Whole genome sequencing of nearly isogenic WMI and WLI inbred rats identifies genes potentially involved in depression and stress reactivity

Abstract

The WMI and WLI inbred rats were generated from the stress-prone, and not yet fully inbred, Wistar Kyoto (WKY) strain. These were selected using bi-directional selection for immobility in the forced swim test and were then sib-mated for over 38 generations. Despite the low level of genetic diversity among WKY progenitors, the WMI substrain is significantly more vulnerable to stress relative to the counter-selected WLI strain. Here we quantify numbers and classes of genomic sequence variants distinguishing these substrains with the long term goal of uncovering functional and behavioral polymorphism that modulate sensitivity to stress and depression-like phenotypes. DNA from WLI and WMI was sequenced using Illumina xTen, IonTorrent, and 10X Chromium linked-read platforms to obtain a combined coverage of ~ 100X for each strain. We identified 4,296 high quality homozygous SNPs and indels between the WMI and WLI. We detected high impact variants in genes previously implicated in depression (e.g. Gnat2), depression-like behavior (e.g. Prlr, Nlrp1a), other psychiatric disease (e.g. Pou6f2, Kdm5a, Reep3, Wdfy3), and responses to psychological stressors (e.g. Pigr). High coverage sequencing data confirm that the two substrains are nearly coisogenic. Nonetheless, the small number of sequence variants contributes to numerous well characterized differences including depression-like behavior, stress reactivity, and addiction related phenotypes. These selected substrains are an ideal resource for forward and reverse genetic studies using a reduced complexity cross.

The Wistar Kyoto Rat: A Model of Depression Traits

“…Additional work is needed to evaluate the potential utility of WMIs as models of comorbid alcohol use disorder and depression. This high phenotypic variability between and within (sex differences) the isogenic, WMI/WLI substrains [ 188 ] underscores their broad utility within and beyond the fields of nociception and addiction.…”

“…These included three WKY substrains: WKY/NHsd, WKY/ NCrl, and WKY/Gla (from Glasco). In addition, de Jong et al [ 188 ] sequenced the WLI and WMI strains. While the results described in the original publications were analyzed using an older version of the rat reference genome, we obtained the original sequencing data and reanalyzed them against the latest mRatBN7.2 [ 192 ] reference.…”

MicroRNAs as novel peripheral markers for suicidality in patients with major depressive disorder

“…Concerning potential targets of miRNA-30a, miR-30e, and miR-200a, in silico analysis identified 20 mRNAs that were predicted to be regulated by all three miRNAs via their respective 3' UTRs. To our knowledge, out of these predicted targets, only three [i.e., muscleblind like splicing regulator 1 (MBNL1), receptor accessory protein 3 (REEP3), retinoic acid receptor beta (RARB)] have previously been reported in the context of depression or depression-like phenotypes in the literature and none were described to be associated with suicidality (65)(66)(67)(68). In this regard, only RARB has been reported in the context of MDD in humans (68) and rodents (66), while MBNL1 and REEP3 were reported only in rodent models (65,67).…”

“…To our knowledge, out of these predicted targets, only three [i.e., muscleblind like splicing regulator 1 (MBNL1), receptor accessory protein 3 (REEP3), retinoic acid receptor beta (RARB)] have previously been reported in the context of depression or depression-like phenotypes in the literature and none were described to be associated with suicidality ( 65 – 68 ). In this regard, only RARB has been reported in the context of MDD in humans ( 68 ) and rodents ( 66 ), while MBNL1 and REEP3 were reported only in rodent models ( 65 , 67 ). The respective studies utilized screening approaches and we are unaware of studies that have investigated the function of the respective genes in the context of depression and/or suicidality.…”

The prolactin receptor (PRLR) gene is linked to and associated with the comorbidity of depression and type 2 diabetes in Italian families

“…Under stress, the pituitary gland releases prolactin (PRL), whose effects are pleiotropic and include mood control and insulin secretion from the beta cells. 1 Variations in the prolactin receptor ( PRLR ) gene are associated in rodent models with stress level, depression-like behavior, 2 and hepatic insulin sensitivity 3 and in humans with maternal glucose homeostasis and gestational diabetes. 4 Furthermore, prolonged breastfeeding has been associated with reduced incidence of T2D, potentially related to PRL action.…”