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Koury, E. J.

Publications and source records attributed to Koury, E. J..

2 recordsLinked to original sources

Caenorhabditis briggsae ancestral genomic hyper-diversity contrasts with globally distributed genome-wide haplotypes

Comparative genomics provides a powerful framework to uncover the molecular and evolutionary mechanisms that shape genetic diversity within and across species, revealing how shared and lineage-specific processes influence their evolutionary trajectories through time. The nematode Caenorhabditis briggsae is distributed world-wide and is a comparative model to Caenorhabditis elegans in the biology of development, cellular mechanisms, neurobiology, genetic mappings of complex traits, and genome evolution. Following massive collection efforts by the nematode research community, we present the isolation of over 2,000 wild strains and analyses of genome sequences that catalog over six million single-nucleotide and insertion-deletion variants. This genome and strain resource provide a powerful means to interrogate the causal genetic bases of phenotypic variation for diverse traits. Additionally, we describe its global population structure and discover new and genetically distinct groups within this primarily self-fertilizing species, including groups of highly related strains that were sampled across different continents. We leverage expansive genetic variation to decipher the effects of linkage and selection on the distribution of genetic diversity across the genome and across geographic regions. Within the species, we find genomic regions with extremely high levels of genetic variation similar to hyper-divergent regions found in C. elegans and other species. These regions harbor new genes and variation enriched for environmental sensing and pathogen responses. In comparison to the outbreeding sister species Caenorhabditis nigoni, we conclude that long-term balancing selection has maintained substantial functional variation since the divergence from their outbreeding ancestor, likely in response to differences in the ecological niche. Overall, this massive strain resource enables future comparative genetics and genomics studies, including genome-wide association studies between Caenorhabditis species.

genomics↗

Natural variation in protein kinase D modifies alcohol sensitivity in Caenorhabditis elegans

Differences in naive alcohol sensitivity among individuals are a strong predictor of later-life alcohol use disorders (AUD). However, the genetic bases of alcohol sensitivity (beyond ethanol metabolism) and pharmacological approaches to modulate alcohol sensitivity remain poorly understood. We used a high-throughput behavioral screen to measure acute behavioral sensitivity to alcohol, a model of intoxication, in a genetically diverse set of over 150 wild strains of the nematode Caenorhabditis elegans. We performed a genome-wide association study and identified five quantitative trait loci (QTL) that underlie natural variation in alcohol sensitivity. We validated that a variant in the conserved ubiquitin-like domain of a C. elegans ortholog of protein kinase D, dkf-2, likely underlies the chromosome V QTL. Furthermore, lower alcohol sensitivity, i.e. resistance to intoxication, was conferred by dkf-2 loss-of-function mutations. Protein kinase D might represent a conserved, druggable target to modify alcohol sensitivity with application towards AUD. Article summaryWe investigated the genetic basis of differences in alcohol sensitivity, a key predictor of alcohol use disorder. We measured alcohol-induced behavioral changes in over 150 genetically diverse nematode strains. Using a genome-wide association study, which links genetic differences to traits, we identified five genomic regions associated with alcohol sensitivity. We then showed that variation in a gene encoding protein kinase D influences resistance to intoxication. These findings identify a conserved molecular pathway that affects alcohol sensitivity and highlight a potential target for intervention. They show how natural genetic variation can reveal mechanisms underlying complex, human-relevant traits.

genetics↗