Biology subjects

Gonzales, N. M.

Publications and source records attributed to Gonzales, N. M..

3 recordsLinked to original sources

bioRxiv2018

Genetic characterization of outbred Sprague Dawley rats and utility for genome-wide association studies

Sprague Dawley (SD) rats are among the most widely used outbred laboratory rat populations. Despite this, the genetic characteristics of SD rats have not been clearly described, and SD rats are rarely used for experiments aimed at exploring genotype-phenotype relationships. In order to use SD rats to perform a genome-wide association study (GWAS), we collected behavioral data from 4,625 SD rats that were predominantly obtained from two commercial vendors, Charles River Laboratories and Harlan Sprague Dawley Inc. Using double-digest genotyping-by-sequencing (ddGBS), we obtained dense, high-quality genotypes at 291,438 SNPs across 4,061 rats. This genetic data allowed us to characterize the variation present in Charles River vs. Harlan SD rats. We found that the two populations are highly diverged (FST > 0.4). Furthermore, even for rats obtained from the same vendor, there was strong population structure across breeding facilities and even between rooms at the same facility. We performed multiple separate GWAS by fitting a linear mixed model that accounted population structure and using meta-analysis to jointly analyze all cohorts. Our study examined Pavlovian conditioned approach (PavCA) behavior, which assesses the propensity for rats to attribute incentive salience to reward-associated cues. We identified 46 significant associations for the various metrics used to define PavCA. The surprising degree of population structure among SD rats from different sources has important implications for their use in both genetic and non-genetic studies. Author SummaryOutbred Sprague Dawley rats are among the most commonly used rats for neuroscience, physiology and pharmacological research; in the year 2020, 4,188 publications contained the keyword "Sprague Dawley". Rats identified as "Sprague Dawley" are sold by several commercial vendors, including Charles River Laboratories and Harlan Sprague Dawley Inc. (now Envigo). Despite their widespread use, little is known about the genetic diversity of SD. We genotyped more than 4,000 SD rats, which we used for a genome-wide association study (GWAS) and to characterize genetic differences between SD rats from Charles River Laboratories and Harlan. Our analysis revealed extensive population structure both between and within vendors. The GWAS for Pavlovian conditioned approach (PavCA) identified a number of genome-wide significant loci for that complex behavioral trait. Our results demonstrate that, despite sharing an identical name, SD rats that are obtained from different vendors are very different. Future studies should carefully define the exact source of SD rats being used and may exploit their genetic diversity for genetic studies of complex traits.

genetics↗

bioRxiv2018

Genome-wide association study, replication, and mega-analysis using a dense marker panel in a multi-generational mouse advanced intercross line

Replication is considered to be critical for genome-wide association studies (GWAS) in humans, but is not routinely performed in model organisms. We explored replication using an advanced intercross line (AIL) which is the simplest possible multigenerational intercross. We re-genotyped a previously published cohort of LG/J x SM/J AIL mice (F34; n=428) using a denser marker set and also genotyped a novel cohort of AIL mice (F39-43; n=600) for the first time. We identified 110 significant loci in the F34 cohort, 36 of which were new discoveries attributable to the denser marker set; we also identified 27 novel significant loci in the F39-43 cohort. For traits measured in both cohorts (locomotor activity, body weight, and coat color), the genetic correlations were high, although, the F39-43 cohort showed systematically lower SNP-heritability estimates. We then attempted to replicate loci identified in either F34 or F39-43 in the other cohort. Albino coat color was robustly replicated; we observed only partial replication of associations for locomotor activity and body weight. Finally, we performed a mega-analysis of locomotor activity and body weight by combining F34 and F39-43 cohorts (n=1,028), which identified four novel loci. The incomplete replication was inconsistent with simulations we performed to estimate our power to replicate. This may reflect: 1) false positives errors in the discovery cohort, 2) environmental or genetic heterogeneity between the two samples, or 3) the systematic over estimation of the effect sizes at significant loci (\"Winners Curse\"). Our results demonstrate that it is difficult to replicate GWAS results even when using similarly sized discovery and replication cohorts drawn from the same population.

genetics↗

bioRxiv2017

Genome wide association study of behavioral, physiological and gene expression traits in a multigenerational mouse intercross

The LG/J x SM/J advanced intercross line of mice (LG x SM AIL) is a multigenerational outbred population. High minor allele frequencies, a simple genetic background, and the fully sequenced LG and SM genomes make it a powerful population for genome-wide association studies. Here we use 1,063 AIL mice to identify 126 significant associations for 50 traits relevant to human health and disease. We also identify thousands of cis- and trans-eQTLs in the hippocampus, striatum, and prefrontal cortex of [~]200 mice. We replicate an association between locomotor activity and Csmd1, which we identified in an earlier generation of this AIL, and show that Csmd1 mutant mice recapitulate the locomotor phenotype. Our results demonstrate the utility of the LG x SM AIL as a mapping population, identify numerous novel associations, and shed light on the genetic architecture of mammalian behavior.

genetics↗