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A 39 kb Sequence Around a Blackbird Mhc Class II Gene Ghost of Selection Past and Songbird Genome Architecture Scott V Edwards Joe Gasper Daniel Garrigan 1 Duane Martindale and Ben F Koop Department of Zoology University of Washington and Center for Environmental Health Department of Biology University of Victoria British Columbia Canada To gain an understanding of the evolution and genomic context of avian major histocompatibility complex Mhc genes we sequenced a 38 8 kb Mhc bearing cosmid insert from a red winged blackbird Agelaius phoeniceus The DNA sequence the longest yet retrieved from a bird other than a chicken provides a detailed view of the process of gene duplication divergence and degeneration birth and death in the avian Mhc as well as a glimpse into major noncoding features of a songbird genome The peptide binding region PBR of the single Mhc class II B gene in this region Agph DAB2 is almost devoid of polymorphism and a still segregating single base pair deletion and other features suggest that it is nonfunctional Agph DAB2 is estimated to have diverged about 40 MYA from a previously characterized and highly polymorphic blackbird Mhc gene Aph DAB1 and is therefore younger than most mammalian Mhc paralogs and arose relatively late in avian evolution Despite its nonfunctionality AgphDAB2 shows very high levels of nonsynonymous divergence from Agph DAB1 and from reconstructed ancestral sequences in antigen binding PBR codons a strong indication of a period of adaptive divergence preceding loss of function We also found that the region sequenced contains very few other unambiguous genes a partial Mhcclass II gene fragment and a paucity of simple sequence and other repeats Thus this sequence exhibits some of the genomic streamlining expected for avian as compared with mammalian genomes but is not as densely packed with functional genes as is the chicken Mhc Introduction The genomes of various vertebrate groups are characterized by differences in size gene and repeat density and isochore composition We expect these features to be reflected in the genomic structure of multigene families of these groups For example avian genomes are 50 smaller than those of mammals Tiersch and Wachtel 1991 and chicken genomes are depauperate in simple sequence repeats Primmer et al 1997 have higher GC contents Bernardi Hughes and Mouchiroud 1997 higher gene densities McQueen et al 1996 and smaller introns Hughes and Hughes 1995 than do those of mammals These genomic differences between birds and mammals have been suggested to have their origin in lineage specific selection for small cell and genome size imposed by flight and its associated metabolic and behavioral demands Tiersch and Wachtel 1991 Hughes 1995 or possibly other unknown selective agents The major histocompatibility complex Mhc of vertebrates a region containing the most polymorphic genes in the vertebrate genome Edwards and Hedrick 1998 many of which have functions in defense against pathogens appears to reflect some of these trends For example the chicken Mhc 100 kb is orders of magnitude smaller than the Mhc of mice and humans 4 Mb Trowsdale 1995 It has long been known that chicken Mhc genes possess much smaller introns than those of mammalian Mhc genes Kaufman Salamonsen and Flajnik 1991 and it was recently shown that at Key words Mhc microsatellites introns CpG islands balancing selection 1 Present address Department of Zoology Arizona State University Address for correspondence and reprints Scott V Edwards Department of Zoology University of Washington Box 351800 Seattle Washington 98195 E mail sedwards u washington edu Mol Biol Evol 17 9 1384 1395 2000 q 2000 by the Society for Molecular Biology and Evolution ISSN 0737 4038 1384 one gene per 5 kb the chicken Mhc B complex is much more gene dense than the class I or II regions of mammals Kaufman et al 1999b These differences suggest that the chicken Mhc may have responded to the same selective pressures as the rest of the avian genome The smaller number of Mhc genes in the minimal essential chicken Mhc is thought to focus parasite mediated selection adaptively on a few target genes thereby resulting in associations between specific haplotypes and disease resistance that are stronger than those observed in mammals Kaufman 1995 In addition the specific organization and tight linkage of genes in the chicken Mhc has been suggested to facilitate coevolution of functionally associated protein products such as Mhc class I and peptide transporters TAP Kaufman et al 1999a However we know little about the genomic organization of Mhcs in birds other than the chicken with which to test the generality of these structural features Coding sequences of Mhc genes in songbirds and game birds suggest that the long term pattern of class II gene evolution in birds is characterized by higher rates of concerted evolution or more recent postspeciation duplications of genes than are found in mammals Edwards Wakeland and Potts 1995 Edwards et al 1999 Wittzel et al 1999 However some songbirds exhibit a greater complexity of class II genes on Southern blots than do chickens Edwards Nusser and Gasper 2000 and a recent molecular analysis of class I genes in the great reed warbler Acrocephalus arundinaceus suggested a much greater number of expressed class I genes in this songbird than in chickens Westerdahl Wittzell and von Schantz 1999 Thus it is not clear the extent to which evolutionary trends and genomic organization of chicken Mhc genes will represent those of songbirds and other avian lineages Understanding in detail the long term evolution of the Mhc in birds requires appropriate phylogenetic sam Sequence of an Mhc Bearing Cosmid in Blackbirds pling at both the root and the tips of the avian tree Edwards et al 1999 It has recently been proposed on the basis of complete mitochondrial genome sequences that perching birds Passeriformes may represent a basal lineages within birds perhaps the sister group to all other birds Ha rlid and Arnason 1999 but see Groth and Barrowclough 1999 van Tuinen Sibley and Hedges 2000 Thus pending clarification of the phylogenetic placement of perching birds it would be useful to gain insight into Mhc structure in this lineage We recently characterized Mhc class II B genes at the genomic level in two songbirds red winged blackbirds Agelaius phoeniceus and house finches Carpodacus mexicanus Edwards Gasper and Stone 1998 Hess et al 2000 both of which have served as


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