Biology subjects

Carlborg, O.

Publications and source records attributed to Carlborg, O..

9 recordsLinked to original sources

bioRxiv2021

Low-coverage sequencing in a deep intercross of the Virginia body weight lines provides insight to the polygenic genetic architecture of growth: novel loci revealed by increased power and improved genome-coverage

Genetic dissection of highly polygenic traits is a challenge, in part due to the power necessary to confidently identify loci with minor effects. Experimental crosses are valuable resources for mapping such traits. Traditionally, genome-wide analyses of experimental crosses have targeted major loci using data from a single generation, often the F2, with additional, later generation individuals being generated for replication and fine-mapping. Here, we aim to confidently identify minor-effect loci contributing to the highly polygenic basis of the long-term, divergent bi-directional selection responses for 56-day body weight in the Virginia chicken lines. To achieve this, a powerful strategy was developed to make use of data from all generations (F2-F18) of an advanced intercross line, developed by crossing the low and high selected lines after 40 generations of selection. A cost-efficient low-coverage sequencing based approach was used to obtain high-confidence genotypes in 1Mb bins across 99.3% of the chicken genome for >3,300 intercross individuals. In total, 12 genome-wide significant and 10 additional suggestive QTL for 56-day body weight were mapped, with only two of these QTL reaching genome-wide, and one suggestive, significance in analyses of the F2 generation. Five of the significant, and four of the suggestive, QTL were among the 20 loci reaching a 20% FDR-threshold in previous analyses of data from generation F15. The novel, minor-effect QTL mapped here were generally mapped due to an overall increase in power by integrating data across generations, with minor contributions from increased genome-coverage and improved marker information content. Significant and suggestive QTL now explain >60% of the difference between the parental lines, three times more than the previously reported significant QTL. Making integrated use of all available samples from multiple generations in experimental crosses is now economically feasible using the low-cost, sequencing-based genotyping strategies outlined here. Our empirical results illustrate the value of this strategy for mapping novel minor-effect loci contributing to complex traits to provide a more confident, comprehensive view of the individual loci that form the genetic basis of the highly polygenic, long-term selection responses for 56-day body weight in the Virginia chicken lines.

genetics↗

bioRxiv2019

Yeast growth responses to environmental perturbations are associated with rewiring of large epistatic networks

The phenotypic effects of genetic polymorphisms often depend on the genetic and environmental context. Here, we explore how polymorphic loci in large interaction networks contribute to complex trait variation and in particular how genetic effects and network topologies are influenced by environmental perturbations. This was done by reanalysing a dataset of >4,000 haploid yeast segregants grown on 20 different media. In total, 130 epistatic loci were associated with growth in at least one environment. The across-environment interaction network defined by these loci explained 69 - 100% of the narrow sense heritability in the individual environments. Environmental changes often resulted in network hubs being connected and disconnected from their interactors, leading to changes in additive effects of individual loci, epistatic effects of multi-locus interactions and the total level of genetic variance in growth. The largest variation in genetic effects across environments was found for epistatic loci that were highly connected network hubs in some environments but not in others. In environments where loci were highly connected, the segregating alleles epistatically suppressed or released genetic effects from their interactors. In environments where they were lowly connected, the same alleles made small or no contributions to growth. Hub-loci thus often serve as modulators, influencing the phenotypic effects of environmentally specific sets of interacting effector genes, rather than being effectors themselves. These findings illustrate the importance of the interplay between large genetic interactions networks and the living environment, both for individual phenotypes and population level metrics of genetic variation.

genetics↗

bioRxiv2018

Bidirectional selection for body weight on standing genetic variation in a chicken model

Experimental populations of model organisms provide valuable opportunities to unravel the genomic impact of selection in a controlled system. The Virginia body weight chicken lines represent a unique resource to investigate signatures of selection in a system where long-term, single-trait, bidirectional selection has been carried out for more than 60 generations. Using pooled genome resequencing of paired generations of these lines, we reveal the within and between-line genomic signatures of selection. At 55 generations of divergent selection, 14.2% of the genome showed extreme differentiation between the selected lines were contained within 395 genomic regions. The lines often displayed a duality of the sweep signatures: an extended region of homozygosity in one line, in contrast to mosaic pattern of heterozygosity in the other line. These haplotype mosaics consist of short, distinct haploblocks of variable between-line divergence. Formed during what probably was a complex history of bottlenecks, inbreeding, and introgressions, these mosaics represent the standing genetic variation available at the onset of selection in the founder population. Selection on standing genetic variation can thus result in different signatures depending on the intensity and direction of selection.

genomics↗

bioRxiv2018

Genotyping by low-coverage whole-genome sequencing in intercross pedigrees from outbred founders: a cost efficient approach

BackgroundExperimental intercrosses between outbred founder populations are powerful resources for mapping loci contributing to complex traits (Quantitative Trait Loci or QTL). Here, we present an approach and accompanying software for high-resolution genotype imputation in such populations using whole-genome high coverage sequence data on founder individuals ([~]30x) and low coverage sequence data on intercross individuals ([~]0.4x). The method is illustrated in a large F2 pedigree between lines of chickens that have been divergently selected for 40 generations for the same trait (body weight at 8 weeks of age).\n\nResultsDescribed is how hundreds of individuals were whole-genome sequenced in a cost- and time-efficient manner using a Tn5-based library preparation protocol optimized for this application. In total, 7.6M markers segregated in this pedigree and 10.0 to 13.7% were informative for imputing the founder line genotypes within the F0-F2 families. The genotypes imputed from low coverage sequence data were consistent with the founder line genotypes estimated using SNP and microsatellite markers both at individual imputed sites (92%) and across the genome of individual chickens (93%). The resolution of the recombination breakpoints was high with 50% being resolved within <10kb.\n\nConclusionsA method for genotype imputation from low-coverage whole-genome sequencing in outbred intercrosses is described and evaluated. By applying it to an outbred chicken F2 cross it is illustrated that it provides high quality, high-resolution genotypes in a time and cost efficient manner.

genetics↗

bioRxiv2018

On the relationship between high-order linkage disequilibrium and epistasis

A plausible explanation for statistical epistasis revealed in genome wide association analyses is the presence of high order linkage disequilibrium (LD) between the genotyped markers tested for interactions and unobserved functional polymorphisms. Based on findings in experimental data, it has been suggested that high order LD might be a common explanation for statistical epistasis inferred between local polymorphisms in the same genomic region. Here, we empirically evaluate how prevalent high order LD is between local, as well as distal, polymorphisms in the genome. This could provide insights into whether we should account for this when interpreting results from genome wide scans for statistical epistasis. An extensive and strong genome wide high order LD was revealed between pairs of markers on the high density 250k SNP-chip and individual markers revealed by whole genome sequencing in the A. thaliana 1001-genomes collection. The high order LD was found to be more prevalent in smaller populations, but present also in samples including several hundred individuals. An empirical example illustrates that high order LD might be an even greater challenge in cases when the genetic architecture is more complex than the common assumption of bi-allelic loci. The example shows how significant statistical epistasis is detected for a pair of markers in high order LD with a complex multi allelic locus. Overall, our study illustrates the importance of considering also other explanations than functional genetic interactions when genome wide statistical epistasis is detected, in particular when the results are obtained in small populations of inbred individuals.

genetics↗

bioRxiv2017

Explorations of the polygenic genetic architecture of flowering time in the worldwide Arabidopsis thaliana population

As a locally adapted complex trait, flowering time in Arabidopsis thaliana has attracted much attention in genetics. Most studies have, however, focused on contributions by individual loci rather than the joint contributions by the large number of loci in the genetic architecture of flowering time to local and global adaptation. In an earlier study, we reported 46 loci associated with flowering time variation during growth at 10{degrees}C, 16{degrees}C or both in the 1,001-genomes collection of Arabidopsis thaliana accessions. Here, we explore how these loci together contribute to differences among genetically defined, and geographically divided, subpopulations across the native range of this species. Our approach was to define flowering time as a trait, and the measurements at 10 and 16 {degrees}C as two independent measurements of it. This facilitated explorations of the dynamics in the genetic architecture -which loci contribute and their effects- of flowering time across growth temperatures and their potential roles in local and global adaptation. The overall flowering time differences between populations could be explained by subtle changes in allele-frequencies and gradual changes in phenotype due to globally present alleles. More extreme local adaptations were on several occasions due to contributions by regional alleles with relatively large effects. About 2/3 of the 48 evaluated flowering time loci had similar effects on flowering time at 10{degrees}C and 16{degrees}C, while the remaining 1/3 had different effects in the two temperatures, suggesting an important contribution of gene by temperature interactions to this trait. There are also indications that co-evolution of functionally connected alleles in local populations has been important for local adaptation. Overall, this study provides deeper insights to the polygenic genetic basis of flowering time variation in Arabidopsis thaliana across a wide range of ecological habitats.\n\nAuthor SummaryMany genes can affect flowering time in Arabidopsis thaliana, but their contribution to natural flowering time variation in the worldwide population is largely unknown. We explored how 48 loci associated with flowering time, measured at 10{degrees}C and 16{degrees}C, or their difference, for the same wild collected 1,001-genomes Arabidopsis thaliana accessions together contribute to differences among the genetically defined and geographically divided subpopulations from the native species range. The overall flowering time differences among these subpopulations could be explained by the joint small effects of globally present alleles, suggesting an important contribution by polygenic adaptation for this trait. Most alleles with large effects on flowering were present only in some populations, facilitating more extreme local adaptations. Long-range LD was observed between genes in several biological pathways, indicating possible local adaptation via co-evolution of functionally connected polymorphisms. The genetic architecture of flowering time was also found to depend on the growth temperature. Most flowering time loci had similar effects on flowering time measured at 10{degrees}C and 16{degrees}C, but the effects of about 1/3 of them had effects that varied with temperature. Overall, new insights are provided to how the polygenic architecture of flowering time has facilitated its colonisation of a wide range of ecological habitats.

genetics↗

bioRxiv2017

A multi-locus association analysis method integrating phenotype and expression data reveals multiple novel associations to flowering time variation in wild-collected Arabidopsis thaliana

AO_SCPLOWBSTRACTC_SCPLOWWhen a species adapts to a new habitat, selection for the fitness traits often result in a confounding between genome-wide genotype and adaptive alleles. It is a major statistical challenge to detect such adaptive polymorphisms if the confounding is strong, or the effects of the adaptive alleles are weak. Here, we describe a novel approach to dissect polygenic traits in natural populations. First, candidate adaptive loci are identified by screening for loci that are directly associated to the trait or control the expression of genes known to affect it. Then, the multi-locus genetic architecture is inferred using a backward elimination association analysis across all the candidate loci using an adaptive false-discovery rate based threshold. Effects of population stratification are controlled by corrections for population structure in the pre-screening step and by simultaneously testing all candidate loci in the multi-locus model. We illustrate the method by exploring the polygenic basis of an important adaptive trait, flowering time in Arabidopsis thaliana, using public data from the 1,001 genomes project. Our method revealed associations between 33 (29) loci and flowering time at 10 (16){degrees}C in this collection of natural accessions, where standard genome wide association analysis methods detected 5 (3) loci. The 33 (29) loci explained approximately 55 (48)% of the total phenotypic variance of the respective traits. Our work illustrates how the genetic basis of highly polygenic adaptive traits in natural populations can be explored in much greater detail by using new multi-locus mapping approaches taking advantage of prior biological information as well as genome and transcriptome data.

genetics↗

bioRxiv2017

On The Relationship Between Epistasis And Genetic Variance-Heterogeneity

Epistasis and genetic variance heterogeneity are two non-additive genetic inheritance patterns that are often, but not always, related. Here we use theoretical examples and empirical results from analyses of experimental data to illustrate the connection between the two. This includes an introduction to the relationship between epistatic gene-action, statistical epistasis and genetic variance heterogeneity and a brief discussion about how other genetic processes than epistasis can also give rise to genetic variance heterogeneity.\n\nHighlightGenetic effects on the trait variance, rather than the mean, have been found in several studies. Here we discuss how this sometimes, but not always, can be caused by epistasis.

genetics↗

bioRxiv2017

A complex multi-locus, multi-allelic genetic architecture underlying the long-term selection-response in the Virginia body weight line of chickens

The ability of a population to adapt to changes in their living conditions, whether in nature or captivity, often depends on polymorphisms in multiple genes across the genome. In-depth studies of such polygenic adaptations are difficult in natural populations, but can be approached using the resources provided by artificial selection experiments. Here, we dissect the genetic mechanisms involved in long-term selection responses of the Virginia chicken lines, populations that after 40 generations of divergent selection for 56-day body weight display a nine-fold difference in the selected trait. In the F15 generation of an intercross between the divergent lines, 20 loci explained more than 60% of the additive genetic variance for the selected trait. We focused particularly on seven major QTL and found that only two fine-mapped to single, bi-allelic loci; the other five contained linked loci, multiple alleles or were epistatic. This detailed dissection of the polygenic adaptations in the Virginia lines provides a deeper understanding of genome-wide mechanisms involved in the long-term selection responses. The results illustrate that long-term selection responses, even from populations with a limited genetic diversity, can be polygenic and influenced by a range of genetic mechanisms.

genetics↗