The role of pseudo-overdominance in maintaining inbreeding depression

Classical models ignoring linkage predict that deleterious recessive mutations purge or fix within inbred populations, yet these often retain moderate to high segregating load. True overdominance generates balancing selection that sustains inbreeding depression even in inbred populations but is rare. In contrast, arrays of mildly deleterious recessives linked in repulsion may occur commonly enough to generate pseudo-overdominance and sustain segregating load. We used simulations to explore how long pseudo-overdominant regions (POD's) persist following their creation via hybridization between populations fixed for alternative mutations at linked loci. Balancing haplotype loads, tight linkage, and moderate to strong cumulative selective effects serve to maintain POD's, suggesting that POD's may most often arise and persist in low recombination regions (e.g., inversions). Selection and drift unbalance the load, eventually eliminating POD's, but this process is very slow when pseudo-overdominance is strong. Background selection across the genome accelerates the loss of weak POD's but reinforces strong POD's in inbred populations by disfavoring homozygotes. Further modeling and studies of POD dynamics within populations could help us understand how POD's affect persistence of the load and how inbred mating systems evolve.

Parent-offspring inference in highly inbred populations

Genealogical relationships are fundamental components of genetic studies. However, it is often challenging to infer correct and complete pedigrees even when genome-wide information is available. For example, inbreeding can obfuscate genetic differences between individuals, making it difficult to even distinguish first-degree relatives such as parent-offspring from full siblings. Similarly, genotyping errors can interfere with the detection of genetic similarity between parents and their offspring. Inbreeding is common in natural, domesticated, and experimental populations and genotyping of these populations often has more errors than in human datasets, so efficient methods for building pedigrees under these conditions are necessary. Here, we present a new method for parent-offspring inference in inbred pedigrees called SPORE (Specific Parent-Offspring Relationship Estimation). SPORE is vastly superior to existing pedigree-inference methods at detecting parent-offspring relationships, in particular when inbreeding is high or in the presence of genotyping errors, or both. SPORE therefore fills an important void in the arsenal of pedigree inference tools.

Development of a 95 SNP Panel To Individually Genotype Mountain Lions (Puma Concolor) For Microfluidic and Other Genotyping Platforms

The mountain lion (Puma concolor) is one of the few remaining large predators in California, USA with density estimation from fecal genotypes becoming an essential component of conservation and management. In highly urbanized southern California, mountain lions are fragmented into small, inbred populations making proper marker selection critical for individual identification. We developed a panel of single nucleotide polymorphism (SNP) markers that can be used for consistent, routine mountain lion monitoring by different laboratories. We used a subset of existing Illumina HiSeq data for 104 individuals from throughout California to design a single, highly heterozygous multiplex of 95 SNPs for the Fluidigm platform. This panel confidently differentiates individual mountain lions, identifies sex, and discriminates mountain lions from bobcats. The panel performed well on fecal DNA extracts and based on design, had sufficient resolution to differentiate individual genotypes in even the population with lowest genetic diversity in southern California.

The Evolution of Host Specialization in an Insect Pathogen

Niche breadth coevolution between biotic partners underpins theories of diversity and co-existence and influences patterns of disease emergence and transmission in host-parasite systems. Despite these broad implications, we still do not fully understand how the breadth of parasites’ infectivity evolves, the nature of any associated costs, or the genetic basis of specialization. Here, we serially passage a granulosis virus on multiple inbred populations of its Plodia interpunctella host to explore the dynamics and outcomes of specialization. In particular, we collect time series of phenotypic and genetic data to explore the dynamics of host genotype specialization throughout the course of experimental evolution and examine two fitness components. We find that the Plodia interpunctella granulosis virus consistently evolves increases in overall specialization, but that our two fitness components evolve independently such that lines specialize in either productivity or infectivity. Furthermore, we find that specialization in our experiment is a highly polygenic trait best explained by a combination of evolutionary mechanisms including conditionally positive fitness asymmetries and mutation accumulation. These results are important for understanding the evolution of specialization in host-parasite interactions and its broader implications for co-existence, diversification, and infectious disease management.

Significance of Linkage Disequilibrium and Epistasis on the Genetic Variances in Non- Inbred and Inbred Populations

Background The influence of linkage disequilibrium (LD), epistasis, and inbreeding on the genotypic variance continues to be an important area of investigation in genetics and evolution. Although the current knowledge about biological pathways and gene networks imply that epistasis is important in determining quantitative traits, the empirical evidence for a range of species and traits is that the genetic variance is most additive. This is confirmed by some recent theoretical studies. However, because these investigations have assumed linkage equilibrium, only additive effects, or simplified assumptions for the two- and high-order epistatic effects, the objective of this investigation was to provide additional information about the impact of LD and epistasis on the genetic variances in non-inbred and inbred populations, using a simulated data set.Results The epistatic variance in generation 0 corresponded to 1 to 10% of the genotypic variance, with 30% of epistatic genes, but it corresponded to 5 to 45% assuming 100% of epistatic genes. After 10 generations of random cross or selfing the ratio epistatic variance/genotypic variance increased in the range of 15 to 1,079%. The epistatic variances are maximized assuming dominant epistasis, duplicate genes with cumulative effects, and non-epistatic gene interaction. A minimization occurs with complementary, recessive, and dominant and recessive epistasis. In non-inbred populations, the genetic covariances have negligible magnitude compared with the genetic variances. In inbred populations, excepting for duplicate epistasis, the sum of the epistatic covariances was in general negative and with magnitude higher than the non-additive variances, especially under 100% of epistatic genes.Conclusions The LD level for genes, even under a relatively low gene density, has a significant effect on the genetic variances in non-inbred and inbred populations. Assuming digenic epistasis, the additive variance is in general the most important component of the genotypic variance in non-inbred and inbred populations. The ratio epistatic variance/genotypic variance is proportional to the percentage of interacting genes and increases with random cross and selfing. In general, the additive x additive variance is the most important component of the epistatic variance. The maximization of the epistatic variance depends on the allele frequency, LD level, and epistasis type.

Multilocus disease-causing genomic variations for Mendelian disorders: role of systematic phenotyping and implications on genetic counselling

Multilocus disease-causing genomic variations (MGVs) and multiple genetic diagnoses (MGDs) are increasingly being recognised in individuals and families with Mendelian disorders. This can be mainly attributed to the widespread use of genomic tests for the evaluation of these disorders. We conducted a retrospective study of families evaluated over the last 6 years at our centre to identify families with MGVs and MGDs. MGVs were observed in fourteen families. We observed five different consequences: (i) individuals with MGVs presenting as blended phenotypes (ii) individuals with MGVs presenting with distinct phenotypes (iii) individuals with MGVs with age-dependent penetrance (iv) individuals with MGVs with one phenotype obscured by another more predominant phenotype (v) two distinct phenotypes in different individuals in families with MGVs. Consanguinity was present in eight (8/14, 57.1%) of them. Thirteen families had two Mendelian disorders and one had three Mendelian disorders. The risk of recurrence of one or more conditions in these families ranged from 25% to 75%. Our findings underline the importance of the role of a clinical geneticist in systematic phenotyping, challenges in genetic counselling and risk estimation in families with MGVs and MGDs, especially in highly inbred populations.

Fisher vs. The Worms: Extraordinary Sex Ratios in Nematodes and the Mechanisms That Produce Them

Parker, Baker, and Smith provided the first robust theory explaining why anisogamy evolves in parallel in multicellular organisms. Anisogamy sets the stage for the emergence of separate sexes, and for another phenomenon with which Parker is associated: sperm competition. In outcrossing taxa with separate sexes, Fisher proposed that the sex ratio will tend towards unity in large, randomly mating populations due to a fitness advantage that accrues in individuals of the rarer sex. This creates a vast excess of sperm over that required to fertilize all available eggs, and intense competition as a result. However, small, inbred populations can experience selection for skewed sex ratios. This is widely appreciated in haplodiploid organisms, in which females can control the sex ratio behaviorally. In this review, we discuss recent research in nematodes that has characterized the mechanisms underlying highly skewed sex ratios in fully diploid systems. These include self-fertile hermaphroditism and the adaptive elimination of sperm competition factors, facultative parthenogenesis, non-Mendelian meiotic oddities involving the sex chromosomes, and environmental sex determination. By connecting sex ratio evolution and sperm biology in surprising ways, these phenomena link two “seminal” contributions of G. A. Parker.

An evolutionary perspective on contemporary genetic load in threatened species to inform future conservation efforts

In theory, genomic erosion can be reduced in fragile “recipient” populations by translocating individuals from genetically diverse “donor” populations. However, recent simulation studies have argued that such translocations can, in principle, serve as a conduit for new deleterious mutations to enter recipient populations. A reduction in evolutionary fitness is associated with a higher load of deleterious mutations and thus, a better understanding of evolutionary processes driving the empirical distribution of deleterious mutations is crucial. Here, we show that genetic load is evolutionarily dynamic in nature and that demographic history greatly influences the distribution of deleterious mutations over time. Our analyses, based on both demographically explicit simulations as well as whole genome sequences of potential donor-recipient pairs of Montezuma Quail (Cyrtonyx montezumae) populations, indicate that all populations tend to lose deleterious mutations during bottlenecks, but that genetic purging is pronounced in smaller populations with stronger bottlenecks. Despite carrying relatively fewer deleterious mutations, we demonstrate how small, isolated populations are more likely to suffer inbreeding depression as deleterious mutations that escape purging are homogenized due to drift, inbreeding, and ineffective purifying selection. We apply a population genomics framework to showcase how the phylogeography and historical demography of a given species can enlighten genetic rescue efforts. Our data suggest that small, inbred populations should benefit the most when assisted gene flow stems from genetically diverse donor populations that have the lowest proportion of deleterious mutations.

Significance of Linkage Disequilibrium and Epistasis on the Genetic Variances in Non-Inbred and Inbred Populations

Background The influence of linkage disequilibrium (LD), epistasis, and inbreeding on the genotypic variance continues to be an important area of investigation in genetics and evolution. Although the current knowledge about biological pathways and gene networks imply that epistasis is important in determining quantitative traits, the empirical evidence for a range of species and traits is that the genetic variance is most additive. This is confirmed by some recent theoretical studies. However, because these investigations have assumed linkage equilibrium, only additive effects, or simplified assumptions for the two- and high-order epistatic effects, the objective of this investigation was to provide additional information about the impact of LD and epistasis on the genetic variances in non-inbred and inbred populations, using a simulated data set.Results The epistatic variance in generation 0 corresponded to 1 to 10% of the genotypic variance, with 30% of epistatic genes, but it corresponded to 5 to 45% assuming 100% of epistatic genes. After 10 generations of random cross or selfing the ratio epistatic variance/genotypic variance increased in the range of 15 to 1,079%. The epistatic variances are maximized assuming dominant epistasis, duplicate genes with cumulative effects, and non-epistatic gene interaction. A minimization occurs with complementary, recessive, and dominant and recessive epistasis. In non-inbred populations, the genetic covariances have negligible magnitude compared with the genetic variances. In inbred populations, excepting for duplicate epistasis, the sum of the epistatic covariances was in general negative and with magnitude higher than the non-additive variances, especially under 100% of epistatic genes.Conclusions The LD level for genes, even under a relatively low gene density, has a significant effect on the genetic variances in non-inbred and inbred populations. Assuming digenic epistasis, the additive variance is in general the most important component of the genotypic variance in non-inbred and inbred populations. The ratio epistatic variance/genotypic variance is proportional to the percentage of interacting genes and increases with random cross and selfing. In general, the additive x additive variance is the most important component of the epistatic variance. The maximization of the epistatic variance depends on the allele frequency, LD level, and epistasis type.