A Powerful New Quantitative Genetics Platform, Combining Caenorhabditis elegans High-Throughput Fitness Assays with a Large Collection of Recombinant Strains.

The genetic variants underlying complex traits are often elusive even in powerful model organisms such as Caenorhabditis elegans with controlled genetic backgrounds and environmental conditions. Two major contributing factors are: (1) the lack of statistical power from measuring the phenotypes of small numbers of individuals, and (2) the use of phenotyping platforms that do not scale to hundreds of individuals and are prone to noisy measurements. Here, we generated a new resource of 359 recombinant inbred strains that augments the existing C. elegans N2xCB4856 recombinant inbred advanced intercross line population. This new strain collection removes variation in the neuropeptide receptor gene npr-1, known to have large physiological and behavioral effects on C. elegans and mitigates the hybrid strain incompatibility caused by zeel-1 and peel-1, allowing for identification of quantitative trait loci that otherwise would have been masked by those effects. Additionally, we optimized highly scalable and accurate high-throughput assays of fecundity and body size using the COPAS BIOSORT large particle nematode sorter. Using these assays, we identified quantitative trait loci involved in fecundity and growth under normal growth conditions and after exposure to the herbicide paraquat, including independent genetic loci that regulate different stages of larval growth. Our results offer a powerful platform for the discovery of the genetic variants that control differences in responses to drugs, other aqueous compounds, bacterial foods, and pathogenic stresses

A systematic framework for selecting gene-condition pairs for inclusion in newborn sequencing panels: Early Check implementation

Purpose Research is underway worldwide to investigate the feasibility, acceptability, and utility of sequencing-based newborn screening. Different methods have been used to select gene-condition pairs for screening, leading to highly inconsistent gene lists across studies. Methods Early Check developed and utilized actionability-based frameworks for evaluating gene-condition pairs for inclusion in newborn panels (Panel 1 - high actionability, Panel 2 - possible actionability). A previously developed framework, the Age-based Semi Quantitative Metric (ASQM), was adapted. Increasing ASQM scores, with a maximum of 15, suggest greater actionability. Wilcoxon tests were performed to compare Panel 1 gene-condition pairs on the Recommended Uniform Screening Panel (RUSP) to non-RUSP pairs. Results In our first round of assessment, Early Check identified 178 gene-condition pairs for inclusion in Panel 1 and 29 for Panel 2. Median ASQM scores of RUSP conditions on Panel 1 was 12 (range 4 to 15) and non-RUSP was 13 (range 9 to 15). Median scores for Panel 2 was 10 (range 6 to 14). Conclusion The Early Check frameworks provide a transparent, semiquantitative, and reproducible methodology for selecting gene-condition pairs for NBS sequencing pilot studies that may inform future integration of genomic sequencing into population-level NBS. Collaborative efforts among newborn sequencing studies to establish shared criteria is needed to enhance cross-study comparisons

Hierarchical genetic analysis of German cockroach (Blattella germanica) populations from within buildings to across continents.

Understanding the population structure of species that disperse primarily by human transport is essential to predicting and controlling human-mediated spread of invasive species. The German cockroach (Blattella germanica) is a widespread urban invader that can actively disperse within buildings but is spread solely by human-mediated dispersal over longer distances; however, its population structure is poorly understood. Using microsatellite markers we investigated population structure at several spatial scales, from populations within single apartment buildings to populations from several cities across the U.S. and Eurasia. Both traditional measures of genetic differentiation and Bayesian clustering methods revealed increasing levels of genetic differentiation at greater geographic scales. Our results are consistent with active dispersal of cockroaches largely limited to movement within a building. Their low levels of genetic differentiation, yet limited active spread between buildings, suggests a greater likelihood of human-mediated dispersal at more local scales (within a city) than at larger spatial scales (within and between continents). About half the populations from across the U.S. clustered together with other U.S. populations, and isolation by distance was evident across the U.S. Levels of genetic differentiation among Eurasian cities were greater than those in the U.S. and greater than those between the U.S. and Eurasia, but no clear pattern of structure at the continent level was detected. MtDNA sequence variation was low and failed to reveal any geographical structure. The weak genetic structure detected here is likely due to a combination of historical admixture among populations and periodic population bottlenecks and founder events, but more extensive studies are needed to determine whether signatures of global movement may be present in this species

A Powerful New Quantitative Genetics Platform, Combining Caenorhabditis elegans High-Throughput Fitness Assays with a Large Collection of Recombinant Strains.

The genetic variants underlying complex traits are often elusive even in powerful model organisms such as Caenorhabditis elegans with controlled genetic backgrounds and environmental conditions. Two major contributing factors are: (1) the lack of statistical power from measuring the phenotypes of small numbers of individuals, and (2) the use of phenotyping platforms that do not scale to hundreds of individuals and are prone to noisy measurements. Here, we generated a new resource of 359 recombinant inbred strains that augments the existing C. elegans N2xCB4856 recombinant inbred advanced intercross line population. This new strain collection removes variation in the neuropeptide receptor gene npr-1, known to have large physiological and behavioral effects on C. elegans and mitigates the hybrid strain incompatibility caused by zeel-1 and peel-1, allowing for identification of quantitative trait loci that otherwise would have been masked by those effects. Additionally, we optimized highly scalable and accurate high-throughput assays of fecundity and body size using the COPAS BIOSORT large particle nematode sorter. Using these assays, we identified quantitative trait loci involved in fecundity and growth under normal growth conditions and after exposure to the herbicide paraquat, including independent genetic loci that regulate different stages of larval growth. Our results offer a powerful platform for the discovery of the genetic variants that control differences in responses to drugs, other aqueous compounds, bacterial foods, and pathogenic stresses

A Powerful New Quantitative Genetics Platform, Combining Caenorhabditis elegans

The genetic variants underlying complex traits are often elusive even in powerful model organisms such as Caenorhabditis elegans with controlled genetic backgrounds and environmental conditions. Two major contributing factors are: (1) the lack of statistical power from measuring the phenotypes of small numbers of individuals, and (2) the use of phenotyping platforms that do not scale to hundreds of individuals and are prone to noisy measurements. Here, we generated a new resource of 359 recombinant inbred strains that augments the existing C. elegans N2xCB4856 recombinant inbred advanced intercross line population. This new strain collection removes variation in the neuropeptide receptor gene npr-1, known to have large physiological and behavioral effects on C. elegans and mitigates the hybrid strain incompatibility caused by zeel-1 and peel-1, allowing for identification of quantitative trait loci that otherwise would have been masked by those effects. Additionally, we optimized highly scalable and accurate high-throughput assays of fecundity and body size using the COPAS BIOSORT large particle nematode sorter. Using these assays, we identified quantitative trait loci involved in fecundity and growth under normal growth conditions and after exposure to the herbicide paraquat, including independent genetic loci that regulate different stages of larval growth. Our results offer a powerful platform for the discovery of the genetic variants that control differences in responses to drugs, other aqueous compounds, bacterial foods, and pathogenic stresses

Chromosome-scale selective sweeps shape Caenorhabditis elegans genomic diversity.

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 of C. elegans. Little is known about the population genomic and evolutionary history of this species. We characterized C. elegans genetic variation using high-throughput selective sequencing of a worldwide collection of 200 wild strains and identified 41,188 SNPs. Notably, C. elegans genome variation is dominated by a set of commonly shared haplotypes on four of its six chromosomes, each spanning many megabases. Population genetic modeling showed that this pattern was generated by chromosome-scale selective sweeps that have reduced variation worldwide; at least one of these sweeps probably occurred in the last few hundred years. These sweeps, which we hypothesize to be a result of human activity, have drastically reshaped the global C. elegans population in the recent past

Results from the Bayesian admixture analysis showing the grouping of populations into clusters and the proportion of significantly admixed individuals (<i>P</i><0.05) in each population.

<p>Results from the Bayesian admixture analysis showing the grouping of populations into clusters and the proportion of significantly admixed individuals (<i>P</i><0.05) in each population.</p

Isolation by distance analysis for <i>B. germanica</i> populations across the U.S.

<p>Pairwise comparisons between populations are plotted as genetic distance transformed as <i>F</i>_ST/(1-<i>F</i>_ST) versus the natural log of geographic distance. The correlation coefficient (<i>r</i>) and results for the Mantel test of significance are given for (a) all U.S. populations, including comparisons between apartments within the same complex in Raleigh, North Carolina; and (b) for comparisons between populations in the continental U.S. using six populations from Raleigh, one population from each of the studied apartment complexes (LS-A, CR-A, CS-A, DR-X, DRD-X, FC-X).</p

Bayesian cluster analysis of 40 global <i>B. germanica</i> populations as identified by the program BAPS.

<p>Populations given the same color were grouped into the same genetic cluster. The analysis identified 17 distinct clusters, 11 for the 36 U.S. populations, whereas each of the six Eurasian populations formed a unique cluster. The 18 Raleigh, North Carolina samples are grouped by apartment complex. In only one case (complex DRD) was an apartment not clustered together with populations from apartments in the same apartment complex. A finer resolution map showing the location of the Raleigh, NC populations is given in Crissman et al. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0102321#pone.0102321-Crissman1" target="_blank">[33]</a>.</p