In the Bateson-Dobzhansky-Muller (BDM) model of speciation, incompatibilities emerge from the deleterious interactions between alleles that are neutral or advantageous in the original genetic backgrounds, i.e., negative epistatic effects. Within species such interactions are responsible for outbreeding depression and F2 (hybrid) breakdown. We sought to identify BDM incompatibilities in the nematode Caenorhabditis elegans by looking for genomic regions that disrupt egg laying; a complex, highly regulated, and coordinated phenotype. Investigation of introgression lines and recombinant inbred lines derived from the isolates CB4856 and N2 uncovered multiple incompatibility quantitative trait loci (QTL). These QTL produce a synthetic egg-laying defective phenotype not seen in CB4856 and N2 nor in other wild isolates. For two of the QTL regions, results are inconsistent with a model of pairwise interaction between two loci, suggesting that the incompatibilities are a consequence of complex interactions between multiple loci. Analysis of additional life history traits indicates that the QTL regions identified in these screens are associated with effects on other traits such as lifespan and reproduction, suggesting that the incompatibilities are likely to be deleterious. Taken together, these results indicate that numerous BDM incompatibilities that could contribute to reproductive isolation can be detected and mapped within C. elegans.

Dietary restriction appears to act as a general non-genetic mechanism that can robustly prolong lifespan. There have however been reports in many systems of cases where restricted food intake either shortens, or does not affect, lifespan. Here we analyze lifespan and the effect of food restriction via deprived peptone levels on lifespan in wild isolates and introgression lines (ILs) of the nematode Caenorhabditis elegans. These analyses identify genetic variation in lifespan, in the effect of this variation in diet on lifespan and also in the likelihood of maternal, matricidal, hatching. Importantly, in the wild isolates and the ILs, we identify genotypes in which peptone deprivation mediated dietary restriction reduces lifespan. We also identify, in recombinant inbred lines, a locus that affects maternal hatching, a phenotype closely linked to dietary restriction in C. elegans. These results indicate that peptone deprivation mediated dietary restriction affects lifespan in C. elegans in a genotype-dependent manner, reducing lifespan in some genotypes. This may operate by a mechanism similar to dietary restriction.

25 Local populations of the bacterivorous nematode Caenorhabditis elegans can be genetically 26 almost as diverse as global populations. To investigate the effect of local genetic variation on 27 heritable traits, we developed a new recombinant inbred line (RIL) population derived from 28 four wild isolates. The wild isolates were collected from two closely located sites in France: 29 Orsay and Santeuil. By crossing these four genetically diverse parental isolates a population 30 of 200 RILs was constructed. RNA-seq was used to obtain sequence polymorphisms 31 identifying almost 9000 SNPs variable between the four genotypes with an average spacing 32 of 11 kb, possibly doubling the mapping resolution relative to currently available RIL panels. 33The SNPs were used to construct a genetic map to facilitate QTL analysis. Life history traits, 34 such as lifespan, stress resistance, developmental speed and population growth were 35 measured in different environments. For most traits substantial variation was found, and 36 multiple QTLs could be detected, including novel QTLs not found in previous QTL analysis, 37 for example for lifespan or pathogen responses. This shows that recombining genetic 38 variation across C. elegans populations that are in geographical close proximity provides 39 ample variation for QTL mapping. Taken together, we show that RNA-seq can be used for 40 genotyping, that using more parents than the classical two parental genotypes to construct a 41 RIL population facilitates the detection of QTLs and that the use of wild isolates permits 42 analysis of local adaptation and life history trade-offs.43 44Determining how genotype-phenotype relationships are controlled is at the heart of genetics. 45Understanding how the relationships between traits, genotypes and environments are controlled is 46 also crucial for traits relevant to the evolved context of the species [1, 2]. The identification and 47 characterization of allelic variants associated with complex traits has been a major challenge in 48 plant and animal breeding as well as disease genetics. Many complex traits vary in a continuous 49 way across different genotypes of a species. It is this phenotypic variation that can be mapped to 50 the genome using quantitative trait locus (QTL) analysis. Standard QTL mapping for many 51 different species is based on recombinant inbred lines (RILs) derived from a cross between two 52 genetically and phenotypically divergent parents. One of the many species that has extensively 53 been used for exploring the genetics of complex traits is the bacterivorous nematode 54 Caenorhabditis elegans [3, 4]. 55Genetic diversity between C. elegans populations on a local scale can be almost as diverse 56 as on a global scale, with genetically distinct populations occurring within a few kilometers 57 distance [5-9] and it is likely that both local adaptation and local competition between genotypes 58 are critical for the species [1, 2, 10]. Most inbred mapping populations of C. elegans were derived 59 from two glo...

Accumulation of protein aggregates is a major cause of Parkinson's disease (PD), a progressive neurodegenerative condition that is one of the most common causes of dementia. Transgenic Caenorhabditis elegans worms expressing the human synaptic protein α-synuclein show inclusions of aggregated protein and replicate the defining pathological hallmarks of PD. It is however not known how PD progression and pathology differs among individual genetic backgrounds. Here, we compared gene expression patterns, and investigated the phenotypic consequences of transgenic α-synuclein expression in five different C. elegans genetic backgrounds. Transcriptome analysis indicates that the effects of α-synuclein expression on pathways associated with nutrient storage, lipid transportation and ion exchange depend on the genetic background. The gene expression changes we observe suggest that a range of phenotypes will be affected by α-synuclein expression. We experimentally confirm this, showing that the transgenic lines generally show delayed development, reduced lifespan, and an increased rate of matricidal hatching. These phenotypic effects coincide with the core changes in gene expression, linking developmental arrest, mobility, metabolic and cellular repair mechanisms to α-synuclein expression.Together, our results show both genotype-specific effects and core alterations in global gene expression and in phenotype in response to α-synuclein. We conclude that the PD effects are substantially modified by the genetic background, illustrating that genetic background mechanisms should be elucidated to understand individual variation in PD.