The origin of MHC class II gene polymorphism within the genus Mus

Abstract

The I region of the major histocompatibility complex (MHC) of the mouse (H-2) contains a tightly-linked cluster of highly polymorphic genes (class II MHC genes) which control immune responsiveness. Speculation on the origin of this polymorphism, which is believed to be essential for the function of the class II proteins in immune responses to disease, has given rise to two hypotheses. The first is that hypermutational mechanisms (gene conversion or segmental exchange) promote the rapid generation of diversity in MHC genes. The alternative is that polymorphism has arisen from the steady accumulation of mutations over long evolutionary periods, and multiple specific alleles have survived speciation (trans-species evolution). We have looked for evidence of 'segmental exchange' and/or 'trans-species evolution' in the class II genes of the genus Mus by molecular genetic analysis of I-A beta alleles. The results indicate that greater than 90% (28 out of 31) of the alleles examined can be organized into two evolutionary groups both on the basis of restriction site polymorphisms and by the presence or absence of a short interspersed nucleotide element (SINE). Using this SINE sequence as an evolutionary tag, we demonstrate that I-A beta alleles in these two evolutionary groups diverged at least three million years ago and have survived the speciation events leading to several modern Mus species. Nucleotide sequence comparisons of eight Mus m. domesticus I-A beta alleles representing all three evolutionary groups indicate that most of the divergence in exon sequences is due to the steady accumulation of mutations that are maintained independently in the different alleles. But segmental exchanges between alleles from different evolutionary groups have also played a role in the diversification of beta 1 exons.

Thymic Selection Generates T Cells Expressing Self-Reactive TCRs in the Absence of CD45

“…None of the 45E9T hybridomas tested displayed alloreactivity to H-2 k (Fig. 2, bottom right), which reflects the considerable disparity between H-2 k and H-2 b (65).…”

“…Hence, a fraction of the class II MHC-peptide complexes expressed in these mice are foreign with respect to the H-2 b background. DBA/2 and B10.BR mice carry the H-2 d and H-2 k haplotypes, respectively, the former being more closely related to H-2 b than the latter (65). When stimulated with syngeneic APCs (CD45 Ϫ/Ϫ H-2 b ), several 45E9T hybridomas displayed anti-self reactivity (Fig.…”

Prevalence and evolutionary origins of autoimmune susceptibility alleles in natural mouse populations

“…[1][2][3][4] Allelic lineages of MHC class I and class II genes also have extremely long coalescence times, often persisting in natural populations over time spans that encompass multiple speciation events. [5][6][7] Although the diversity found at MHC loci remains unparalleled in the mammalian genome, several other immunoregulatory gene complexes also exhibit significant levels of diversity 8,9 suggesting that selection may favor the development and retention of functional polymorphisms in immunoregulatory genes.…”

Contrasting responses to selection in class I and class IIα major histocompatibility-linked markers in salmon

“…However, pathogen-driven balancing selection (through overdominance, negative frequency dependence or temporal/spatial heterogeneity in pathogen phenotype) is thought by many to be the main force driving MHC evolution (Klein and O'Huigin, 1994;Parham and Ohta, 1996;Edwards and Hedrick, 1998;Hedrick and Kim, 2000;Jeffery and Bangham, 2000). Evidence of selection on MHC genes has traditionally come from four sources (Hughes and Yeager, 1998): (a) long persistence times for MHC alleles compared with neutral expectation (often resulting in trans-specific polymorphism) (Figueroa et al, 1988;Lawlor et al, 1988;McConnell et al, 1988;Klein et al, 2007); (b) frequency distributions of MHC alleles in natural populations that are more even than that expected under a neutral model (Hedrick and Thompson, 1983;Markow et al, 1993); (c) high levels of nonsynonymous versus synonymous substitutions in codons for peptide binding residues (Hughes and Nei, 1988, 1989; and (d) homogenization of introns with concurrent diversification of exons at MHC loci (Cereb et al, 1997;Reusch and Langefors, 2005).…”