Tests of association based on genomic windows can lead to spurious associations when using genotype panels with heterogeneous SNP densities

Dense single nucleotide polymorphism (SNP) panels are widely used for genome-wide association studies (GWAS). In these panels, SNPs within a genomic segment tend to be highly correlated. Thus, association studies based on testing the significance of single SNPs are not very effective, and genomic-window based tests have been proposed to address this problem. However, when the SNP density on the genotype panel is not homogeneous, genomic-window based tests can lead to the detection of spurious associations by declaring effects of genomic windows that explain a large proportion of genetic variance as significant. We propose two methods to solve this problem.

PSIII-2 Assessment of runs of homozygosity and estimates of inbreeding in three purebred turkey (Meleagris gallopavo) lines

Runs of homozygosity (ROH) are continuous stretches of homozygous genotypes in an individual that have been passed down from a common ancestor and can be used to accurately characterize genomic data. These ROH are correlated with other measures of inbreeding and have been applied to quantify individual autozygosity. The aim of this study was to detect and describe ROH in the turkey genome and estimate and compare measures of pedigree-based inbreeding coefficients (FPED) and genomic-based inbreeding coefficients estimated from ROH (FROH) and the genomic relationship matrix (FGRM). Pedigree records (n = 2,616,890) and genotypic records (n = 6,371) were available from three purebred turkey (Meleagris gallopavo) lines. Genotypic records were collected between 2013 and 2019 and were obtained using a dense single nucleotide polymorphism array (56,452 SNP). The overall mean length of detected ROH per animal was 2.87±0.29 Mb and mean number of ROH per animal was 84.87±8.79. Short ROH with lengths of 1–2 Mb long were the most abundant throughout the genome, accounting for approximately 45% of the identified segments. Mean ROH coverage differed greatly between chromosomes and lines. Across all lines, genomic derived inbreeding coefficients (FROH=0.27; FGRM=0.32) were higher than coefficients estimated from pedigree records (FPED=0.14). Ranges of correlations between FROH and FPED (0.19–0.31), FROH and FGRM (0.68–0.73), and FPED and FGRM (0.17–0.30) were estimated. Results from the current research provide a fundamental description of inbreeding in the turkey genome which is critical considering the growing concerns of the detrimental effects of increased inbreeding on fitness and health in livestock production. The knowledge gained from this study may subsequently be used to evaluate and maintain genetic diversity that is necessary for genetic improvement and minimizing inbreeding in turkey breeding programs.

Low Additive Genetic Variation in a Trait Under Selection in Domesticated Rice

Quantitative traits are important targets of both natural and artificial selection. The genetic architecture of these traits and its change during the adaptive process is thus of fundamental interest. The fate of the additive effects of variants underlying a trait receives particular attention because they constitute the genetic variation component that is transferred from parents to offspring and thus governs the response to selection. While estimation of this component of phenotypic variation is challenging, the increasing availability of dense molecular markers puts it within reach. Inbred plant species offer an additional advantage because phenotypes of genetically identical individuals can be measured in replicate. This makes it possible to estimate marker effects separately from the contribution of the genetic background not captured by genotyped loci. We focused on root growth in domesticated rice, Oryza sativa, under normal and aluminum (Al) stress conditions, a trait under recent selection because it correlates with survival under drought. A dense single nucleotide polymorphism (SNP) map is available for all accessions studied. Taking advantage of this map and a set of Bayesian models, we assessed additive marker effects. While total genetic variation accounted for a large proportion of phenotypic variance, marker effects contributed little information, particularly in the Al-tolerant tropical japonica population of rice. We were unable to identify any loci associated with root growth in this population. Models estimating the aggregate effects of all measured genotypes likewise produced low estimates of marker heritability and were unable to predict total genetic values accurately. Our results support the long-standing conjecture that additive genetic variation is depleted in traits under selection. We further provide evidence that this depletion is due to the prevalence of low-frequency alleles that underlie the trait.

Low additive genetic variation in a trait under selection in domesticated rice

Quantitative traits are important targets of both natural and artificial selection. The genetic architecture of these traits and its change during the adaptive process is thus of fundamental interest. The fate of the additive effects of variants underlying a trait receives particular attention because they constitute the genetic variation component that is transferred from parents to offspring and thus governs the response to selection. While estimation of this component of phenotypic variation is challenging, the increasing availability of dense molecular markers puts it within reach. Inbred plant species offer an additional advantage because phenotypes of genetically identical individuals can be measured in replicate. This makes it possible to estimate marker effects separately from the contribution of the genetic background. We focused on root growth in domesticated rice,Oryza sativa, under normal and aluminum (Al) stress conditions, a trait under recent selection because it correlates with survival under drought. A dense single nucleotide polymorphism (SNP) map is available for all accessions studied. Taking advantage of this map and a set of Bayesian models, we assessed additive marker effects. While total genetic variation accounted for a large proportion of phenotypic variance, marker effects contributed little information, particularly in the Al-toleranttropical japonicapopulation of rice. We were unable to identify any loci associated with root growth in this population. Models estimating the aggregate effects of all measured genotypes like-wise produced low estimates of marker heritability and were unable to predict total genetic values accurately. Our results support the long-standing conjecture that additive genetic variation is depleted in traits under selection. We further provide evidence that this depletion is due to the prevalence of low-frequency alleles that underlie the trait.

Somatic recombination underlies frequent revertant mosaicism in loricrin keratoderma

Revertant mosaicism is a phenomenon in which pathogenic mutations are rescued by somatic events, representing a form of natural gene therapy. Here, we report on the first evidence for revertant mosaicism in loricrin keratoderma (LK), an autosomal dominant form of ichthyosis caused by mutations in LOR on 1q21.3. We identified two unrelated LK families exhibiting dozens of previously unreported white spots, which increased in both number and size with age. Biopsies of these spots revealed that they had normal histology and that causal LOR mutations were lost. Notably, dense single nucleotide polymorphism mapping identified independent copy-neutral loss-of-heterozygosity events on chromosome 1q extending from regions centromeric to LOR to the telomere in all investigated spots, suggesting that somatic recombination represents a common reversion mechanism in LK. Furthermore, we demonstrated that reversion of LOR mutations confers a growth advantage to cells in vitro, but the clinically limited size of revertant spots suggests the existence of mechanisms constraining revertant clone expansion. Nevertheless, the identification of revertant mosaicism in LK might pave the way for revertant therapy for this intractable disease.