Comparative Genome Organization of Human, Murine, and Feline MHC Class II Region

Abstract

To study comparative molecular dynamics in the genesis of the major histocompatibility complex (MHC), we determined a complete nucleotide sequence spanning 758,291 bp of the domestic cat (Felis catus) extended and classical class II region. The feline class II MHC includes 44 genes (31 predicted to be expressed) which display DNA sequence homology and ordered gene synteny with human HLA and mouse H2, in extended class II and centromere proximal regions (DM to DO) of the classical class II region. However, remarkable genomic alterations including gene gain and loss plus size differentials of 250 kb are evident in comparisons of the cat class II with those of human and mouse. The cat MHC lacks the entire DQ region and retains only relict pseudogene homologs of DP genes, compensated by expansion and reorganization of seven modern DR genes. Repetitive gene families within the feline MHC comprise 35% of the feline MHC with very different density and abundance of GC levels, SINES, LINES, STRs, and retro-elements from the same repeats in human and mouse MHC. Comparison of the feline MHC with the murine and human MHC offers a detailed view of the consequences of genome organization in three mammalian lineages.The vertebrate major histocompatibility complex (MHC) offers an unusual opportunity for comparative genomics, as it consists of a chromosomally linked community of over 100 expressed genes, nearly half having a defined role in immune defenses. A complete sequence of human HLA (3.6 Mb), chicken B-locus (92 kb), and a partial mouse H2 sequence (4.0 Mb) have been determined (Kaufman et al. 1999; The MHC Sequencing Consortium 1999;Shiina et al. 1999;Stephens et al. 1999;Yu et al. 2000;Takada et al. 2003; L. Rowen, pers. comm.). Initial comparisons reveal remarkable differences in gene inclusion, gene order, and sequence divergence, likely driven by natural selective pressures of infectious disease outbreaks in the ancestors of these species (Doherty and Zinkernagel 1976;Klein 1986;Parham and Ohta 1996;Zinkernagel 1996;Hughes and Yeager 1998;Carrington et al. 1999). A deep understanding of the immunological functions, disease influences, evolutionary constraints, and driving forces of MHC adaptation in several mammalian species provides a fertile venue to discern and interpret adaptive events which predate living vertebrate genomes.HLA, the human MHC, is composed of 224 tightly linked genes, including 128 expressed genes, 96 pseudogenes, and repetitive elements (SINES, LINES, LTRs, and STRs) that comprise nearly 50% of the sequence (The MHC Sequencing Consortium 1999; Shiina et al. 1999). The mouse MHC, H2, includes 120 expressed genes encoding functions similar to those ascribed to human MHC genes plus various pseudogenes and repeat sequences (Klein 1986;Stephens et al. 1999;Yu et al. 2000;Takada et al. 2003; L. Rowen, pers. comm.).Both human and mouse MHC show linked segments of five subregions named for the individual gene families and ordered as follows from the centromere (size of the human subregion): (1) extend...

Direct sequence comparison of two divergent class I MHC natural killer cell receptor haplotypes

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Every genome sequence needs a good map

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The Genomic Sequence and Comparative Analysis of the Rat Major Histocompatibility Complex

“…Other mammals for which partial MHC sequences are available are the chimpanzee (class I region, complete), pig (class I region, partial), cat (class II region), and mouse (class II, III, and incomplete class I region). The comparison of MHC sequences from human and these mammals has revealed a high degree of plasticity that is encountered within class I regions and to a lesser extent in the class II region Renard et al 2001;Kumánovics et al 2002;Anzai et al 2003;Takada et al 2003;Yuhki et al 2003). After having established a BAC/PAC contig-based map of the rat MHC (Walter and Günther 2000;Ioannidu et al 2001;Walter et al 2002), we determined the sequence of a genomic segment of 3921 kb on the short arm of rat chromosome 20 that encompasses the MHC of the rat, the RT1 complex.…”