Biology subjects

Örjan Carlborg

Publications and source records attributed to Örjan Carlborg.

6 recordsLinked to original sources

bioRxiv2016

Accounting for genetic interactions is necessary for accurate prediction of extreme phenotypic values of quantitative traits in yeast

Experiments in model organisms report abundant genetic interactions underlying biologically important traits, whereas quantitative genetics theory predicts, and data support, that most genetic variance in populations is additive. Here we describe networks of capacitating genetic interactions that contribute to quantitative trait variation in a large yeast intercross population. The additive variance explained by individual loci in a network is highly dependent on the allele frequencies of the interacting loci. Modeling of phenotypes for multi-locus genotype classes in the epistatic networks is often improved by accounting for the interactions. We discuss the implications of these results for attempts to dissect genetic architectures and to predict individual phenotypes and long-term responses to selection.

Genetics↗

bioRxiv2016

Wide genome involvement in response to long-term selection for antibody response in an experimental population of White Leghorn chickens

Long-term selection experiments provide a powerful approach to gain empirical insights into adaptation. They allow researchers to uncover the targets of selection and how these contribute to the mode and tempo of adaptation. Here we report results from a pooled genome re-sequencing study to investigate the consequences of 39 generations of bidirectional selection in White Leghorn chickens on a humoral immune trait: antibody response to sheep red blood cells. We observed wide genome involvement in response to this selection regime, with over 200 candidate sweep regions characterised by spans of high genetic differentiation (FST). These sweep signatures, encompassing almost 20% of the chicken genome (208.8 Mb), are primarily the result from bidirectional selection on haplotypes present in the base population. These extensive genomic changes highlight both the extent of standing genetic variation at immune loci available at the onset of selection, as well as how the long-term selection response results from selection on a highly polygenic genetic architecture. Furthermore, we present three examples of strong candidate genes that may have contributed to the profound phenotypic response to selection.\n\nData AvailabilityPooled genome data generated for this study will become available via SRA upon acceptance of manuscript

Genomics↗

bioRxiv2015

The Multi-allelic Genetic Architecture of a Variance-heterogeneity Locus for Molybdenum Accumulation Acts as a Source of Unexplained Additive Genetic Variance

Most biological traits are regulated by both genetic and environmental factors. Individual loci contributing to the phenotypic diversity in a population are generally identified by their contributions to the trait mean. Genome-wide association (GWA) analyses can also detect loci based on variance differences between genotypes and several hypotheses have been proposed regarding the possible genetic mechanisms leading to such signals. Little is, however, known about what causes them and whether this genetic variance-heterogeneity reflects mechanisms of importance in natural populations. Previously, we identified a variance-heterogeneity GWA (vGWA) signal for leaf molybdenum concentrations in Arabidopsis thaliana. Here, fine-mapping of this association to a [~]78 kb Linkage Disequilibrium (LD)-block reveals that it emerges from the independent effects of three genetic polymorphisms on the high-variance associated version of this LD-block. By revealing the genetic architecture underlying this vGWA signal, we uncovered the molecular source of a significant amount of hidden additive genetic variation (\"missing heritability\"). Two of the three polymorphisms on the high-variance LD-block are promoter variants for Molybdate transporter 1 (MOT1), and the third a variant located [~]25 kb downstream of this gene. A fourth independent association was also detected [~]600 kb upstream of the LD-block. Testing of T-DNA knockout alleles for genes in the associated regions suggest AT2G25660 (unknown function) and AT2G26975 (Copper Transporter 6; COPT6) as the strongest candidates for the associations outside MOT1. Our results show that multi-allelic genetic architectures within a single LD-block can lead to a variance-heterogeneity between genotypes in natural populations. Further they provide novel insights into the genetic regulation of ion homeostasis in A. thaliana, and empirically confirm that variance-heterogeneity based GWA methods are a valuable tool to detect novel associations of biological importance in natural populations.

Genetics↗

bioRxiv2015

Standing genetic variation as a major contributor to adaptation in the Virginia chicken lines selection experiment

Artificial selection has, for decades, provided a powerful approach to study the genetics of adaptation. Using selective-sweep mapping, it is possible to identify genomic regions in populations where the allele-frequencies have diverged during selection. To avoid misleading signatures of selection, it is necessary to show that a sweep has an effect on the selected trait before it can be considered adaptive. Here, we confirm candidate selective-sweeps on a genome-wide scale in one of the longest, on-going bi-directional selection experiments in vertebrates, the Virginia high and low body-weight selected chicken lines. The candidate selective-sweeps represent standing genetic variants originating from the common base-population. Using a deep-intercross between the selected lines, 16 of 99 evaluated regions were confirmed to contain adaptive selective-sweeps based on their association with the selected trait, 56-day body-weight. Although individual additive effects were small, the fixation for alternative alleles in the high and low body-weight lines across these loci contributed at least 40% of the divergence between them and about half of the additive genetic variance present within and between the lines after 40 generations of selection. The genetic variance contributed by the sweeps corresponds to about 85% of the additive genetic variance of the base-population, illustrating that these loci were major contributors to the realised selection-response. Thus, the gradual, continued, long-term selection response in the Virginia lines was likely due to a considerable standing genetic variation in a highly polygenic genetic architecture in the base-population with contributions from a steady release of selectable genetic variation from new mutations and epistasis throughout the course of selection.

Genetics↗

bioRxiv2014

A Genome-Wide Association Analysis Reveals Epistatic Cancellation of Additive Genetic Variance for Root Length in Arabidopsis thaliana

Efforts to identify loci underlying complex traits generally assume that most genetic variance is additive. Here, we examined the genetics of Arabidopsis thaliana root length and found that the narrow-sense heritability for this trait was statistically zero. This low additive genetic variance likely explains why no associations to root length could be found using standard additive-model-based genome-wide association (GWA) approaches. However, the broad-sense heritability for root length was significantly larger, and we therefore also performed an epistatic GWA analysis to map loci contributing to the epistatic genetic variance. This analysis revealed four interacting pairs involving seven chromosomal loci that passed a standard multiple-testing corrected significance threshold. Explorations of the genotype-phenotype maps for these pairs revealed that the detected epistasis cancelled out the additive genetic variance, explaining why these loci were not detected in the additive GWA analysis. Small population sizes, such as in our experiment, increase the risk of identifying false epistatic interactions due to testing for associations with very large numbers of multi-marker genotypes in few phenotyped individuals. Therefore, we estimated the false-positive risk using a new statistical approach that suggested half of the associated pairs to be true positive associations. Our experimental evaluation of candidate genes within the seven associated loci suggests that this estimate is conservative; we identified functional candidate genes that affected root development in four loci that were part of three of the pairs. In summary, statistical epistatic analyses were found to be indispensable for confirming known, and identifying several new, functional candidate genes for root length using a population of wild-collected A. thaliana accessions. We also illustrated how epistatic cancellation of the additive genetic variance resulted in an insignificant narrow-sense, but significant broad-sense heritability that could be dissected into the contributions of several individual loci using a combination of careful statistical epistatic analyses and functional genetic experiments.\n\nAuthor summaryComplex traits, such as many human diseases or climate adaptation and production traits in crops, arise through the action and interaction of many genes and environmental factors. Classic approaches to identify contributing genes generally assume that these factors contribute mainly additive genetic variance. Recent methods, such as genome-wide association studies, often adhere to this additive genetics paradigm. However, additive models of complex traits do not reflect that genes can also contribute with non-additive genetic variance. In this study, we use Arabidopsis thaliana to determine the additive and non-additive genetic contributions to the phenotypic variation in root length. Surprisingly, much of the observed phenotypic variation in root length across genetically divergent strains was explained by epistasis. We mapped seven loci contributing to the epistatic genetic variance and validated four genes in these loci with mutant analysis. For three of these genes, this is their first implication in root development. Together, our results emphasize the importance of considering both non-additive and additive genetic variance when dissecting complex trait variation, in order not to lose sensitivity in genetic analyses.

Genomics↗

bioRxiv2014

Natural CMT2 variation is associated with genome-wide methylation changes and temperature seasonality

As Arabidopsis thaliana has colonized a wide range of habitats across the world it is an attractive model for studying the genetic mechanisms underlying environmental adaptation. Here, we used public data from two collections of A. thaliana accessions to associate genetic variability at individual loci with differences in climates at the sampling sites. We use a novel method to screen the genome for plastic alleles that tolerate a broader climate range than the major allele. This approach reduces confounding with population structure and increases power compared to standard genome-wide association methods. Sixteen novel loci were found, including an association between Chromomethylase 2 (CMT2) and temperature seasonality where the genome-wide CHH methylation was different for the group of accessions carrying the plastic allele. Cmt2 mutants were shown to be more tolerant to heat-stress, suggesting genetic regulation of epigenetic modifications as a likely mechanism underlying natural adaptation to variable temperatures, potentially through differential allelic plasticity to temperature-stress.\n\nAUTHOR SUMMARYA central problem when studying adaptation to a new environment is the interplay between genetic variation and phenotypic plasticity. Arabidopsis thaliana has colonized a wide range of habitats across the world and it is therefore an attractive model for studying the genetic mechanisms underlying environmental adaptation. Here, we study two collections of A. thaliana accessions from across Eurasia to identify loci associated with differences in climates at the sampling sites. A new genome-wide association analysis method was developed to detect adaptive loci where the alleles tolerate different climate ranges. Sixteen novel such loci were found including a strong association between Chromomethylase 2 (CMT2) and temperature seasonality. The reference allele dominated in areas with less seasonal variability in temperature, and the alternative allele existed in both stable and variable regions. Our results thus link natural variation in CMT2 and epigenetic changes to temperature adaptation. We showed experimentally that plants with a defective CMT2 gene tolerate heat-stress better than plants with a functional gene. Together this strongly suggests a role for genetic regulation of epigenetic modifications in natural adaptation to temperature and illustrates the importance of re-analyses of existing data using new analytical methods to obtain deeper insights into the underlying biology from available data.

Genomics↗