Efficient network-guided multi-locus association mapping with graph cuts

As an increasing number of genome-wide association studies reveal the limitations of attempting to explain phenotypic heritability by single genetic loci, there is growing interest for associating complex phenotypes with sets of genetic loci. While several methods for multi-locus mapping have been proposed, it is often unclear how to relate the detected loci to the growing knowledge about gene pathways and networks. The few methods that take biological pathways or networks into account are either restricted to investigating a limited number of predetermined sets of loci, or do not scale to genome-wide settings. We present SConES, a new efficient method to discover sets of genetic loci that are maximally associated with a phenotype, while being connected in an underlying network. Our approach is based on a minimum cut reformulation of the problem of selecting features under sparsity and connectivity constraints that can be solved exactly and rapidly. SConES outperforms state-of-the-art competitors in terms of runtime, scales to hundreds of thousands of genetic loci, and exhibits higher power in detecting causal SNPs in simulation studies than existing methods. On flowering time phenotypes and genotypes from Arabidopsis thaliana, SConES detects loci that enable accurate phenotype prediction and that are supported by the literature. Matlab code for SConES is available at http://webdav.tuebingen.mpg.de/u/karsten/Forschung/scones/Comment: 20 pages, 6 figures, accepted at ISMB (International Conference on Intelligent Systems for Molecular Biology) 201

Genetics of Intraspecies Variation in Avoidance Behavior Induced by a Thermal Stimulus in Caenorhabditis elegans.

Individuals within a species vary in their responses to a wide range of stimuli, partly as a result of differences in their genetic makeup. Relatively little is known about the genetic and neuronal mechanisms contributing to diversity of behavior in natural populations. By studying intraspecies variation in innate avoidance behavior to thermal stimuli in the nematode Caenorhabditis elegans, we uncovered genetic principles of how different components of a behavioral response can be altered in nature to generate behavioral diversity. Using a thermal pulse assay, we uncovered heritable variation in responses to a transient temperature increase. Quantitative trait locus mapping revealed that separate components of this response were controlled by distinct genomic loci. The loci we identified contributed to variation in components of thermal pulse avoidance behavior in an additive fashion. Our results show that the escape behavior induced by thermal stimuli is composed of simpler behavioral components that are influenced by at least six distinct genetic loci. The loci that decouple components of the escape behavior reveal a genetic system that allows independent modification of behavioral parameters. Our work sets the foundation for future studies of evolution of innate behaviors at the molecular and neuronal level

Genetic Influences on Brain Gene Expression in Rats Selected for Tameness and Aggression

Inter-individual differences in many behaviors are partly due to genetic differences, but the identification of the genes and variants that influence behavior remains challenging. Here, we studied an F2 intercross of two outbred lines of rats selected for tame and aggressive behavior towards humans for more than 64 generations. By using a mapping approach that is able to identify genetic loci segregating within the lines, we identified four times more loci influencing tameness and aggression than by an approach that assumes fixation of causative alleles, suggesting that many causative loci were not driven to fixation by the selection. We used RNA sequencing in 150 F2 animals to identify hundreds of loci that influence brain gene expression. Several of these loci colocalize with tameness loci and may reflect the same genetic variants. Through analyses of correlations between allele effects on behavior and gene expression, differential expression between the tame and aggressive rat selection lines, and correlations between gene expression and tameness in F2 animals, we identify the genes Gltscr2, Lgi4, Zfp40 and Slc17a7 as candidate contributors to the strikingly different behavior of the tame and aggressive animals

Bose-Einstein distribution, condensation transition and multiple stationary states in multiloci evolution of diploid population

The mapping between genotype and phenotype is encoded in the complex web of epistatic interaction between genetic loci. In this rugged fitness landscape, recombination processes, which tend to increase variation in the population, compete with selection processes that tend to reduce genetic variation. Here we show that the Bose-Einstein distribution describe the multiple stationary states of a diploid population under this multi-loci evolutionary dynamics. Moreover, the evolutionary process might undergo an interesting condensation phase transition in the universality class of a Bose-Einstein condensation when a finite fraction of pairs of linked loci, is fixed into given allelic states. Below this phase transition the genetic variation within a species is significantly reduced and only maintained by the remaining polymorphic loci.Comment: (12 pages, 7 figures

Multi-ancestry study of blood lipid levels identifies four loci interacting with physical activity.

Many genetic loci affect circulating lipid levels, but it remains unknown whether lifestyle factors, such as physical activity, modify these genetic effects. To identify lipid loci interacting with physical activity, we performed genome-wide analyses of circulating HDL cholesterol, LDL cholesterol, and triglyceride levels in up to 120,979 individuals of European, African, Asian, Hispanic, and Brazilian ancestry, with follow-up of suggestive associations in an additional 131,012 individuals. We find four loci, in/near CLASP1, LHX1, SNTA1, and CNTNAP2, that are associated with circulating lipid levels through interaction with physical activity; higher levels of physical activity enhance the HDL cholesterol-increasing effects of the CLASP1, LHX1, and SNTA1 loci and attenuate the LDL cholesterol-increasing effect of the CNTNAP2 locus. The CLASP1, LHX1, and SNTA1 regions harbor genes linked to muscle function and lipid metabolism. Our results elucidate the role of physical activity interactions in the genetic contribution to blood lipid levels

Double-digest RADseq loci using standard Illumina indexes improve deep and shallow phylogenetic resolution of Lophodermium, a widespread fungal endophyte of pine needles.

The phylogenetic and population genetic structure of symbiotic microorganisms may correlate with important ecological traits that can be difficult to directly measure, such as host preferences or dispersal rates. This study develops and tests a low-cost double-digest restriction site-associated DNA sequencing (ddRADseq) protocol to reveal among- and within-species genetic structure for Lophodermium, a genus of fungal endophytes whose evolutionary analyses have been limited by the scarcity of informative markers. The protocol avoids expensive barcoded adapters and incorporates universal indexes for multiplexing. We tested for reproducibility and functionality by comparing shared loci from sample replicates and assessed the effects of numbers of ambiguous sites and clustering thresholds on coverage depths, number of shared loci among samples, and phylogenetic reconstruction. Errors between technical replicates were minimal. Relaxing the quality-filtering criteria increased the mean coverage depth per locus and the number of loci recovered within a sample, but had little effect on the number of shared loci across samples. Increasing clustering threshold decreased the mean coverage depth per cluster and increased the number of loci recovered within a sample but also decreased the number of shared loci across samples, especially among distantly related species. The combination of low similarity clustering (70%) and relaxed quality-filtering (allowing up to 30 ambiguous sites per read) performed the best in phylogenetic analyses at both recent and deep genetic divergences. Hence, this method generated sufficient number of shared homologous loci to investigate the evolutionary relationships among divergent fungal lineages with small haploid genomes. The greater genetic resolution also revealed new structure within species that correlated with ecological traits, providing valuable insights into their cryptic life histories

Characterization of spotted hyena, Crocuta crocuta microsatellite loci

We have isolated 10 polymorphic microsatellite loci in the spotted hyena,Crocuta crocuta.The loci displayed between eight and 14 alleles in a minimum of 12 individuals tested. These loci will be used to investigate relatedness within social groups, the genetic structure of populations, sexual selection, and mate choice in spotted hyenas

The evolution of genetic architectures underlying quantitative traits

In the classic view introduced by R. A. Fisher, a quantitative trait is encoded by many loci with small, additive effects. Recent advances in QTL mapping have begun to elucidate the genetic architectures underlying vast numbers of phenotypes across diverse taxa, producing observations that sometimes contrast with Fisher's blueprint. Despite these considerable empirical efforts to map the genetic determinants of traits, it remains poorly understood how the genetic architecture of a trait should evolve, or how it depends on the selection pressures on the trait. Here we develop a simple, population-genetic model for the evolution of genetic architectures. Our model predicts that traits under moderate selection should be encoded by many loci with highly variable effects, whereas traits under either weak or strong selection should be encoded by relatively few loci. We compare these theoretical predictions to qualitative trends in the genetics of human traits, and to systematic data on the genetics of gene expression levels in yeast. Our analysis provides an evolutionary explanation for broad empirical patterns in the genetic basis of traits, and it introduces a single framework that unifies the diversity of observed genetic architectures, ranging from Mendelian to Fisherian.Comment: Minor changes in the text; Added supplementary materia