Reactivation by exon shuffling of a conserved<i>HLA-DR3</i>-like pseudogene segment in a New World primate species

Doxiadis, Gaby G. M.; Wiel, Marit K. H. van der; Brok, Herbert; Groot, Natasja G. de; Otting, Nel; Hart, Bert A. ’t; Rood, Jon J. van; Bontrop, Ronald E.

doi:10.1073/pnas.0600643103

Cited by 44 publications

(42 citation statements)

References 40 publications

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“…The observed number of such shared polymorphic sites is far beyond that explained by multiple mutations. There are a number of shared polymorphic sites among other HLA-DRB genes (not shown), indicating that gene conversion has been active in the HLA-DRB cluster, thereby contributing to the introduction of new types of PBR.Very similar patterns are also observed in other primates (Go et al 2003;Abbott et al 2006;Doxiadis et al 2006). Of particular interest is chimpanzee's ortholog of HLA-DRB6 (represented by Patr-DRB6), which has a very high level of variation, although it is a pseudogene.…”

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confidence: 54%

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Preservation of a Pseudogene by Gene Conversion and Diversifying Selection

et al. 2008

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Interlocus gene conversion is considered a crucial mechanism for generating novel combinations of polymorphisms in duplicated genes. The importance of gene conversion between duplicated genes has been recognized in the major histocompatibility complex and self-incompatibility genes, which are likely subject to diversifying selection. To theoretically understand the potential role of gene conversion in such situations, forward simulations are performed in various two-locus models. The results show that gene conversion could significantly increase the number of haplotypes when diversifying selection works on both loci. We find that the tract length of gene conversion is an important factor to determine the efficacy of gene conversion: shorter tract lengths can more effectively generate novel haplotypes given the gene conversion rate per site is the same. Similar results are also obtained when one of the duplicated genes is assumed to be a pseudogene. It is suggested that a duplicated gene, even after being silenced, will contribute to increasing the variability in the other locus through gene conversion. Consequently, the fixation probability and longevity of duplicated genes increase under the presence of gene conversion. On the basis of these findings, we propose a new scenario for the preservation of a duplicated gene: when the original donor gene is under diversifying selection, a duplicated copy can be preserved by gene conversion even after it is pseudogenized. I NTERLOCUS gene conversion plays significant roles in shaping the pattern of polymorphism and divergence in duplicated genes (Ohta 1980;Li 1997;Innan 2003;Teshima and Innan 2004). Gene conversion exchanges DNA segments between duplicated genes, which is usually described as a copy-and-paste event ( Figure 1). With this mechanism, duplicated genes undergo nonindependent molecular evolution. There are at least two major outcomes of gene conversion, which seem somewhat conflicting. One is the phenomenon called ''concerted evolution,'' in which gene conversion reduces sequence variation between duplicates (Ohta 1980;Zimmer et al. 1980;Dover 1982;Li 1997). The other is that gene conversion creates and enhances genetic variation within a gene family (Miyata et al. 1980;Baltimore 1981;Ohta 1991Ohta , 1992Ohta , 1997. This discrepancy between the two conflicting outcomes can be explained when considering the role of selection and how ''genetic variation'' is defined.Concerted evolution is the outcome that can be more intuitively understandable, because it is obvious that a gene conversion event makes the sequence identical for the converted region regardless of its tract length (Figure 1). When gene conversion occurs frequently, the sequence identity between duplicated genes is likely high, while there would be some divergence from their orthologous genes in a different species. This phenomenon was first observed in the rDNA genes (Brown et al. 1972;Coen et al. 1982), and the genomewide significance of the role of gene conversion has been recently em...

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confidence: 54%

“…Very similar patterns are also observed in other primates (Go et al 2003;Abbott et al 2006;Doxiadis et al 2006). Of particular interest is chimpanzee's ortholog of HLA-DRB6 (represented by Patr-DRB6), which has a very high level of variation, although it is a pseudogene.…”

Section: Genetic Variation and Haplotype Structure In The Mhc And Si mentioning

confidence: 52%

Preservation of a Pseudogene by Gene Conversion and Diversifying Selection

et al. 2008

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“…An alternative interpretation of the stability of the DRB7 pseudogene and/or its region configuration could be that the integration of the HERV-K14I in the intron 2 of DRB7 may have acted against recombination events with other DRB genes. One of the benefits of highly conserved pseudogenes is that gene segments can be recruited or reactivated by recombination processes (22). This type of genetic mechanism, which promotes reuse of old entities that once worked, is more frequent and far more probable than point mutations.…”

Section: Discussionmentioning

confidence: 99%

Impact of Endogenous Intronic Retroviruses on Major Histocompatibility Complex Class II Diversity and Stability

Doxiadis

Groot

Bontrop

2008

J Virol

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The major histocompatibility complex (MHC) represents a multigene family that is known to display allelic and gene copy number variations. Primate species such as humans, chimpanzees (Pan troglodytes), and rhesus macaques (Macaca mulatta) show DRB region configuration polymorphism at the population level, meaning that the number and content of DRB loci may vary per haplotype. Introns of primate DRB alleles differ significantly in length due to insertions of transposable elements as long endogenous retrovirus (ERV) and human ERV (HERV) sequences in the DRB2, DRB6, and DRB7 pseudogenes. Although the integration of intronic HERVs resulted sooner or later in the inactivation of the targeted genes, the fixation of these endogenous retroviral segments over long time spans seems to have provided evolutionary advantage. Intronic HERVs may have integrated in a sense or an antisense manner. On the one hand, antisense-oriented retroelements such as HERV-K14I, observed in intron 2 of the DRB7 genes in humans and chimpanzees, seem to promote stability, as configurations/alleles containing these hits have experienced strong conservative selection during primate evolution. On the other hand, the HERVK3I present in intron 1 of all DRB2 and/or DRB6 alleles tested so far integrated in a sense orientation. The data suggest that multigenic regions in particular may benefit from sense introgressions by HERVs, as these elements seem to promote and maintain the generation of diversity, whereas these types of integrations may be lethal in monogenic systems, since they are known to influence transcript regulation negatively.

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“…Immunization of marmosets with rhMOG in CFA leads to a 100% disease incidence that maps to the MHC class II allele Caja-DRB*W1201, which is ubiquitously expressed in marmosets (Antunes et al 1998;Brok et al 2000;Doxiadis et al 2006). In marmosets immunized with rhMOG, Caja-DRB*W1201 presentation of MOG 24-36 leads to the activation of MOG 24-36 specific Th1-cells in all animals .…”

Section: Specificitymentioning

confidence: 99%

“…Caja-DRB*W12 appears to be monomorphic with two alleles, which differ only at two codons. All marmosets express DRB*W1201 or DRB*W1202 (Antunes et al 1998;Doxiadis et al 2006;Prasad et al 2006;Wu et al 2000). Despite the limited polymorphism of the MHC, marmosets contain a diverse and evolutionary stable T cell receptor -and -chain repertoire (Fujii et al 2010;Uccelli et al 1997).…”

mentioning

confidence: 99%