A revamped rat reference genome improves the discovery of genetic diversity in laboratory rats

de Jong, Tristan V.; Pan, Yanchao; Rastas, Pasi; Munro, Daniel; Tutaj, Monika; Akil, Huda; Benner, Chris; Chen, Denghui; Chitre, Apurva S.; Chow, William; Colonna, Vincenza; Dalgard, Clifton L.; Demos, Wendy M.; Doris, Peter A.; Garrison, Erik; Geurts, Aron M.; Gunturkun, Hakan M.; Guryev, Victor; Hourlier, Thibaut; Howe, Kerstin; Huang, Jun; Kalbfleisch, Ted; Kim, Panjun; Li, Ling; Mahaffey, Spencer; Martin, Fergal J.; Mohammadi, Pejman; Ozel, Ayse Bilge; Polesskaya, Oksana; Pravenec, Michal; Prins, Pjotr; Sebat, Jonathan; Smith, Jennifer R.; Solberg Woods, Leah C.; Tabakoff, Boris; Tracey, Alan; Uliano-Silva, Marcela; Villani, Flavia; Wang, Hongyang; Sharp, Burt M.; Telese, Francesca; Jiang, Zhihua; Saba, Laura; Wang, Xusheng; Murphy, Terence D.; Palmer, Abraham A.; Kwitek, Anne E.; Dwinell, Melinda R.; Williams, Robert W.; Li, Jun Z.; Chen, Hao

doi:10.1016/j.xgen.2024.100527

Cited by 6 publications

References 100 publications

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Y and mitochondrial chromosomes in the heterogeneous stock rat population

Okamoto,

Chitre,

Missfeldt Sanches

et al. 2024

G3: Genes, Genomes, Genetics

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Genome-wide association studies typically evaluate the autosomes and sometimes the X Chromosome, but seldom consider the Y or mitochondrial (MT) Chromosomes. We genotyped the Y and MT Chromosomes in heterogeneous stock (HS) rats (Rattus norvegicus), an outbred population created from 8 inbred strains. We identified 8 distinct Y and 4 distinct MT Chromosomes among the 8 founders. However, only 2 types of each nonrecombinant chromosome were observed in our modern HS rat population (generations 81–97). Despite the relatively large sample size, there were virtually no significant associations for behavioral, physiological, metabolome, or microbiome traits after correcting for multiple comparisons. However, both Y and MT Chromosomes were strongly associated with the expression of a few genes located on those chromosomes, which provided a positive control. Our results suggest that within modern HS rats there are no Y and MT Chromosomes differences that strongly influence behavioral or physiological traits. These results do not address other ancestral Y and MT Chromosomes that do not appear in modern HS rats, nor do they address effects that may exist in other rat populations, or in other species.

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Y and mitochondrial chromosomes in the heterogeneous stock rat population

Okamoto,

Chitre,

Missfeldt Sanches

et al. 2024

G3: Genes, Genomes, Genetics

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Inbred rat heredity and sex affect oral oxycodone self-administration and augmented intake in long sessions: correlations with anxiety and novelty-seeking

Sharp,

Leng,

Huang

et al. 2023

Preprint

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Most individuals affected in the national epidemic of oxycodone abuse began taking oral oxycodone by prescription. We studied vulnerability to oxycodone intake in a rat model of oral drug self-administration (SA), since pharmacokinetics affect abuse potential. Females (33 inbred strains) and males (26) obtained oxycodone at increasing concentrations in operant sessions (FR5; 1-16-h) followed by extinction and reinstatement. Active spout licks were greater in females than males during 4-h and 16-h sessions (p< 0.001 for all). Across all stages of oxycodone SA, intake/session was greater in females (p<0.001). Both sexes escalated intake during 16-h extended access vs 4-h sessions (p<2e-16). Intake and active licks varied greatly by strain. The heritability (h2) of active licks/4-h at increasing oxycodone dose was larger in males (h2females: 0.30-0.39 vs. males: 0.41-0.53). Under a progressive ratio schedule, breakpoints differed by strain (p<2e-16) and by sex in some strains (p=0.018). For cue-induced reinstatement, active licks were greater in females than males (p<0.001). Behavior in naive rats was assessed using elevated plus maze (EPM), open field (OF) and novel object interaction. (NOI) tests. We correlated these behaviors with 28 parameters of oxycodone SA. EPM-defining traits were most commonly associated with SA in both sexes, whereas more OF and NOI traits were SA-associated in males. Overall, sex and heredity are major determinants of the motivation to take and seek oxycodone, which escalates during extended access. The correlation of EPM, a measure of anxiety, with multiple SA parameters indicates the influence of pleiotropic genes.

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Unique Transcriptomic Cell Types of the Granular Retrosplenial Cortex are Preserved Across Mice and Rats Despite Dramatic Changes in Key Marker Genes

Brooks,

Jedrasiak-Cape,

Rybicki-Kler

et al. 2024

Preprint

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The granular retrosplenial cortex (RSG) supports key functions ranging from memory consolidation to spatial navigation. The mouse RSG contains several cell types that are remarkably distinct from those found in other cortical regions. This includes the physiologically and transcriptomically unique low rheobase neuron that is the dominant cell-type in RSG layers 2/3 (L2/3 LR), as well as the similarly exclusive pyramidal cells that comprise much of RSG layer 5a (L5a RSG). While the functions of the RSG are extensively studied in both mice and rats, it remains unknown if the transcriptomically unique cell types of the mouse RSG are evolutionarily conserved in rats. Here, we show that mouse and rat RSG not only contain the same cell types, but key subtypes including the L2/3 LR and L5a RSG neurons are amplified in their representations in rats compared to mice. This preservation of cell types in male and female rats happens despite dramatic changes in key cell-type-specific marker genes, with the Scnn1a expression that selectively tags mouse L5a RSG neurons completely absent in rats. Important for Cre-driver line development, we identify alternative, cross-species genes that can be used to selectively target the cell types of the RSG in both mice and rats. Our results show that the unique cell types of the RSG are evolutionarily conserved across millions of years of evolution between mice and rats, but also emphasize stark species-specific differences in marker genes that need to be considered when making cell-type-specific transgenic lines of mice versus rats.

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A revamped rat reference genome improves the discovery of genetic diversity in laboratory rats

Cited by 6 publications

References 100 publications

Y and mitochondrial chromosomes in the heterogeneous stock rat population

Y and mitochondrial chromosomes in the heterogeneous stock rat population

Inbred rat heredity and sex affect oral oxycodone self-administration and augmented intake in long sessions: correlations with anxiety and novelty-seeking

Unique Transcriptomic Cell Types of the Granular Retrosplenial Cortex are Preserved Across Mice and Rats Despite Dramatic Changes in Key Marker Genes

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