ones of the A2 and A3 families, probably because this intron comes from a common ancestor for the two families. Nucleotide G at position 2585 is exclusive to the A*80:01:01:01 allele (Figure 1). Intron 7 has the same A3 family pattern with similarities to the A9 family. Also, the G nucleotide at position 2769 is unique in the A*80:01:01:01 allele (Figure 1). Phylogenetic trees of the intron sequences yield two groups of evolution, one of them comprising the 5′ UTR, intron 1, and intron 2 related to the A2 and A10 families and in a lesser degree to the A19 and A9 families. The other includes the introns 3, 5, 6, and 7 and is related to the A3 family and in a lesser degree to A9 family (Figure 2). Intron 4 phylogenetic tree locates the A*80:01:01:01 as an outgroup of the rest of the HLA-A alleles and probably could reflect the age of the A*80:01:01:01 allele (Figure 2). In conclusion, when the exon sequences are only considered, a more complex pattern of evolution is found: exons 1, 4, and © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Tissue Antigens, 2015, 85, 58–67
6 share a pattern corresponding to the A3 family with some A9 family common characteristics and exon 7 includes A3, A9, and A2 family characteristics (Figure 1). However, exons 2 and 3 do not present similarities with any HLA-A family (Figure 1). Two clear patterns of evolution of the A*80:01:01:01 allele are found when the non-coding regions are considered. One comprising the 5′ UTR, intron 1, 2, and partial intron 3 whose sequences are common to those of the A2, A10 and in a lesser degree A19 family alleles, and another comprising partial intron 3 until intron 7 shared with the A3 family alleles. The latter has certain characteristics of the A9 (last part of introns 3, 5, and 7) and A2 family alleles (intron 6) (Figures 1 and 2). There are a lot of data supporting the idea that intron sequences give a more clear view of the evolutionary pathways of the HLA alleles generation than the exon sequences (22–24). These data confirm that intron sequences are coming from a recombination from to HLA-A ancestral sequences belonging to A2 and A3 families, respectively, followed by an evolutionary pressure mainly in exons 2 and 3 with point mutations, and other recombination events as cross-linking or gene conversion events with the surrounding alleles. The presence of specific A*80:01:01:01 allele nucleotides (some of them only present in non-human primates, see below) confirms the ancient origin of this allele.
HLA-A and non-human primates MHC-A sequence comparisons
There are 24 nucleotides in intron sequences and 14 in exon sequences only present in the A*80:01:01:01 allele (Figures 1 and 3). Five of 14 nucleotides appearing in exon sequences are present in a specific and low frequency HLA-A alleles (see above). Two of them appear in the A*30 group of alleles, probably due a gene conversion event between the A*30 ancestral alleles and the ancestral A*80:01:01:01 allele. Because of the lack of the intron sequences from the non-human primates MHC-A alleles, a study of the presence of the unique 65
HLA-A*80:01:01:01 allele generation
I. Cervera et al.
Figure 3 Characteristic HLA-A*80:01:01:01 nucleotides and its comparison with the corresponding ones of the non-human primates MHC-A alleles. Grey nucleotides represent the common nucleotides between HLA-A*80:01:01:01 and MHC-A non-human primates alleles. Patr: Pan troglodytes (Chimpazee); Papa: P. Paniscus (Bonobo); Gogo: Gorilla gorilla (Gorilla), Popy: Pongo Pygmaeus (Orangutan) between the considered alleles. E1, exon 1; E2, exon 2; E3, exon 3; E5, exon 5; E6, exon 6. Numbers of the positions are taken from ref. IMGT/HLA database (http://www.ebi.ac.uk/imgt/hla).
A*80:01:01:01 nucleotides of the exon sequences is only possible. From the 14 nucleotides found as unique, 9 appear in the non-human primates (Figure 3): C at position 13 in exon 1, shared with Patr and Papa MHC-A sequences; A-369 in exon 2 present only in Gogo MHC-A sequences; A-422 in exon 2 present in Patr, Papa, and Popy MHC-A sequences; G and A at positions 930 and 931, respectively, in exon 3 appearing in Gogo and Popy MHC-A alleles and are characteristic of the HLA-A*30 alleles; A-1779 in exon 4 shared with Gogo and Popy MHC-A alleles; G-1824 in exon 4 and present in Gogo and Popy MHC-A alleles; and A-2053 present only in Gogo MHC-A allele (Figure 3). From these comparisons, a possible ancestral origin for the A*80:01:01:01 allele could be postulated. The nucleotides T, A, C, A, and T at positions 293, 306, 897, 1785, and 2507, respectively, belonging to HLA-A*80:01:01:01 are not present in any MHC-A non-human primates alleles tested. These data support the notion that the A*80:01:01:01 allele is evolutionarily older than the other HLA-A alleles because these nucleotides are not shared with non-human primate MHC-A sequences (Figure 3). A phylogenetic analysis has been made with the exon sequences of human HLA-A alleles and non-human primate MHC-A alleles (data not shown), confirming the results previously described. The families of A3 and A9 appear to be nearest to the Chimpanzee MHC-A alleles while A2, A10, and A19 are more closely aligned with Gorilla MHC-A alleles. 66
In conclusion, the ancient origin of the A*80:01:01:01 is confirmed from the data obtained. The study of the intron sequences could give a better view of the origin of specific or rare alleles, because they do not support the evolutionary pressure of the exons (mainly exons 2 and 3). In this work, the use of intron sequences has led to the hypothesis of the generation of A*80:01:01:01 coming from a recombination event between an ancestral allele belonging to the A2/A10/A19 common family (shared with Gorilla) with an ancestral allele from the A3 family (shared with Chimpanzee). Therefore, this allele could have been generated before the speciation of the different non-human primates, although other hypotheses can not be discarded. Besides, A*80:01:01:01 has specific nucleotides belonging to Orangutans and has other nucleotides specific for this allele and not present in other HLA-A alleles. The available evidence raises the possibility that A*80:01:01:01 is an old allele of African origin that did not disseminate from Africa during the first colonisation of Europe and Asia by humans. It is of interest that it is defined as an old allele because age is usually associated with subtypic diversity (3, 17). The only explanation is that the A*80 alleles have been isolated in very specific conditions in Africa, and natural selection has deleted the possible variations that appear because these ancient proteins have unique properties that may have conferred evolutionary benefits (15, 25–27). It would be necessary to study the different populations in Africa to detect © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Tissue Antigens, 2015, 85, 58–67
I. Cervera et al.
HLA-A*80:01:01:01 allele generation
the presence/frequency of these alleles to establish a possible explanation. 13.
Acknowledgments
This work was supported, in part, by grant of the Ministerio de Ciencia e Innovación (PI-11/0333).
14.
Conflict of interest
15.
There is no conflict of interest in the present manuscript. 16.
References 1. Robinson J, Halliwell JA, McWiliam H, Lopez R, Parham P, Marsh SGE. The IMGT/HLA database. Nucleic Acid Res 2013: 41: D1222–7. 2. Robinson J, McWiliam H, Lopez R, Marsh SGE. IPD – the Immuno Polymorphism Database. Nuceic Acid Res 2013: 41: D1234–40. 3. Domena JD, Hildebrand WH, Bias WB, Parham P. A sixth family of HLA-A alleles defined by HLA-A*8001. Tissue Antigens 1993: 42: 156–9. 4. Kato K, Trapani JA, Allopenna J, Dupont B, Yang SY. Molecular analysis of the serologically defined HLA-Aw19 antigens. A genetically distinct family of HLA-A antigens comprising A29, A31, A32, and Aw33, but probably not A30. Immunology 1989: 143: 3371–8. 5. Adam EJ, Cooper S, Thomson G, Parham P. Common chimpanzees have greater diversity than humans at two of the three highly polymorphic MHC class I genes. Immunogenetics 2000: 51: 410–4. 6. Cowan EP, Jelachich ML, Biddison WE, Coligan JE. DNA sequence of HLA-A11: remarkable homology with HLA-A3 allows identification of residues involved in epitopes recognized by antibodies and T cells. Immunogenetics 1987: 25: 241–50. 7. Jakobsen IB, Gao X, Easteal S, Chelvanayagam G. Correlating sequence variation with HLA-A allelic families: implications for T cell receptor binding specificities. Immunol Cell Biol 1998: 76: 135–42. 8. Lawlor DA, Warren E, Ward FE, Parham P. Comparisons of class I MHC alleles in humans and apes. Immunol Rev 1990: 113: 147–85. 9. Lawlor DA, Warren E, Taylor P, Parham P. Gorilla class I major histocompatibility complex alleles: comparison to human and chimpanzee class I. J Exp Med 1991: 174: 1491–509. 10. Little AM, Madrigal JA, Parham P. Molecular definition of an elusive third HLA-A9 molecule: HLA-A9.3. Immunogenetics 1992: 35: 41–5. 11. Madrigal JA, Hildebrand WH, Belich MP et al. Structural diversity in the HLA-A10 family of alleles: correlations with serology. Tissue Antigens 1993: 41: 72–80. 12. Chen ZW, Hughes AL, Ghim SH, Letvin NL, Watkins DI. Two more chimpanzee Patr-A locus alleles related to the
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Tissue Antigens, 2015, 85, 58–67
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
HLA-A1/A3/A11 family. Immunogenetics 1993: 38: 238–40. Lawlor DA, Ward FE, Ennis PD, Jackson AP, Parham P. HLA-A and B polymorphisms predate the divergence of humans and chimpanzees. Nature 1988: 335: 268–71. Mayer WE, Jonker M, Klein D, Ivanyi P, van Seventer G, Klein J. Nucleotide sequences of chimpanzee MHC class I alleles: evidence for trans-species mode of evolution. EMBO J 1988: 7: 2765–74. Klein J. Origin of major histocompatibility complex polymorphism: the trans-species hypothesis. Hum Immunol 1987: 19: 155–62. Wagner AG, Hughes AL, Iandoli ML et al. HLA-A*8001 is a member of a newly discovered ancient family of HLA-A alleles. Tissue Antigens 1993: 42: 522–9. Starling GC, Witkowski JA, Speerbrecher LS, McKinney SK, Hansen JA, Choo SY. A novel HLA-A*8001 allele identified in an African-American population. Hum Immunol 1994: 39: 163–8. de Groot NG, Otting N, Robinson J et al. Nomenclature report on the major histocompatibility complex genes and alleles of Great Ape, Old and New World monkey species. Immunogenetics 2012: 64: 615–31. Martinez-Laso J, Moscoso J, Zamora J et al. Different evolutionary pathway of B*570101 and B*5801 (B17 group) alleles based in intron sequences. Immunogenetics 2004: 55: 866–72. Higgins D, Thompson J, Gibson T, Thompson JD, Higgins DG, Gibson TJ. CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. Nucleic Acids Res 1994: 22: 4673–80. Tamura K, Stecher G, Peterson D, Filipski A, Kumar S. MEGA6: Molecular Evolutionary Genetics Analysis version 6.0. Mol Biol Evol 2013: 30: 2725–9. Gomez-Casado E, Vargas-Alarcón G, Martínez-Laso J et al. Evolutionary relationship between HLA-B alleles as indicated by an analysis of intron sequences. Tissue Antigens 1999: 53: 153–60. Martínez-Laso J, Herraiz MA, Vidart JA et al. Polymorphism of the HLA-B*15 group of alleles is generated following 5 lineages of evolution. Hum Immunol 2011: 72: 412–21. Roman A, Cervera I, Head J, Rodríguez M, Martínez-Laso J. Generation of HLA-B*1516/B*1567/B*1595 and B*1517 alleles (B15 specific group) by transpecies evolution. Hum Immunol 2007: 68: 1001–8. Hughes AL, Nei M. Pattern of nucleotide substitution at major histocompatibility complex class I loci reveals over dominant selection. Nature 1988: 335: 167–70. Hughes AL, Nei M. Nucleotide substitution at major histocompatibility complex class II loci: evidence for overdominant selection. Proc Natl Acad Sci U S A 1989: 86: 958–62. Parham P, Arnett KL, Adams EJ et al. Episodic evolution and turnover of HLA-B in the indigenous human populations of the Americas. Tissue Antigens 1997: 50: 219–32.
67
Copyright of Tissue Antigens is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
