Journal Mobile Options
Table of Contents
Vol. 110, No. 1-4, 2005
Issue release date: 2005
Cytogenet Genome Res 110:193–202 (2005)

Polymorphic Alu insertions within the Major Histocompatibility Complex class I genomic region: a brief review

Kulski J.K. · Dunn D.S.
Centre for Bioinformatics and Biological Computing, School of Information Technology, Murdoch University, Murdoch (Western Australia)

Individual Users: Register with Karger Login Information

Please create your User ID & Password

Contact Information

I have read the Karger Terms and Conditions and agree.

To view the fulltext, please log in

To view the pdf, please log in


Most polymorphic Alu insertions (POALINs) belong to a subgroup of the Alu multicopy retrotransposon family of short interspersed nucleotide elements (SINEs) that are categorized as AluYb8 and AluYa5. The number of AluYb8/AluYa5 members (∼4,492 copies) is significantly less than the ∼one million fixed Alu copies per human genome. We have studied the presence of POALINs within the Major Histocompatibility Complex (MHC) class I region on the short arm of chromosome 6 (6p21.3) because this region has a high gene density, many genes with immune system functions, large sequence variations and diversity, duplications and redundancy, and a strong association with more than 100 different diseases. Since little is known about POALINs within the MHC genomic region, we undertook to identify some of the members of the AluYb8/AluYa5 subfamily and to study their frequency of distribution and genetic characteristics in different populations. As a result of our comparative genomic analyses, we identified the insertion sites for five POALINs distributed within the MHC class I region. This brief review outlines the locations of the insertions and sequence features of the five MHC POALINs, their single site and haplotype frequencies in different geographic populations, and their association with different HLA class I genes and disease. We show that the MHC POALINs have a potential value as lineage and linkage markers for the study of human population genetics, disease associations, genomic diversity and evolution.   

Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.


  1. Antunez-de-Mayolo G, Antunez-de-Mayolo A, Antunez-de-Mayolo P, Papiha SS, Hammer M, Yunis JJ, Yunis EJ, Damodaran C, Martinez de Pancorbo M, Caeiro JL, Puzyrev VP, Herrera RJ: Phylogenetics of worldwide human populations as determined by polymorphic Alu insertions. Electrophoresis 23:3346–3356 (2002).
  2. Bamshad M, Kivisild T, Watkins WS, Dixon ME, Ricker CE, Rao BB, Naidu JM, Prasad BV, Reddy PG, Rasanayagam A, Papiha SS, Villems R, Redd AJ, Hammer MF, Nguyen SV, Carroll ML, Batzer MA, Jorde LB: Genetic evidence on the origins of Indian caste populations. Genome Res 11:994–1004 (2001).
  3. Batzer MA, Alegria-Hartman M, Deininger PL: A consensus Alu repeat probe for physical mapping. Genet Anal Tech Appl 11:34–38 (1994).
  4. Batzer MA, Arcot SS, Phinney JW, Alegria-Hartman M, Kass DH, Milligan SM, Kimpton C, Gill P, Hochmeister M, Ioannou PA, Herrera RJ, Boudreau DA, Scheer WD, Keats BJ, Deininger PL, Stoneking M: Genetic variation of recent Alu insertions in human populations. J Mol Evol 42:22–29 (1996).
  5. Bergfeldt L: HLA-B27-associated cardiac disease. Ann Intern Med 127:621–629 (1997).
  6. Bowcock AM, Ruiz-Linares A, Tomfohrde J, Minch E, Kidd JR, Cavalli-Sforza LL: High resolution of human evolutionary trees with polymorphic microsatellites. Nature 368:455–457 (1994).
  7. Calderon R, Carrion M, Perez-Miranda A, Pena JA, Dugoujon JM, Crouau-Roy B: Allele variation of DYS19 and Y-Alu insertion (YAP) polymorphisms in Basques: an insight into the peopling of Europe and the Mediterranean region. Hum Biol 75:117–127 (2003).
  8. Carroll ML, Roy-Engel AM, Nguyen SV, Salem AH, Vogel E, Vincent B, Myers J, Ahmad Z, Nguyen L, Sammarco M, Watkins WS, Henke J, Makalowski W, Jorde LB, Deininger PL, Batzer MA: Large-scale analysis of the Alu Ya5 and Yb8 subfamilies and their contribution to human genomic diversity. J Mol Biol 311:17–40 (2001).
  9. Chang D-Y, Maraia RJ: A cellular protein binds B1 and Alu small cytoplasmic RNAs in vitro. J Biol Chem 268:6423–6428 (1993).
  10. Chu WM, Ballard R, Carpick BW, Williams BR, Schmid CW: Potential Alu function. Mol Cell Biol 18:58–68 (1998).
  11. Comas D, Plaza S, Calafell F, Sajantila A, Bertranpetit J: Recent insertion of an Alu element within a polymorphic human-specific Alu insertion. Mol Biol Evol 18:85–88 (2001).
  12. Couzin J: New mapping project splits the community. Science 296:1391–1393 (2002).
  13. Deininger PL, Batzer MA: A human-specific subfamily of Alu sequences. Genomics 9:481–487 (1991).
  14. Deininger PL, Batzer MA: Evolutionary analyses of repetitive DNA sequences. Meth Enzymol 224:213–232 (1993).
  15. Deininger PL, Batzer MA: Alu repeats and human disease. Mol Genet Metab 67:183–193 (1999).
  16. Donev R, Horton R, Beck S, Doneva T, Vatcheva R, Bowen WR, Sheer D: Recruitment of heterogeneous nuclear ribonucleoprotein A1 in vivo to the LMP/TAP region of the major histocompatibility complex. J Biol Chem 278:5214–5226 (2003).
  17. Dunn DS, Naruse T, Inoko H, Kulski JK: The association between HLA-A aleles and young Alu dimorphisms near the HLA-J, -H, and -F genes in workshop cell lines and Japanese and Australian populations. J Mol Evol 55:718–726 (2002).
  18. Dunn DS, Ota M, Inoko H, Kulski JK: Association of MHC dimorphic Alu insertions with HLA class I and MHC genes in Japanese HLA-B48 haplotypes. Tissue Antigens 62:259-262 (2003a).
  19. Dunn DS, Inoko H, Kulski JK: Dimorphic Alu element located between the TFIIH and CDSN genes within the Major Histocompatibility Complex. Electrophoresis 24:2740–2748 (2003b).
  20. Gaudieri S, Kulski JK, Dawkins RL, Gojobori T: Extensive nucleotide variability within a 370 kb sequence from the central region of the Major Histocompatibility Complex. Gene 238:157–161 (1999).
  21. Gaudieri S, Dawkins RL, Habara K, Kulski JK, Gojobori T: SNP profile within the Human Histocompatibility Complex reveals an extreme and interrupted level of nucleotide diversity. Genome Res 10:1579–1586 (2000).
  22. Hammer MF: A recent insertion of an Alu element on the Y chromosome is a useful marker for human population studies. Mol Biol Evol 11:749–761 (1994).
  23. Hammer MF, Spurdle AB, Karafet T, Bonner MR, Wood ET, Novelletto A, Malaspina P, Mitchell RJ, Horai S, Jenkins T, Zegura SL: The geographic distribution of human Y chromosome variation. Genetics 145:787–805 (1997).
  24. Judson R, Stephens JC, Windemuth A: The predictive power of haplotypes in clinical response. Pharmocogenomics 1:15–26 (2000).
  25. Jurka J, Klonowski P, Dagman V, Pelton P: CENSOR – a program for identification and elimination of repetitive elements from DNA sequences. Comp Chem 20:119–121 (1996).
  26. Kass DH, Batzer MA, Deininger PL: Gene conversion as a secondary mechanism in SINE evolution. Mol Cell Biol 15:19–25 (1995).
  27. Klein MR, van der Burg SH, Hovenkamp E, Holwerda AM, Drijfhout JW, Melief CJ, Miedema F: Characterisation of HLA-B57-restricted HIV type 1 Gag- and RT-specific cytotoxic T lymphocyte responses. J Gen Virol 79:2191–2201 (1998).
  28. Kropotov A, Sedova V, Ivanov V, Sazeeva N, Tomilin A, Krutilina R, Oei SL, Griesenbeck J, Buchlow G, Tomilin N: A novel human DNA-binding protein with sequence similarity to a subfamily of redox proteins which is able to repress RNA-polymerase-III-driven transcription of the Alu-family retroposons in vitro. Eur J Biochem 260:336–346 (1999).
  29. Kulski JK, Dawkins, RL: The P5 multicopy gene family in the MHC is related in sequence to human endogenous retroviruses HERV-L and HERV-16. Immunogenetics 49:404–412 (1999).
  30. Kulski JK, Inoko H: MHC Genes, in: The Encyclopedia of the Human Genome, pp 778–785 (Nature Publishing Group, Macmillan Publishers Ltd, Basingstoke 2003).
  31. Kulski JK, Martinez P, Shiina T, Longman-Jacobsen N, Naruse T, Inoko H, Wang W, Williamson J, Dawkins RL: The association between HLA-A alleles and an Alu dimorphism near HLA-G. J Mol Evol 53:114–123 (2001).
  32. Kulski JK, Dunn D, Hui J, Martinez P, Rhomphruk AV, Leelayuwat C, Tay G, Oka A, Inoko H: Alu polymorphism within the MICB gene and association with HLA-B alleles. Immunogenetics 53:975–979 (2002a). Erratum in Immunogenetics 54:365 (2002a).
  33. Kulski JK, Shiina T, Anzai T, Kohara S, Inoko H: Comparative genomic analysis of the MHC: the evolution of class I duplication blocks, diversity and complexity from shark to man. Immunol Rev 190:95–122 (2002b).
  34. Kulski JK, Anzai T, Inoko H: ERVK9, transposons and the evolution of MHC class I duplicons within the alpha-block of the human and chimpanzee. Cytogenet Genome Res 110:181–192 (2005).
  35. Lander ES, Linton LM, Birren B, et al: Initial sequencing and the analysis of the human genome. Nature 409:860–921 (2001).
  36. Le Bouteiller P: HLA class I chromosomal region, genes, and products: facts and questions. Crit Rev Immunol 14:89–129 (1994).
  37. Li T-H, Schmid CW: Differential stress induction of individual Alu loci: implications for transcription and retrotransposition. Gene 276:135–141 (2001).
  38. Lukyanov DV, Urusova ME, Shcherba KM, Podgornaya OI: Alu-DNA repeat-binding protein p68 is part of Alu-RNA containing alpha-RNP. Eur J Biochem 267:2362–2371 (2000).
  39. Makalowski W: Not junk after all. Science 300:1246–1247 (2003).
  40. Mallal S, Nolan D, Witt C, Martin AM, Moore C, Sayer D, Castley A, Mamotte C, Maxwell D, James I, Christiansen FT: Association between presence of HLA-B*5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir. Lancet 359:727–732 (2002).
  41. Martinez J, Dugaiczyk LJ, Zielinski R, Dugaiczyk A: Human genetic disorders, a phylogenetic perspective. J Mol Biol 308:587–596 (2001).
  42. Matsuzaka Y, Makino S, Nakajima K, Tomizawa M, Oka A, Bahram S, Kulski JK, Tamiya G, Inoko H: New polymorphic markers in the human MHC class III region. Tissue Antigens 57:397–404 (2001).
  43. Mattick JS: The new genetics. The human genome and the future of medicine. Med J Aust 179:212–216 (2003).
  44. Mighell AJ, Markham AF, Robinson PA: Minireview: Alu sequences. FEBS Letters 417:1–5 (1997).
  45. Nasidze I, Risch GM, Robichaux M, Sherry ST, Batzer MA, Stoneking M: Alu insertion polymorphisms and the genetic structure of human populations from the Caucasus. Eur J Hum Genet 9:267–272 (2001).
  46. Oka A, Hayashi H, Tomizawa M, Okamoto K, Hui J, Kulski JK, Beilby J, Inoko H, Tamiya G: Localization of a non-melonoma skin cancer susceptibility region within the Major Histocompatibility Complex by association analysis using microsatellite markers. Tissue Antigens 61:203–210 (2003).
  47. Ohler LD, Rose EA: Optimization of long-distance PCR using a transposon-based model system. PCR Methods Appl 2:51–59 (1992).
  48. Ohno S, Yomo T: The grammatical rule for all DNA: junk and coding sequences. Electrophoresis 12:103–108 (1991).
  49. Orgel LE, Crick FHC: Selfish DNA: The ultimate parasite. Nature 284:604–607 (1980).
  50. de Pancorbo MM, Lopez-Martinez M, Martinez-Bouzas C, Castro A, Fernandez-Fernandez I, de Mayolo GA, de Mayolo AA, de Mayolo PA, Rowold DJ, Herrera RJ: The Basques according to polymorphic Alu insertions. Hum Genet 109:224–233 (2001).
  51. Parham P: Virtual reality in the MHC. Immunol Rev 167:5–15 (1999).
  52. Picornell A, Tomas C, Jimenez G, Castro JA, Ramon MM: Jewish population genetic data in 20 polymorphic loci. Forensic Sci Int 125:52–58 (2002).
  53. Potts WK, Wakeland EK: The maintenance of MHC polymorphism. Immunol Today 11:39–40 (1990).
  54. Rani R, Narayan R, Fernandez-Vina MA, Stastny P: Role of HLA-B and C alleles in the development of psoriasis in patients from North India. Tissue Antigens 51:618–622 (1998).
  55. Rodriguez-Delfin L, Santos SE, Zago MA: Diversity of the human Y chromosome of South American Amerindians: a comparison with blacks, whites, and Japanese from Brazil. Ann Hum Genet 61:439–448 (1997).
  56. Rowold DJ, Herrera RJ: Alu elements and the human genome. Genetica 108:57–72 (2000).
  57. Roy AM, Carroll ML, Nguyen SV, Salem A-H, Oldridge AOM, Batzer MA, Deininger PL: Potential gene conversion and source genes for recently integrated Alu elements. Genome Res 10:1485–1495 (2000a).
  58. Roy AM, West NC, Rao A, Adhikari P, Aleman C, Barnes AP, Deininger PL: Upstream flanking sequences and transcription of SINEs. J Mol Biol 302:17–25 (2000b).
  59. Roy-Engel AM, Carroll ML, Vogel E, Garber RK, Nguyen SV, Salem AH, Batzer MA, Deininger PL: Alu insertion polymorphisms for the study of human genomic diversity. Genetics 61:6640–6648 (2001).
  60. Santos EJM, Epplen JT, Epplen C: Extensive gene flow in human populations as revealed by protein and microsatellite DNA markers. Hum Hered 47:165–172 (1997).
  61. Sachidanandam R, Weissman D, Schmidt SC, Kakol JM, Stein LD, Marth G, Sherry S, Mullikin JC, Mortimore BJ, Willey DL, et al: A map of human genome sequence variation containing 1.442 million single nucleotide polymorphisms. Nature 409:928–933 (2001).
  62. Schneider S, Roessli D, Excofier L: Arlequin: a software for population genetics data analysis. Version 2.000 (2000).
  63. Sherry ST, Harpending HC, Batzer MA, Stoneking M: Alu evolution in human populations. Genetics 147:1977–1982 (1994).
  64. Stephens JC, Schneider JA, Tanguay DA, Choi J, Acharya T, Stanley SE, Jiang R, Messer CJ, Chew A, Han JH, et al: Haplotype variation and linkage disequilibrium in 313 human genes. Science 293:489–493 (2001).
  65. Stoneking M, Fontius JJ, Clifford SL, Soodyall H, Arcot SS, Saha N, Jenkins T, Tahir MA, Deininger PL, Batzer MA: Alu insertion polymorphisms and human evolution. Evidence for a larger population size in Africa. Genome Res 7:1061–1071 (1997).
  66. Tajima A, Pan IH, Fucharoen G, Fucharoen S, Matsuo M, Tokunaga K, Juji T, Hayami M, Omoto K, Horai S: Three major lineages of Asian Y chromosomes: implications for the peopling of east and southeast Asia. Hum Genet 110:80–88 (2002).
  67. Ullu E, Tschudi C: Alu sequences are processed 7SL RNA genes. Nature 312:171–172 (1984).
  68. Vansant G, Reynolds WF: The consensus sequence of a major Alu subfamily contains a functional retinoic acid response element. Proc Natl Acad Sci USA 92:8229–8233 (1995).
  69. Watkins WS, Ricker CE, Bamshad MJ, Carroll ML, Nguyen SV, Batzer MA, Harpending HC, Rogers AR, Jorde LB: Patterns of ancestral human diversity: an analysis of Alu-insertion and restriction-site polymorphisms. Am J Hum Genet 68:738–752 (2001).
  70. Watkins WS, Rogers AR, Ostler CT, Wooding S, Bamshad MJ, Brassington A-M, Carroll, ML, Nguyen SV, Walker JA, Prasad BVR, Reddy PG, Das PK, Batzer MA, Jorde LB: Genetic variation among world populations: Inferences from 100 Alu insertion polymorphisms. Genome Res 13:1607–1618 (2003).
  71. Weichenrieder O, Stehlin C, Kapp U, Birse DE, Timmins PA, Strub K, Cusack S: Hierarchical assembly of the Alu domain of the mammalian signal recognition particle. RNA 7:731–740 (2001).
  72. West NC, Roy-Engel AM, Imataka H, Sonenberg N, Deininger PL: Shared protein components of SINE RNPs. J Mol Biol 321:423–432 (2002).
  73. York DS, Blum VM, Low JA, Rowold DJ, Puzyrev V, Saliukov V, Odinokova O, Herrera RJ: Phylogenetic signals from point mutations and polymorphic Alu insertions. Genetica 107:163–170 (1999).
  74. Zerjal T, Wells RS, Yuldasheva N, Ruzibakiev R, Tyler-Smith C: A genetic landscape reshaped by recent events: Y-chromosomal insights into Central Asia. Am J Hum Genet 7:466–482 (2002).

Pay-per-View Options
Direct payment This item at the regular price: USD 38.00
Payment from account With a Karger Pay-per-View account (down payment USD 150) you profit from a special rate for this and other single items.
This item at the discounted price: USD 26.50