Definition of Emphasis Type="Italic"MafaA/Emph

Authors: Nel Otting Gaby G M Doxiadis Ronald E Bontrop

Publish Date: 2009/11/24

Volume: 61, Issue: 11-12, Pages: 745-753

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Abstract

The major histocompatibility complex MHC class I B gene/allelic repertoire was investigated in a pedigreed population of cynomolgus macaques of mixed Indonesian/Malaysian origin The MafaB alleles detected in this cohort are mostly specific for a given geographic area and only a small number of alleles appears to be shared with other populations This suggests the fast evolution of MafaB alleles due to adaptation to new environments In contrast to humans the B locus in Old World monkeys displays extensive copy number variation The MafaB and previously defined A gene combinations segregate in families and thus allowed the definition of extended haplotypes In many cases it was possible to assign a particular MafaI allele to one of these MafaA/B haplotypes as well The presence of a large number of stable haplotypes in this cohort of animals which was pedigreed for up to eight generations looks promising for developing discriminative MHC typing tools that are less cumbersome Furthermore the discovery of 53 unreported MafaB sequences expands the lexicon of alleles significantly and may help in understanding the complex organisation of the macaque B regionThe cynomolgus macaque Macaca fascicularis also known as the crabeating or longtailed macaque is widely used as an animal model in biomedical studies Currently this species is applied as often as the commonly used rhesus macaque Macaca mulatta Cynomolgus monkeys are used as models for infectious diseases such as AIDS SARS and tuberculosis as well as for transplantation research McAuliffe et al 2004 Wiseman et al 2007 Aoyama et al 2009 Mee et al 2009 Reed et al 2009 Owing to use of macaques in immunerelated research thorough investigations of their major histocompatibility complexes MHC are required The MHC represents a multigene family in which the proteins play a key role in the generation of adaptive immune responses in vertebrate species The class I and II genes of the MHC display abundant polymorphism that has a profound impact on features such as disease susceptibility organ transplantation and reproduction successThe MHC systems in humans HLA and in other primate species have been studied extensively Bontrop 2006 The orthologues of the classical HLAA and B genes which are involved in the presentation of intracellularly processed peptides to cytotoxic T cells are present in the rhesus and cynomolgus macaque Boyson et al 1996 Krebs et al 2005 However in these animals the genes have undergone several rounds of duplication and display copy number variation Anzai et al 2003 DazaVamenta et al 2004 Otting et al 2005 Whereas in humans only one copy of the HLAA and B genes is present in macaques seven Alike genes are distinguished On each haplotype one polymorphic gene is observed named MamuA1 or MafaA1 in combination with one or two oligomorphic genes designated Mamu or MafaA2 up to A7 respectively Otting et al 2007 Pendley et al 2008 Campbell et al 2009 Kita et al 2009 The same organisation is also applicable to the pigtailed macaque Macaca nemestrina Lafont et al 2007 Wu et al 2008The situation for the HLAB orthologues in macaque species is even more complicated In one rhesus macaque the MHC region was completely sequenced yielding one complete haplotype of 53 megabasepairs On this haplotype 19 distinct MamuB genes were present of which 14 genes have the potential to code for bonafide proteins Anzai et al 2003 DazaVamenta et al 2004 Bonhomme et al 2008 Doxiadis et al 2009 For the MHC of cynomolgus macaque a BACbased contig map was constructed Watanabe et al 2007 Although the degree of gene multiplication is less than in the rhesus macaque this contig map still contains 12 distinct MafaB like loci Sequencing studies at the cDNA level however have shown that only two or three genes per haplotype are transcribed at considerable levels majors in rhesus and in cynomolgus macaques Krebs et al 2005 Otting et al 2005 2008 Pendley et al 2008 At least one other Blike gene characterised by low levels of polymorphism and transcription minors is present on all haplotypes It has been designated MamuI MafaI and ManeI in the respective species of macaques Urvater et al 2000 Robinson et al 2003 On the completely sequenced MHCregion of the rhesus macaque this locus is designated as the MamuB3 gene DazaVamenta et al 2004 Doxiadis et al 2009The sequencing of macaques from different geographic areas has shown that each population has its own characteristic set of Mamu/MafaA and B alleles and only a few alleles are shared between cohorts/populations Krebs et al 2005 Otting et al 2008 Campbell et al 2009 This is in contrast to the data that were observed for the MHC class II sequences obtained from these species Otting et al 2002 Doxiadis et al 2006 O’Connor et al 2007 de Groot et al 2008 Moreover the interspecies sharing of MHC class I alleles in rhesus and cynomolgus macaques is in the same order of magnitude as the intraspecies sharing Otting et al 2007We have access to cynomolgus macaques that have been pedigreed for eight generations and the origin of the animals was determined based on mtDNA analyses In an earlier study we showed that the MafaA alleles are mostly unique for this population Hence a unique set of MafaB alleles is expected to be present in the same animals The question is whether these Balleles segregate in a stable linkage to the already described MafaA sequences in these animals Should this be the case MHC typing on this cohort may be then performed using less cumbersome techniques for instance those based on microsatellite or SNP analyses

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