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Darwin spent years investigating the effects of self-fertilization, concluding that "nature abhors perpetual self-fertilization." Given that selection purges inbred populations of strongly deleterious mutations and drift fixes mild mutations, why does inbreeding depression (ID) persist in highly inbred taxa and why do no purely selfing taxa exist? Background selection, associations and interference among loci, and drift within small inbred populations all limit selection while often increasing fixation. These mechanisms help to explain why more inbred populations in most species consistently show more fixed load. This drift load is manifest in the considerable heterosis regularly observed in between-population crosses. Such heterosis results in subsequent high ID, suggesting a mechanism by which small populations could retain variation and inbreeding load. Multiple deleterious recessive mutations linked in repulsion generate pseudo-overdominance. Many tightly linked load loci could generate a balanced segregating load high enough to sustain ID over many generations. Such pseudo-overdominance blocks (or "PODs") are more likely to occur in regions of low recombination. They should also result in clear genetic signatures including genomic hotspots of heterozygosity; distinct haplotypes supporting alleles at intermediate frequency; and high linkage disequilibrium in and around POD regions. Simulation and empirical studies tend to support these predictions. Additional simulations and comparative genomic analyses should explore POD dynamics in greater detail to resolve whether PODs exist in sufficient strength and number to account for why ID and load persist within inbred lineages.

The practice of hybridization has greatly contributed to the increase in crop productivity. A major component that exploits heterosis in crops is the cytoplasmic male sterility (CMS)/nucleus-controlled fertility restoration (Rf) system. Through positional cloning, it is shown that heterozygous alleles (RsRf3-1/RsRf3-2) encoding pentatricopeptide repeat (PPR) proteins are responsible for restoring fertility to cytoplasmic male-sterile radish (Raphanus sativus L.). Furthermore, it was found that heterozygous alleles (RsRf3-1/RsRf3-2) show higher expression and RNA polymerase II occupancy in the CMS cytoplasmic background compared with their homozygous alleles (RsRf3-1/RsRf3-1 or RsRf3-2/RsRf3-2). These data provide new insights into the molecular mechanism of fertility restoration to cytoplasmic male-sterile plants and illustrate a case of overdominance.

The major histocompatibility complex (MHC) contains the most variable genes in vertebrates, but despite extensive research, the mechanisms maintaining this polymorphism are still unresolved. One hypothesis is that MHC polymorphism is a result of balancing selection operating by overdominance, but convincing evidence for overdominant selection in natural populations has been lacking. We present strong evidence consistent with MHC-specific overdominance in a free-living population of Arctic charr (Salvelinus alpinus) in northernmost Europe. In this population, where just two MHC alleles were observed, MHC heterozygous fish had a lower parasite load, were in better condition (as estimated by a fatness indicator) and had higher survival under stress than either of the homozygotes. Conversely, there was no consistent association between these fitness measures and assumedly neutral microsatellite variability, indicating an MHC-specific effect. Our results provide convincing empirical evidence consistent with the notion that overdominance can be an important evolutionary mechanism contributing to MHC polymorphism in wild animal populations. They also support a recent simulation study indicating that the number of alleles expected to be maintained at an MHC loci can be low, even under strong heterozygote advantage.

Population genetic data are presented which should contribute to evaluation of the hypothesis that the extraordinary evolutionary patterns observed at the b locus of the rabbit immunoglobulin light chain constant region can be the outcome of overdominance-type selection. The analysis of allele correlations in natural populations revealed an excess of heterozygotes of about 10% at the b locus while heterozygote excess was not observed at loci determining the immunoglobulin heavy chain. Data from the published literature, where homozygote advantage was suggested, were reevaluated and found in agreement with data here presented. Gene diversity was evenly distributed among populations and showed similarities with patterns reported for histocompatibility loci. Analysis of genotypic disequilibria revealed strong digenic associations between the leading alleles of heavy and light chain constant region loci in conjunction with trigenic disequilibria corresponding to a preferential association of b locus heterozygosity with the predominant allele of the heavy chain e locus. It is argued that this may indicate compensatory or nonadditive aspects of a putative heterozygosity enhancing mechanism, implying that effects at the light chain might be more pronounced in populations fixed for the heavy chain polymorphism.

DLK1 is part of the Notch signalling pathway that controls various developmental processes. A functional role for DLK1 in adipogenesis is suggested by several animal models. Interestingly, the DLK1 gene is imprinted in eutherian mammals. To study whether variations in DLK1 affect body weight in humans, we analysed 32 polymorphisms in a 109 kb genomic region encompassing DLK1 on human chromosome 14. In a study sample of 1025 French and German trio families comprised of both parents and extremely obese offspring we found a single nucleotide polymorphism (rs1802710) associated with child and adolescent obesity. Analysis of the allelic transmission pattern indicated the existence of polar overdominance, an unusual mode of non-Mendelian inheritance in humans previously known from the callipyge mutation in sheep.

This study aimed to test mate choice and selection during early life stages on major histocompatibility (MH) genotype in natural families of Atlantic salmon Salmo salar spawners and juveniles, using nine microsatellites to reconstruct families, one microsatellite linked to an MH class I gene and one minisatellite linked to an MH class II gene. MH-based mate choice was only detected for the class I locus on the first year, with lower expected heterozygosity in the offspring of actually mated pairs than predicted under random mating. The genotype frequencies of MH-linked loci observed in the juveniles were compared with frequencies expected from Mendelian inheritance of parental alleles to detect selection during early life stages. No selection was detected on the locus linked to class I gene. For the locus linked to class II gene, observed heterozygosity was higher than expected in the first year and lower in the second year, suggesting overdominance and underdominance, respectively. Within family, juveniles' body size was linked to heterozygosity at the same locus, with longer heterozygotes in the first year and longer homozygotes in the second year. Selection therefore seems to differ from one locus to the other and from year to year.

The possible effects of a selected locus on a closely linked microsatellite locus are discussed and analyzed in terms of coalescent theory and models of the mutation process. Background selection caused by recurrent deleterious mutations will reduce the variance of allele size at a microsatellite locus. The occasional substitution of advantageous alleles (genetic hitchhiking) will also reduce the variance, but a high mutation rate at a microsatellite locus can restore the variance relatively rapidly. Overdominance at the selected locus will increase the variance at the microsatellite locus and create partitioning of the variation in allele size among gametes carrying one or the other of the overdominant alleles. These results suggest that neutral microsatellite loci can provide indicators of selective processes at closely linked loci.

We describe the evolutionary dynamics of a modifier of selfing coevolving with a locus subject to symmetric overdominance in viability under general levels of reduction in pollination success as a consequence of self-fertilization (pollen discounting). Simple models of the evolution of breeding systems that represent inbreeding depression as a constant parameter do not admit the possibility of stable mixed mating systems involving both inbreeding and random mating. Contrary to this expectation, we find that coevolution between a modifier of selfing and a single overdominant locus situated anywhere in the genome can generate evolutionarily attracting mixed mating systems. Two forms of association between the modifier locus and the viability locus promote the evolution of outcrossing. The favored heterozygous genotype at the viability locus develops positive associations with modifier alleles that enhance outcrossing and with the heterozygous genotype at the modifier locus. Associations between outcrossing and high viability evolve immediately upon the introduction of a rare modifier allele, even in the absence of linkage.

Concepts and results on selection balance in multiallelic systems are described. These include a multidimensional concept of heterozygote excess and heterozygote deficiency, a hierarchy of means of assessment of heterozygote advantage, comparisons and contrasts of allelic versus gametic polymorphic states, and conditions defining stable equilibria of complementary gametic sets. The concepts are illustrated in the context of viability selection and behavioral models of kin selection and for two major categories of multilocus selection regimes.

An evolutionary dynamical system with explicit diploid genetics is used to investigate the likelihood of observing phenotypically overdominant heterozygotes versus heterozygous phenotypes that are intermediate between the homozygotes. In this model, body size evolves in a population with discrete demographic episodes and with competition limiting reproduction. A genotype-phenotype map for body size is used that can generate the two qualitative types of dominance interactions (overdominance versus intermediate dominance). It is written as a single-locus model with one focal locus and parameters summarizing the effects of alleles at other loci. Two types of evolutionarily stable strategy (ESS; continuously stable strategy, CSS) occur. The ESS is generated either (1) by the population ecology; or (2) by a local maximum of the genotype-phenotype map. Overdominant heterozygotes are expected to arise if the population evolves toward the second type of ESS, where nearly maximum body sizes are found. When other loci with partially dominant inheritance also evolve, the location of the maximum in the genotype-phenotype map repeatedly changes. It is unlikely that an evolving population will track these changes; ESSs of the second type now are at best quasi-stationary states of the evolutionary dynamics. Considering the restrictions on its probability, a pattern of phenotypic overdominance is expected to be rare.

Conditions for the origin of partial sporophytic self-incompatibility (SSI) are obtained from two quantitative models, which differ with respect to the determination of offspring viability. Offspring viability depends solely on the source (self or nonself) of the fertilizing pollen in the first model, which describes changes only at a primitive S-locus itself. Two loci evolve in the second model: overdominant viability selection maintains an arbitrary number of alleles at one locus, with SSI under the control of a separate locus. In both cases, the origin of SSI requires that the relative change in the numbers of offspring derived by the two reproductive modes compensate for the twofold cost of outcrossing. In the first model studied, the viability of inbred offspring fully determines the relative change in the numbers of inbred and outbred offspring produced. In the second model, the relative change in offspring numbers depends in addition on associations between the S-locus and the viability locus. Because these two-locus associations are comparable in magnitude to the differences between the viabilities of inbred and outbred offspring, SSI can arise under less restrictive conditions than expected from the one-locus model. Greater allelic multiplicity at the viability locus facilitates the origin of SSI by reducing the relative viability of inbred offspring. Tight linkage between the S-locus and the viability locus and high rates of receipt of self-pollen promote the generation and maintenance of associations between the S-locus and the viability locus. In populations in which more than two viability alleles are maintained, the active S-allele can invade even in the absence of linkage with the viability locus. The present study establishes that incompatibility systems can arise in response to identity disequilibrium between a modifier of incompatibility and a locus subject to overdominant viability selection; in particular, compensation for the twofold cost of outcrossing does not require preexisting gametic level disequilibria.

Significance Utilization of heterosis has greatly increased productivity of many crops globally. Allele-specific expression (ASE) has been suggested as a mechanism for causing heterosis. We performed a genome-wide analysis of ASE in three tissues of an elite rice hybrid grown under four conditions. The analysis identified 3,270 genes showing various patterns of ASE in response to developmental and environmental cues, which provides a glimpse of the ASE landscape in the hybrid genome. We showed that the ASE patterns may have distinct implications in the genetic basis of heterosis, especially in light of the classical dominance and overdominance hypotheses. The genes showing ASE provide the candidates for future studies of the genetic and molecular mechanism of heterosis., Utilization of heterosis has greatly increased the productivity of many crops worldwide. Although tremendous progress has been made in characterizing the genetic basis of heterosis using genomic technologies, molecular mechanisms underlying the genetic components are much less understood. Allele-specific expression (ASE), or imbalance between the expression levels of two parental alleles in the hybrid, has been suggested as a mechanism of heterosis. Here, we performed a genome-wide analysis of ASE by comparing the read ratios of the parental alleles in RNA-sequencing data of an elite rice hybrid and its parents using three tissues from plants grown under four conditions. The analysis identified a total of 3,270 genes showing ASE (ASEGs) in various ways, which can be classified into two patterns: consistent ASEGs such that the ASE was biased toward one parental allele in all tissues/conditions, and inconsistent ASEGs such that ASE was found in some but not all tissues/conditions, including direction-shifting ASEGs in which the ASE was biased toward one parental allele in some tissues/conditions while toward the other parental allele in other tissues/conditions. The results suggested that these patterns may have distinct implications in the genetic basis of heterosis: The consistent ASEGs may cause partial to full dominance effects on the traits that they regulate, and direction-shifting ASEGs may cause overdominance. We also showed that ASEGs were significantly enriched in genomic regions that were differentially selected during rice breeding. These ASEGs provide an index of the genes for future pursuit of the genetic and molecular mechanism of heterosis.