Contrasting modes of evolution acting on the complex N locus for rust resistance in flax

Three rust resistance specificities, N, N1 and N2, map to the complex N locus of flax. We used a degenerate PCR approach, with primers directed to the nucleotide binding site (NBS) domain characteristic of many plant resistance genes, to isolate resistance gene analogs (RGAs) from flax. One RGA clone detected RFLPs co-segregating with alleles of the N locus. With this probe we isolated four related genes that occur within a 30kbp region and encode proteins with NBS and leucine-rich repeat (LRR) domains and N-terminal Toll/Interleukin-1 Receptor homology (TIR) domains. One of these four genes was identified as the N resistance gene by sequence analysis of three mutant alleles and by transgenic expression. We isolated homologous genes from two flax lines containing the N1 or N2 specificities and from flax lines carrying no N locus resistance specificities. Analysis of shared polymorphisms among this set of 18 N locus sequences revealed three groups of genes with independent lineages. Sequence exchanges have only occurred between genes within each group, but not between groups. Two of the groups contain only one sequence from each haplotype and probably represent orthologous genes. However, the third group contains two genes from each haplotype. We suggest that the re-assortment of variation by recombination/gene conversion at this locus is limited by the degree of sequence identity between genes.     

Six amino acid changes confined to the leucine-rich repeat beta-strand/beta-turn motif determine the difference between the P and P2 rust resistance specificities in flax

At least six rust resistance specificities (P and P1 to P5) map to the complex P locus in flax. The P2 resistance gene was identified by transposon tagging and transgenic expression. P2 is a member of a small multigene family and encodes a protein with nucleotide binding site (NBS) and leucine-rich repeat (LRR) domains and an N-terminal Toll/interleukin-1 receptor (TIR) homology domain, as well as a C-terminal non-LRR (CNL) domain of approximately 150 amino acids. A related CNL domain was detected in almost half of the predicted Arabidopsis TIR-NBS-LRR sequences, including the RPS4 and RPP1 resistance proteins, and in the tobacco N protein, but not in the flax L and M proteins. Presence or absence of this domain defines two subclasses of TIR-NBS-LRR resistance genes. Truncations of the P2 CNL domain cause loss of function, and evidence for diversifying selection was detected in this domain, suggesting a possible role in specificity determination. A spontaneous rust-susceptible mutant of P2 contained a G-->E amino acid substitution in the GLPL motif, which is conserved in the NBS domains of plant resistance proteins and the animal cell death control proteins APAF-1 and CED4, providing direct evidence for the importance of this motif in resistance gene function. A P2 homologous gene isolated from a flax line expressing the P resistance specificity encodes a protein with only 10 amino acid differences from the P2 protein. Chimeric gene constructs indicate that just six of these amino acid changes, all located within the predicted beta-strand/beta-turn motif of four LRR units, are sufficient to alter P2 to the P specificity.     

Linkage of genes for PHI,halothane sensitivity,A-O inhibition,H red blood cell antigens and 6-PGD variants in pigs*

Data from one apparent crossover between S and H, two between PHI and HAL on one side and S on the other, and one between PHI on one side and HAL, S and H on the other, indicate a gene order in pigs of Phi-Hal-S-H-Pgd for genes for PHI, halothane sensitivity, inhibition of expression of A and O, H red blood cell antigens and 6-PGD types. Rasmusen et al. (1980) provided data for a gene order in pigs ofPhi-Hal-H-Pgd for genes for phosphohexose isomerase (PHI) isozyme variants, halothane sensitivity (HAL), H red cell antigens and 6-phosphogluconate dehydrogenase (6-PGD) variants, and suggested that there might be a locus for a gene for inhibition of expression of A and O separate from the locus for H. This is contrary to an earlier proposal by Rasmusen (1972) that the H-system genotype directly influences expression of A and O. Imlah (1980) suggested that the recessive gene for halothane sensitivity has a suppressant effect on the expression of A and O. Andresen (1981) proposed that the locus for inhibition of A and O (for which Rasmusen, 1964, proposed the symbol S) was between the loci for HAL and H types. Data presented in Table 1, which includes haplotypes for three recombinant offspring described by Rasmusen et al. (1980) (883-1, 233-3 and 3864-1) as well as one other recombinant (296-2) provide evidence for the gene order for five genes proposed by Andresen. Types for 6-PGD are listed for all pigs, although they do not provide evidence for gene order in these cases. Male 883-1 (Table 1, and Rasmusen et al., 1980, Table 5) provided the original evidence for recombination between S and H. His phenotype, as well as his genotype as revealed by progeny test (Rasmusen et al., 1980, Table 6) indicated that recombination had occurred between the genes for PHI, HAL and S and the gene for H type in his dam, so that the S locus mapped between H and the loci for the other three traits. The phenotype of one of his sons (233-3, Table 1, and Rasmusen et al., 1980, Table 6) indicated that there had been a recombination between genes for PHI and HAL types on one side and S and H types on the other, providing evidence that the S locus was separate from PHI and HAL as well as H. Another pig listed in Table 1,3864-1, was also described by Rasmusen et al. (1980, Table 9) as a recombinant. This pig provides evidence for recombination between PHI on one side and HAL, S and H on the other, establishing a gene order of Phi-Hal-S-H-Pgd. The last pig listed in Table 1,296-2, is a recombinant comparable to 233-3. The H type of his dam provides markers indicating the recombination was between PHI and HAL on one side and S and H on the other, although the unusual expression of HAL phenotype in both parents of 296-2 makes her haplotypes somewhat uncertain. (Recombination may have been between PHI and HAL rather than as indicated in Table 1.) In spite of incomplete penetrance for HAL (Ollivier et al., 1975; Smith & Bampton, 1977) which makes haplotypes for HAL questionable in some cases, the other genetic markers available are useful to show that recombination has taken place. Without considering the results of halothane testing, if the apparent recombinants are accepted as being as indicated, the order of the genes at the other four loci seems established. Alleles for S types appear to be separable by recombination from those for PHI and H, and the S locus appears to be between the loci for PHI and H. For the five loci, data obtained thus far are cohsistent with a gene order of Phi-Hal-S-H-Pgd.     

Allelic and haplotypic diversity at the rp1 rust resistance locus of maize

The maize Rp1 rust resistance locus is a complex consisting of a family of closely related resistance genes. The number of Rp1 paralogs in different maize lines (haplotypes) varied from a single gene in some stocks of the inbred A188 to >50 genes in haplotypes carrying the Rp1-A and Rp1-H specificities. The sequences of paralogs in unrelated haplotypes differ, indicating that the genetic diversity of Rp1-related genes is extremely broad in maize. Two unrelated haplotypes with five or nine paralogs had identical resistance phenotypes (Rp1-D) encoded in genes that differed by three nucleotides resulting in a single amino acid substitution. Genes in some haplotypes are more similar to each other than to any of the genes in other haplotypes indicating that they are evolving in a concerted fashion.     

Polymorphism of intron-1 in the voltage-gated sodium channel gene of Anopheles gambiae s.s. populations from Cameroon with emphasis on insecticide knockdown resistance mutations

Sequence variation at the intron-1 of the voltage-gated sodium channel gene in Anopheles gambiae M- and S-forms from Cameroon was assessed to explore the number of mutational events originating knockdown resistance ( kdr ) alleles. Mosquitoes were sampled between December 2005 and June 2006 from three geographical areas: (i) Magba in the western region; (ii) Loum, Tiko, Douala, Kribi, and Campo along the Atlantic coast; and (iii) Bertoua, in the eastern continental plateau. Both 1014S and 1014F kdr alleles were found in the S-form with overall frequencies of 14% and 42% respectively. Only the 1014F allele was found in the M-form at lower frequency (11%). Analysis of a 455 bp region of intron-1 upstream the kdr locus revealed four independent mutation events originating kdr alleles, here named MS1 -1014F, S1-1014S and S2-1014S kdr- intron-1 haplotypes in S-form and MS3-1014F kdr- intron-1 haplotype in the M-form. Furthermore, there was evidence for mutual introgression of kdr 1014F allele between the two molecular forms, MS1 and MS3 being widely shared by them. Although no M/S hybrid was observed in analysed samples, this wide distribution of haplotypes MS1 and MS3 suggests inter-form hybridizing at significant level and emphasizes the rapid diffusion of the kdr alleles in Africa. The mosaic of genetic events found in Cameroon is representative of the situation in the West–Central African region and highlights the importance of evaluating the spatial and temporal evolution of kdr alleles for a better management of insecticide resistance.     

Recombination and spontaneous mutation at the major cluster of resistance genes in lettuce (Lactuca sativa)

Two sets of overlapping experiments were conducted to examine recombination and spontaneous mutation events within clusters of resistance genes in lettuce. Multiple generations were screened for recombinants using PCR-based markers flanking Dm3. The Dm3 region is not highly recombinagenic, exhibiting a recombination frequency 18-fold lower than the genome average. Recombinants were identified only rarely within the cluster of Dm3 homologs and no crossovers within genes were detected. Three populations were screened for spontaneous mutations in downy mildew resistance. Sixteen Dm mutants were identified corresponding to spontaneous mutation rates of 10(-3) to 10(-4) per generation for Dm1, Dm3, and Dm7. All mutants carried single locus, recessive mutations at the corresponding Dm locus. Eleven of the 12 Dm3 mutations were associated with large chromosome deletions. When recombination could be analyzed, deletion events were associated with exchange of flanking markers, consistent with unequal crossing over; however, although the number of Dm3 paralogs was changed, no novel chimeric genes were detected. One mutant was the result of a gene conversion event between Dm3 and a closely related homolog, generating a novel chimeric gene. In two families, spontaneous deletions were correlated with elevated levels of recombination. Therefore, the short-term evolution of the major cluster of resistance genes in lettuce involves several genetic mechanisms including unequal crossing over and gene conversion.     

Structural and transcriptional comparative analysis of the S locus regions in two self-incompatible Brassica napus lines

Self-incompatibility (SI) in Brassica is controlled by a single locus, termed the S locus. There is evidence that two of the S locus genes, SLG, which encodes a secreted glycoprotein, and SRK, which encodes a putative receptor kinase, are required for SI on the stigma side. The current model postulates that a pollen ligand recognizing the SLG/SRK receptors is encoded in the genomic region defined by the SLG and SRK genes. A fosmid contig of approximately 65 kb spanning the SLG-910 and SRK-910 genes was isolated from the Brassica napus W1 line. A new gene, SLL3, was identified using a novel approach combining cDNA subtraction and direct selection. This gene encodes a putative secreted small peptide and exists as multiple copies in the Brassica genome. Sequencing analysis of the 65-kb contig revealed seven additional genes and a transposon. None of these seven genes exhibited features expected of S genes on the pollen side. An approximately 88-kb contig of the A14 S region also was isolated from the B. napus T2 line and sequenced. Comparison of the two S regions revealed that (1) the gene organization downstream of SLG in both S haplotypes is highly colinear; (2) the distance between SLG-A14 and SRK-A14 genes is much larger than that between SLG-910 and SRK-910, with the intervening region filled with retroelements and haplotype-specific genes; and (3) the gene organization downstream of SRK in the two haplotypes is divergent. These observations lead us to propose that the SLG downstream region might be one border of the S locus and that the accumulation of heteromorphic sequences, such as retroelements as well as haplotype-unique genes, may act as a mechanism to suppress recombination between SLG and SRK.     

Determining the physical limits of the Brassica S locus by recombinational analysis

A genetic analysis was performed to study the frequency of recombination for intervals across the Brassica S locus region. No recombination was observed between the S locus glycoprotein gene and the S receptor kinase gene in the segregating populations that we analyzed. However, a number of recombination breakpoints in regions flanking these genes were identified, allowing the construction of an integrated genetic and physical map of the genomic region encompassing one S haplotype. We identified, based on the pollination phenotype of plants homozygous for recombinant S haplotypes, a 50-kb region that encompasses all specificity functions in the S haplotype that we analyzed. Mechanisms that might operate to preserve the tight linkage of self-incompatibility specificity genes within the S locus complex are discussed in light of the relatively uniform recombination frequencies that we observed across the S locus region and of the structural heteromorphisms that characterize different S haplotypes.     

The Melampsora lini AvrL567 avirulence genes are expressed in haustoria and their products are recognized inside plant cells

The Linum usitatissimum (flax) L gene alleles, which encode nucleotide binding site-Leu rich repeat class intracellular receptor proteins, confer resistance against the Melampsora lini (flax rust) fungus. At least 11 different L resistance specificities are known, and the corresponding avirulence genes in M. lini map to eight independent loci, some of which are complex and encode multiple specificities. We identified an M. lini cDNA marker that cosegregates in an F2 rust family with a complex locus determining avirulence on the L5, L6, and L7 resistance genes. Two related avirulence gene candidates, designated AvrL567-A and AvrL567-B, were identified in a genomic DNA contig from the avirulence allele, whereas the corresponding virulence allele contained a single copy of a related gene, AvrL567-C. Agrobacterium tumefaciens-mediated transient expression of the mature AvrL567-A or AvrL567-B (but not AvrL567-C) proteins as intracellular products in L. usitatissimum and Nicotiana tabacum (tobacco) induced a hypersensitive response-like necrosis that was dependent on coexpression of the L5, L6, or L7 resistance gene. An F1 seedling lethal or stunted growth phenotype also was observed when transgenic L. usitatissimum plants expressing AvrL567-A or AvrL567-B (but not AvrL567-C) were crossed to resistant lines containing L5, L6, or L7. The AvrL567 genes are expressed in rust haustoria and encode 127 amino acid secreted proteins. Intracellular recognition of these rust avirulence proteins implies that they are delivered into host cells across the plant membrane. Differences in the three AvrL567 protein sequences result from diversifying selection, which is consistent with a coevolutionary arms race.     

Species and Population Level Molecular Profiling Reveals Cryptic Recombination and Emergent Asymmetry in the Dimorphic Mating Locus of C. reinhardtii

Heteromorphic sex-determining regions or mating-type loci can contain large regions of non-recombining sequence where selection operates under different constraints than in freely recombining autosomal regions. Detailed studies of these non-recombining regions can provide insights into how genes are gained and lost, and how genetic isolation is maintained between mating haplotypes or sex chromosomes. The Chlamydomonas reinhardtii mating-type locus (MT) is a complex polygenic region characterized by sequence rearrangements and suppressed recombination between its two haplotypes, MT+ and MT−. We used new sequence information to redefine the genetic contents of MT and found repeated translocations from autosomes as well as sexually controlled expression patterns for several newly identified genes. We examined sequence diversity of MT genes from wild isolates of C. reinhardtii to investigate the impacts of recombination suppression. Our population data revealed two previously unreported types of genetic exchange in Chlamydomonas MT—gene conversion in the rearranged domains, and crossover exchanges in flanking domains—both of which contribute to maintenance of genetic homogeneity between haplotypes. To investigate the cause of blocked recombination in MT we assessed recombination rates in crosses where the parents were homozygous at MT. While normal recombination was restored in MT+×MT+ crosses, it was still suppressed in MT−×MT− crosses. These data revealed an underlying asymmetry in the two MT haplotypes and suggest that sequence rearrangements are insufficient to fully account for recombination suppression. Together our findings reveal new evolutionary dynamics for mating loci and have implications for the evolution of heteromorphic sex chromosomes and other non-recombining genomic regions.     

Effects on production traits of haplotypes among casein genes in Norwegian goats and evidence for a site of preferential recombination

In goat milk the most abundant proteins are the casein genes, CSN1S1, CSN2, CSN1S2, and CSN3. Mutations have been identified within these genes affecting the level of gene expression, and effects on milk production traits have been reported. The aim of this study was to detect polymorphisms (SNPs) in the casein genes of Norwegian goats, resolve haplotype structures within the loci, and assess the effect of these haplotypes on milk production traits. Four hundred thirty-six Norwegian bucks were genotyped for 39 polymorphic sites across the four loci. The numbers of unique haplotypes present in each locus were 10, 6, 4, and 8 for CSN1S1, CSN2, CSN1S2, and CSN3, respectively. The effects of the CSN1S1 haplotypes on protein percentage and fat kilograms were significant, as were the effects of CSN3 haplotypes on fat percentage and protein percentage. A deletion in exon 12 of CSN1S1, unique to the Norwegian goat population, explained the effects of CSN1S1 haplotypes on fat kilograms, but not protein percentage. Investigation of linkage disequilibrium between all possible pairs of SNPs revealed higher levels of linkage disequilbrium for SNP pairs within casein loci than for SNP pairs between casein loci, likely reflecting low levels of intragenic recombination. Further, there was evidence for a site of preferential recombination between CSN2 and CSN1S2. The value of the haplotypes for haplotype-assisted selection (HAS) is discussed.     

Further evidence for recombination between mouse hemoglobin beta b1 and b2 genes based on the nucleotide sequences of intron, UTR, and intergenic spacer regions

Nucleotide sequences of the intron regions and UTRs (Untranslated regions) of the hemoglobin beta adult genes, b1 and b2, and of the intergenic spacer region were determined for mouse strains representing the d, p, and w1 hemoglobin haplotypes defined by protein electrophoretic analyses. The hypothesis of recombination of the b1 and b2 genes between the d and w1 haplotypes previously reported in the cDNA nucleotide sequences was confirmed by neighbor-joining analyses of the intron regions and UTRs within the b1 and b2 genes, suggesting that all of the structures of hemoglobin beta adult genes support the hypothesis that the p haplotype was established by hybridization between d and w1 haplotype mice. The resultant recombinant of the p haplotype was found to have a d-like b1 gene and a w1-like b2 gene. In addition to the possible recombination, a break point was suggested around 2-3 kb downstream of the b1 gene within the intergenic spacer region, despite the absence of clear properties that could stimulate the recombination machinery. Some large insertions or deletions (indels) specific to the p or d haplotypes were located within the intergenic spacer region, in which the 1010-bp indel specific to the p haplotype was shared by all examined strains representing the p haplotype.     

Haplotypes at ATM identify coding-sequence variation and indicate a region of extensive linkage disequilibrium

Genetic variation in the human population may lead to functional variants of genes that contribute to risk for common chronic diseases such as cancer. In an effort to detect such possible predisposing variants, we constructed haplotypes for a candidate gene and tested their efficacy in association studies. We developed haplotypes consisting of 14 biallelic neutral-sequence variants that span 142 kb of the ATM locus. ATM is the gene responsible for the autosomal recessive disease ataxia-telangiectasia (AT). These ATM noncoding single-nucleotide polymorphisms (SNPs) were genotyped in nine CEPH families (89 individuals) and in 260 DNA samples from four different ethnic origins. Analysis of these data with an expectation-maximization algorithm revealed 22 haplotypes at this locus, with three major haplotypes having frequencies > or = .10. Tests for recombination and linkage disequilibrium (LD) show reduced recombination and extensive LD at the ATM locus, in all four ethnic groups studied. The most striking example was found in the study population of European ancestry, in which no evidence for recombination could be discerned. The potential of ATM haplotypes for detection of genetic variants through association studies was tested by analysis of 84 individuals carrying one of three ATM coding SNPs. Each coding SNP was detected by association with an ATM haplotype. We demonstrate that association studies with haplotypes for candidate genes have significant potential for the detection of genetic backgrounds that contribute to disease.     

Genome analysis at different ploidy levels allows cloning of the powdery mildew resistance gene Pm3b from hexaploid wheat

In wheat, race-specific resistance to the fungal pathogen powdery mildew (Blumeria graminis f. sp. tritici) is controlled by the Pm genes. There are 10 alleles conferring resistance at the Pm3 locus (Pm3a to Pm3j) on chromosome 1AS of hexaploid bread wheat (Triticum aestivum L.). The genome of hexaploid wheat has a size of 1.6 x 1010 bp and contains more than 80% of repetitive sequences, making positional cloning difficult. Here, we demonstrate that the combined analysis of genomes from wheat species with different ploidy levels can be exploited for positional cloning in bread wheat. We have mapped the Pm3b gene in hexaploid wheat to a genetic interval of 0.97 centimorgan (cM). The diploid T. monococcum and the tetraploid T. turgidum ssp. durum provided models for the A genome of hexaploid wheat and allowed to establish a physical contig spanning the Pm3 locus. Although the haplotypes at the Pm3 locus differed markedly between the three species, a large resistance gene-like family specific to wheat group 1 chromosomes was consistently found at the Pm3 locus. A candidate gene for Pm3b was identified using partial sequence conservation between resistant line Chul and T. monococcum cv. DV92. A susceptible Pm3b mutant, carrying a single-base pair deletion in the coding region of the candidate gene was isolated. When tested in a single cell transformation assay, the Pm3b candidate gene conferred race-specific resistance to powdery mildew. These results demonstrate that the candidate gene, a member of the coiled-coil nucleotide binding site leucine-rich repeat (NBS-LRR) type of disease resistance genes, is the Pm3b gene.     

Interhaplotypic heterogeneity and heterochromatic features may contribute to recombination suppression at the S locus in apple (Malusxdomestica)

Gametophytic self-incompatibility (GSI) is controlled by a complex S locus containing the pistil determinant S-RNase and pollen determinant SFB/SLF. Tight linkage of the pistil and pollen determinants is necessary to guarantee the self-incompatibility (SI) function. However, multiple probable pollen determinants of apple and Japanese pear, SFBBs (S locus F-box brothers), exist in each S haplotype, and how these multiple genes maintain the SI function remains unclear. It is shown here by high-resolution fluorescence in situ hybridization (FISH) that SFBB genes of the apple S ( 9 ) haplotype are physically linked to the S ( 9 ) -RNase gene, and the S locus is located in the subtelomeric region. FISH analyses also determined the relative order of SFBB genes and S-RNase in the S ( 9 ) haplotype, and showed that gene order differs between the S ( 9 ) and S ( 3 ) haplotypes. Furthermore, it is shown that the apple S locus is located in a knob-like large heterochromatin block where DNA is highly methylated. It is proposed that interhaplotypic heterogeneity and the heterochromatic nature of the S locus help to suppress recombination at the S locus in apple.     

The rearrangement of the human alpha(1)-acid glycoprotein/orosomucoid gene: evidence for tandemly triplicated genes consisting of two AGP1 and one AGP2

The human alpha(1)-acid glycoprotein (AGP) or orosomucoid (ORM) is controlled by the two tandemly arranged genes, AGP1 and AGP2. The further duplication of the AGP1 gene has been suggested by a few duplicated ORM1 locus haplotypes including ORM1*F1. S and ORM1*B9. S, detected by isoelectric focusing. To clarify the triplication of the AGP gene, 39 DNA samples from Japanese subjects were studied by the long-range PCR of intergenic regions. The analysis of PCR products showed that the tandemly triplicated genes, AGP1A-AGP1B-AGP2, occurred on about 20% of chromosomes. These composites were divided into ORM1A*F1-ORM1B*S-ORM2*M and ORM1A*B9-ORM1B*S-ORM2*M by allelic variations. Furthermore, the former was classified into a few haplotypes by three synonymous sequence variations, which might have arisen through gene conversion-like events. The recombination breakpoints existed between the 5' flanking region and intron 2 of the AGP1B gene. Thus, it is likely that the rearrangement of the AGP gene has often occurred.     

Spectroscopic and redox properties of sym1 and (M)F195H: Rhodobacter capsulatus reaction center symmetry mutants which affect the initial electron donor.

The redox properties, absorption, electroabsorption, CD, EPR, and P+QA- recombination kinetics have been measured for the special pairs of two mutants of Rhodobacter capsulatus reaction centers involving amino acid changes in the vicinity of the special pair, P. Both mutants symmetrize amino acid residues so that portions of the M-sequence are replaced with L-sequence: sym1 symmetrizes all residues between M187 and M203, whereas (M)F195H is a single amino acid subset of the sym1 mutation. (M)F195H introduces a His residue in a position where it is likely to form a hydrogen bond to the acetyl group of the M-side bacteriochlorophyll of P. For both mutants compared with wild-type, (i) the redox potential is at least 100 meV greater, (ii) the P+QA- recombination rate is about twice as fast at room temperature, and (iii) the large electroabsorption feature for the QY band of P is shifted relative to the absorption spectrum. The comparison of the properties observed for the sym1 and (M)F195H reaction center mutants and the differences between these mutants and wild-type suggest that residue M195 is an important determinant of the properties of the special pair.     

Recombination events generating a novel Rp1 race specificity

Genes at the maize Rp1 rust resistance complex often mispair in meiosis, which allows genes to recombine unequally, creating recombinant haplotypes. Four recombinant haplotypes were identified from progeny of an Rp1-D/Rp1-I heterozygote that conferred a nonparental resistance specificity designated Rp1-I*. Sequence comparisons of paralogs in the recombinant and parental haplotypes demonstrated that all four recombinants were derived from intergenic (between gene) recombination events. The sequence of paralogs in the HRp1-I parental haplotype indicated this haplotype includes 41 or more rp1 genes, at least 31 of which are transcribed. The results indicate that most of the novel resistance specificities that have arisen spontaneously at Rp1 are the result of reassort ment of existing Rp1 genes.     

A new theory of MHC evolution: beyond selection on the immune genes

The major histocompatibility complex (MHC) is a dense region of immune genes with high levels of polymorphism, which are arranged in haplotype blocks. Traditional models of balancing selection (i.e. overdominance and negative frequency dependence) were developed to study the population genetics of single genes. However, the MHC is a multigene family surrounded by linked (non-neutral) polymorphisms, and not all of its features are well explained by these models. For example, (i) the high levels of polymorphism in small populations, (ii) the unexpectedly large genetic differentiation between populations, (iii) the shape of the allelic genealogy associated with trans-species evolution, and (iv) the close associations between particular MHC (human leucocyte antigen, HLA) haplotypes and the approximately 100 pathologies in humans. Here, I propose a new model of MHC evolution named Associative Balancing Complex evolution that can explain these phenomena. The model proposes that recessive deleterious mutations accumulate as a 'sheltered load' nearby MHC genes. These mutations can accumulate because (i) they are rarely expressed as homozygotes given the high MHC gene diversity and (ii) purifying selection is inefficient with low recombination rates (cf. Muller's ratchet). Once fixed, these mutations add to balancing selection and further reinforce linkage through epistatic selection against recombinants.