The nematode Caenorhabditis elegans is central to research in molecular, cell, and developmental biology, but nearly all of this research has been conducted on a single strain. Comparatively little is known about the population genomic and evolutionary history of this species. We characterized C. elegans genetic variation by high-throughput selective sequencing of a worldwide collection of 200 wild strains, identifying 41,188 single nucleotide polymorphisms. Unexpectedly, C. elegans genome variation is dominated by a set of commonly shared haplotypes on four of the six chromosomes, each spanning many megabases. Population-genetic modeling shows that this pattern was generated by chromosome-scale selective sweeps that have reduced variation worldwide; at least one of these sweeps likely occurred in the past few hundred years. These sweeps, which we hypothesize to be a result of human activity, have dramatically reshaped the global C. elegans population in the recent past.

The phenotypic differences between individual organisms can often be ascribed to underlying genetic and environmental variation. However, even genetically identical organisms in homogenous environments vary, suggesting that randomness in developmental processes such as gene expression may also generate diversity. In order to examine the consequences of gene expression variability in multicellular organisms, we studied intestinal specification in the roundworm Caenorhabditis elegans in which wild-type cell fate is invariant and controlled by a small transcriptional network. Mutations in elements of this network can have indeterminate effects: some mutant embryos fail to develop intestinal cells, while others produce intestinal precursors. By counting transcripts of the genes in this network in individual embryos, we show that the expression of an otherwise redundant gene becomes highly variable in the mutants and that this variation is thresholded to produce an ON/OFF expression pattern of the master regulatory gene of intestinal differentiation. Our results demonstrate that mutations in developmental networks can expose otherwise buffered stochastic variability in gene expression, leading to pronounced phenotypic variation.

Studies in model organisms have yielded considerable insights into the etiology of disease and our understanding of evolutionary processes. Caenorhabditis elegans is among the most powerful model organisms used to understand biology. However, C. elegans is not used as extensively as other model organisms to investigate how natural variation shapes traits, especially through the use of genome-wide association (GWA) analyses. Here, we introduce a new platform, the C. elegans Natural Diversity Resource (CeNDR) to enable statistical genetics and genomics studies of C. elegans and to connect the results to human disease. CeNDR provides the research community with wild strains, genome-wide sequence and variant data for every strain, and a GWA mapping portal for studying natural variation in C. elegans. Additionally, researchers outside of the C. elegans community can benefit from public mappings and integrated tools for comparative analyses. CeNDR uses several databases that are continually updated through the addition of new strains, sequencing data, and association mapping results. The CeNDR data are accessible through a freely available web portal located at http://www.elegansvariation.org or through an application programming interface.

The nematode Caenorhabditis elegans responds to pathogenic bacteria with conserved innate immune responses and pathogen avoidance behaviors. We investigated natural variation in C. elegans resistance to pathogen infection. With the use of quantitative genetic analysis, we determined that the pathogen susceptibility difference between the laboratory wild-type strain N2 and the wild isolate CB4856 is caused by a polymorphism in the npr-1 gene, which encodes a homolog of the mammalian neuropeptide Y receptor. We show that the mechanism of NPR-1-mediated pathogen resistance is through oxygen-dependent behavioral avoidance rather than direct regulation of innate immunity. For C. elegans, bacteria represent food but also a potential source of infection. Our data underscore the importance of behavioral responses to oxygen levels in finding an optimal balance between these potentially conflicting cues.Microbes, including commensal organisms and pathogens, profoundly influence the immune and metabolic physiology of host organisms (1). We used the nematode Caenorhabditis elegans as an experimental host to dissect the molecular basis of interactions between host species and microorganisms. C. elegans exhibits diverse behaviors in response to bacteria provided as a nutrient source (2-4). Feeding behavior can be modulated by environmental conditions, including oxygen concentration (5). Some bacterial species are pathogenic to C. elegans (6), and C. elegans responds by activating conserved innate immune pathways (7-9) and by avoiding pathogens (10).We found that the standard laboratory strain N2 (isolated in Bristol, England) and strain CB4856 (isolated in Hawaii, U.S.A.) exhibited a marked difference in susceptibility to the human opportunistic pathogen Pseudomonas aeruginosa strain PA14 (Fig. 1A). The mean time to 50% lethality (LT50) for CB4856 was shorter (50±7.8 hours) than that for N2 (90±13 hours). Using a collection of recombinant inbred lines (11), we mapped the pathogen susceptibility trait to a 774-kb region of the X chromosome (LGX) containing npr-1, which encodes a G protein-coupled receptor related to the mammalian neuropeptide Y receptor (Fig. 1B). The 215V npr-1 allele in N2 has increased NPR-1 activity relative to the 215F npr-1 allele in CB4856, and the 215V allele confers behavioral differences that are dominant to those conferred by the 215F allele (12). To test the possibility that npr-1 causes the difference in pathogen susceptibility between the N2 and CB4856 strains, we used npr-1 loss-of-function mutants isolated in the N2 background. Like the CB4856 strain, the npr-1 presumptive null †To whom correspondence should be addressed., leonid@genomics.princeton.edu (L.K.)or dhkim@mit.edu (D.H.K.). * These authors contributed equally to this work. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript alleles ad609 and ky13, along with the reduction-of-function alleles ur89 and n1353, had enhanced susceptibility to killing by PA14 ( Fig. 1C and fig. S1). The enha...