Biology subjects

Gonzales, N. M.

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

5 recordsLinked to original sources

bioRxiv2026

Genetic Determinants of Cell-Type-Specific Responses to Cardiotoxic Chemotherapeutic Agents

Doxorubicin (DOX) and 5-fluorouracil (5-FU) are effective for treating a variety of cancers, yet many patients taking these drugs experience adverse cardiovascular events that are severe enough to pause treatment, often prolonging the course of chemotherapy and reducing its efficacy. Individual risk for drug-induced cardiotoxicity is likely mediated, at least in part, by genetic variants that control how the heart and vasculature respond to drug-induced perturbations. To identify loci associated with drug-induced cardiotoxicity, we developed an in vitro model that allows us to characterize the effects of chemotherapeutic drugs on a wide range of cardiac cell types, including cardiomyocytes, endothelial cells, and fibroblasts. Using single-cell RNA-seq, we profiled responses to DOX and 5-FU across 46 individuals and 14 cell types, identifying hundreds of expression quantitative trait loci that modify cardiovascular transcription in response to each drug (response eQTLs). Drug-responsive eQTL genes include genes that were previously linked to drug-induced cardiotoxicity and cardiovascular disease, such as ABCB4, HAS3, TNFRSF1A, and OGFR. Over a third of drug-responsive genes are shared between the DOX and 5-FU treatments, suggesting that genes predictive of DOX-induced cardiotoxicity may extend to 5-FU. Among the credible colocalizations we identified between GWAS signals and drug-response eQTLs, we discovered a locus associated with ischemic heart disease that is also a DOX-responsive eQTL for IL6R. IL6R was previously nominated as a druggable target for heart disease, and its binding partner IL6 is a candidate biomarker for anthracycline-induced cardiotoxicity. These findings advance the discovery of genetic variants underlying cardiotoxicity and support development of genotype-based predictors for treating cancer.

genomics↗

bioRxiv2019

The Effects of Mutations are Modified by Genetic Background in Mice

BackgroundThe majority of quantitative genetic models used to map complex traits assume that alleles have similar effects across all individuals. Significant evidence suggests, however, that epistatic interactions modulate the impact of many alleles. Nevertheless, identifying epistatic interactions remains computationally and statistically challenging. In this work, we address some of these challenges by developing a statistical test for polygenic epistasis that determines whether the effect of an allele is altered by the global genetic ancestry proportion from distinct progenitors. ResultsWe applied our method to data from mice and yeast. For the mice, we observed 49 significant genotype-by-ancestry interaction associations across 14 phenotypes as well as over 1,400 Bonferroni-corrected genotype-by-ancestry interaction associations for mouse gene expression data. For the yeast, we observed 92 significant genotype-by-ancestry interactions across 38 phenotypes. Given this evidence of epistasis, we test for and observe evidence of rapid selection pressure on ancestry specific polymorphisms within one of the cohorts, consistent with epistatic selection. ConclusionsUnlike our prior work in human populations, we observe widespread evidence of ancestry-modified SNP effects, perhaps reflecting the greater divergence present in crosses using mice and yeast. Author SummaryMany statistical tests which link genetic markers in the genome to differences in traits rely on the assumption that the same polymorphism will have identical effects in different individuals. However, there is substantial evidence indicating that this is not the case. Epistasis is the phenomenon in which multiple polymorphisms interact with one another to amplify or negate each others effects on a trait. We hypothesized that individual SNP effects could be changed in a polygenic manner, such that the proportion of as genetic ancestry, rather than specific markers, might be used to capture epistatic interactions. Motivated by this possibility, we develop a new statistical test that allowed us to examine the genome to identify polymorphisms which have different effects depending on the ancestral makeup of each individual. We use our test in two different populations of inbred mice and a yeast panel and demonstrate that these sorts of variable effect polymorphisms exist in 14 different physical traits in mice and 38 phenotypes in yeast as well as in murine gene expression. We use the term "polygenic epistasis" to distinguish these interactions from the more conventional two- or multi-locus interactions.

genomics↗

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↗