Whole genome sequencing of nearly isogenic WMI and WLI inbred rats identifies genes potentially involved in depression and stress reactivity.
Animals
Depression
/ genetics
Disease Models, Animal
Female
Gene Regulatory Networks
Genetic Variation
High-Throughput Nucleotide Sequencing
INDEL Mutation
Male
Phenotype
Polymorphism, Single Nucleotide
Rats
Rats, Inbred Strains
Rats, Inbred WKY
Stress, Psychological
/ genetics
Whole Genome Sequencing
/ methods
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
20 07 2021
20 07 2021
Historique:
received:
22
02
2021
accepted:
17
06
2021
entrez:
21
7
2021
pubmed:
22
7
2021
medline:
16
11
2021
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 34285244
doi: 10.1038/s41598-021-92993-4
pii: 10.1038/s41598-021-92993-4
pmc: PMC8292482
doi:
Types de publication
Comparative Study
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
14774Subventions
Organisme : NIDA NIH HHS
ID : R01 DA048017
Pays : United States
Informations de copyright
© 2021. The Author(s).
Références
WHO. Disease Burden and Mortality Estimates (WHO, Geneva, 2018).
Sullivan, P. F., Neale, M. C. & Kendler, K. S. Genetic epidemiology of major depression: Review and meta-analysis. Am. J. Psychiatry 157, 1552–1562 (2000).
pubmed: 11007705
doi: 10.1176/appi.ajp.157.10.1552
Fernandez-Pujals, A. M. et al. Epidemiology and heritability of major depressive disorder, stratified by age of onset, sex, and illness course in generation Scotland: Scottish Family Health Study (GS:SFHS). PLoS ONE 10, e0142197 (2015).
pubmed: 26571028
pmcid: 4646689
doi: 10.1371/journal.pone.0142197
Wang, K., Gaitsch, H., Poon, H., Cox, N. J. & Rzhetsky, A. Classification of common human diseases derived from shared genetic and environmental determinants. Nat. Genet. 49, 1319–1325 (2017).
pubmed: 28783162
pmcid: 5577363
doi: 10.1038/ng.3931
Flint, J. & Kendler, K. S. The genetics of major depression. Neuron 81, 484–503 (2014).
pubmed: 24507187
pmcid: 3919201
doi: 10.1016/j.neuron.2014.01.027
CONVERGE Consortium. Sparse whole-genome sequencing identifies two loci for major depressive disorder. Nature 523, 588–591 (2015).
pmcid: 4522619
doi: 10.1038/nature14659
Hyde, C. L. et al. Identification of 15 genetic loci associated with risk of major depression in individuals of European descent. Nat. Genet. 48, 1031–1036 (2016).
pubmed: 27479909
pmcid: 5706769
doi: 10.1038/ng.3623
Wray, N. R. et al. Genome-wide association analyses identify 44 risk variants and refine the genetic architecture of major depression. Nat. Genet. 50, 668–681 (2018).
pubmed: 29700475
pmcid: 5934326
doi: 10.1038/s41588-018-0090-3
Howard, D. M. et al. Genome-wide meta-analysis of depression identifies 102 independent variants and highlights the importance of the prefrontal brain regions. Nat. Neurosci. 22, 343–352 (2019).
pubmed: 30718901
pmcid: 6522363
doi: 10.1038/s41593-018-0326-7
Bryant, C. D. et al. Facilitating complex trait analysis via reduced complexity crosses. Trends Genet. 36, 549–562 (2020).
pubmed: 32482413
doi: 10.1016/j.tig.2020.05.003
pmcid: 7365571
Kumar, V. et al. C57BL/6N mutation in cytoplasmic FMRP interacting protein 2 regulates cocaine response. Science 342, 1508–1512 (2013).
pubmed: 24357318
pmcid: 4500108
doi: 10.1126/science.1245503
Mulligan, M. K. et al. Identification of a functional non-coding variant in the GABA A receptor α2 Subunit of the C57BL/6J mouse reference genome: Major implications for neuroscience research. Front. Genet. 10, 188 (2019).
pubmed: 30984232
pmcid: 6449455
doi: 10.3389/fgene.2019.00188
Louis, W. J. & Howes, L. G. Genealogy of the spontaneously hypertensive rat and Wistar-Kyoto rat strains: Implications for studies of inherited hypertension. J. Cardiovasc. Pharmacol. 16(Suppl 7), S1-5 (1990).
pubmed: 1708002
doi: 10.1097/00005344-199006167-00002
Kurtz, T. W., Montano, M., Chan, L. & Kabra, P. Molecular evidence of genetic heterogeneity in Wistar-Kyoto rats: Implications for research with the spontaneously hypertensive rat. Hypertension 13, 188–192 (1989).
pubmed: 2914738
doi: 10.1161/01.HYP.13.2.188
Paré, W. P. & Redei, E. Sex differences and stress response of WKY rats. Physiol. Behav. 54, 1179–1185 (1993).
pubmed: 8295961
doi: 10.1016/0031-9384(93)90345-G
Solberg, L. C. et al. Sex- and lineage-specific inheritance of depression-like behavior in the rat. Mamm. Genome 15, 648–662 (2004).
pubmed: 15457344
pmcid: 3764448
doi: 10.1007/s00335-004-2326-z
Malkesman, O. et al. Two different putative genetic animal models of childhood depression. Biol. Psychiatry 59, 17–23 (2006).
pubmed: 16095569
doi: 10.1016/j.biopsych.2005.05.039
Tizabi, Y. et al. Effects of nicotine on depressive-like behavior and hippocampal volume of female WKY rats. Prog. Neuropsychopharmacol. Biol. Psychiatry 34, 62–69 (2010).
pubmed: 19800382
doi: 10.1016/j.pnpbp.2009.09.024
De La Garza, R. & Mahoney, J. J. A distinct neurochemical profile in WKY rats at baseline and in response to acute stress: Implications for animal models of anxiety and depression. Brain Res. 1021, 209–218 (2004).
doi: 10.1016/j.brainres.2004.06.052
Vinod, K. Y. et al. Dysfunction in fatty acid amide hydrolase is associated with depressive-like behavior in Wistar Kyoto rats. PLoS ONE 7, e36743 (2012).
pubmed: 22606285
pmcid: 3351478
doi: 10.1371/journal.pone.0036743
Dugovic, C., Solberg, L. C., Redei, E., Van Reeth, O. & Turek, F. W. Sleep in the Wistar-Kyoto rat, a putative genetic animal model for depression. NeuroReport 11, 627–631 (2000).
pubmed: 10718326
doi: 10.1097/00001756-200002280-00038
Baum, A. E. et al. Test- and behavior-specific genetic factors affect WKY hypoactivity in tests of emotionality. Behav. Brain Res. 169, 220–230 (2006).
pubmed: 16490266
pmcid: 3762875
doi: 10.1016/j.bbr.2006.01.007
Solberg, L. C., Olson, S. L., Turek, F. W. & Redei, E. Altered hormone levels and circadian rhythm of activity in the WKY rat, a putative animal model of depression. Am. J. Physiol. Regul. Integr. Comp. Physiol. 281, R786–R794 (2001).
pubmed: 11506993
doi: 10.1152/ajpregu.2001.281.3.R786
Schaffer, D. J., Tunc-Ozcan, E., Shukla, P. K., Volenec, A. & Redei, E. E. Nuclear orphan receptor Nor-1 contributes to depressive behavior in the Wistar-Kyoto rat model of depression. Brain Res. 1362, 32–39 (2010).
pubmed: 20851110
doi: 10.1016/j.brainres.2010.09.041
Hurley, L. L. et al. Antidepressant-like effects of curcumin in WKY rat model of depression is associated with an increase in hippocampal BDNF. Behav. Brain Res. 239, 27–30 (2013).
pubmed: 23142609
doi: 10.1016/j.bbr.2012.10.049
Shoval, G. et al. Prohedonic effect of cannabidiol in a rat model of depression. Neuropsychobiology 73, 123–129 (2016).
pubmed: 27010632
doi: 10.1159/000443890
Kurtz, T. W. & Morris, R. C. Jr. Biological variability in Wistar-Kyoto rats. Implications for research with the spontaneously hypertensive rat. Hypertension 10, 127–131 (1987).
pubmed: 3596765
doi: 10.1161/01.HYP.10.1.127
Paré, W. P. & Kluczynski, J. Differences in the stress response of Wistar-Kyoto (WKY) rats from different vendors. Physiol. Behav. 62, 643–648 (1997).
pubmed: 9272677
doi: 10.1016/S0031-9384(97)00191-1
Will, C. C., Aird, F. & Redei, E. E. Selectively bred Wistar-Kyoto rats: An animal model of depression and hyper-responsiveness to antidepressants. Mol. Psychiatry 8, 925–932 (2003).
pubmed: 14593430
doi: 10.1038/sj.mp.4001345
Andrus, B. M. et al. Gene expression patterns in the hippocampus and amygdala of endogenous depression and chronic stress models. Mol. Psychiatry 17, 49–61 (2012).
pubmed: 21079605
doi: 10.1038/mp.2010.119
Mehta, N. S., Wang, L. & Redei, E. E. Sex differences in depressive, anxious behaviors and hippocampal transcript levels in a genetic rat model. Genes Brain Behav. 12, 695–704 (2013).
pubmed: 23876038
Luo, W. et al. Hypothalamic gene expression and postpartum behavior in a genetic rat model of depression. Front. Behav. Neurosci. 14, 190 (2020).
doi: 10.3389/fnbeh.2020.589967
Mehta-Raghavan, N. S., Wert, S. L., Morley, C., Graf, E. N. & Redei, E. E. Nature and nurture: Environmental influences on a genetic rat model of depression. Transl. Psychiatry 6, e770 (2016).
pubmed: 27023176
pmcid: 4872452
doi: 10.1038/tp.2016.28
Williams, K. A., Mehta, N. S., Redei, E. E., Wang, L. & Procissi, D. Aberrant resting-state functional connectivity in a genetic rat model of depression. Psychiatry Res. 222, 111–113 (2014).
pubmed: 24613017
doi: 10.1016/j.pscychresns.2014.02.001
Mulders, P. C., van Eijndhoven, P. F., Schene, A. H., Beckmann, C. F. & Tendolkar, I. Resting-state functional connectivity in major depressive disorder: A review. Neurosci. Biobehav. Rev. 56, 330–344 (2015).
pubmed: 26234819
doi: 10.1016/j.neubiorev.2015.07.014
Lim, P. H. et al. Genetic model to study the co-morbid phenotypes of increased alcohol intake and prior stress-induced enhanced fear memory. Front. Genet. 9, 566 (2018).
pubmed: 30538720
pmcid: 6277590
doi: 10.3389/fgene.2018.00566
Lim, P. H. et al. Premature hippocampus-dependent memory decline in middle-aged females of a genetic rat model of depression. Behav. Brain Res. https://doi.org/10.1016/j.bbr.2018.02.030 (2018).
doi: 10.1016/j.bbr.2018.02.030
pubmed: 30550951
pmcid: 6324994
Pajer, K. et al. Discovery of blood transcriptomic markers for depression in animal models and pilot validation in subjects with early-onset major depression. Transl. Psychiatry 2, e101 (2012).
pubmed: 22832901
pmcid: 3337072
doi: 10.1038/tp.2012.26
Redei, E. E. et al. Blood transcriptomic biomarkers in adult primary care patients with major depressive disorder undergoing cognitive behavioral therapy. Transl. Psychiatry 4, e442 (2014).
pubmed: 25226551
pmcid: 4198533
doi: 10.1038/tp.2014.66
Yu, J. S., Xue, A. Y., Redei, E. E. & Bagheri, N. A support vector machine model provides an accurate transcript-level-based diagnostic for major depressive disorder. Transl. Psychiatry 6, e931 (2016).
pubmed: 27779627
pmcid: 5290347
doi: 10.1038/tp.2016.198
Redei, E. E. et al. Pilot validation of blood-based biomarkers during pregnancy and postpartum in women with prior or current depression. Transl. Psychiatry 11, 1–9 (2020).
Li, H. & Durbin, R. Fast and accurate long-read alignment with Burrows-Wheeler transform. Bioinformatics 26, 589–595 (2010).
pubmed: 20080505
pmcid: 2828108
doi: 10.1093/bioinformatics/btp698
Poplin, R. et al. A universal SNP and small-indel variant caller using deep neural networks. Nat. Biotechnol. https://doi.org/10.1038/nbt.4235 (2018).
doi: 10.1038/nbt.4235
pubmed: 30247488
Yun, T. et al. Accurate, scalable cohort variant calls using DeepVariant and GLnexus. Cold Spring Harbor Lab. https://doi.org/10.1101/2020.02.10.942086 (2020).
doi: 10.1101/2020.02.10.942086
Cingolani, P. et al. A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff: SNPs in the genome of Drosophila melanogaster strain w1118; iso-2; iso-3. Fly 6, 80–92 (2012).
pubmed: 22728672
pmcid: 3679285
doi: 10.4161/fly.19695
Shi, J. et al. Genome-wide association study of recurrent early-onset major depressive disorder. Mol. Psychiatry 16, 193–201 (2011).
pubmed: 20125088
doi: 10.1038/mp.2009.124
Tian, R.-H., Bai, Y., Li, J.-Y. & Guo, K.-M. Reducing PRLR expression and JAK2 activity results in an increase in BDNF expression and inhibits the apoptosis of CA3 hippocampal neurons in a chronic mild stress model of depression. Brain Res. 1725, 146472 (2019).
pubmed: 31545956
doi: 10.1016/j.brainres.2019.146472
Song, A.-Q. et al. NLRP1 inflammasome contributes to chronic stress-induced depressive-like behaviors in mice. J. Neuroinflamm. 17, 178 (2020).
doi: 10.1186/s12974-020-01848-8
Napoli, E. et al. Beyond autophagy: A novel role for autism-linked Wdfy3 in brain mitophagy. Sci. Rep. 8, 11348 (2018).
pubmed: 30054502
pmcid: 6063930
doi: 10.1038/s41598-018-29421-7
Chen, K. et al. Drosophila histone demethylase KDM5 regulates social behavior through immune control and gut microbiota maintenance. Cell Host Microbe 25, 537-552.e8 (2019).
pubmed: 30902578
pmcid: 6749836
doi: 10.1016/j.chom.2019.02.003
Castermans, D. et al. Identification and characterization of the TRIP8 and REEP3 genes on chromosome 10q21.3 as novel candidate genes for autism. Eur. J. Hum. Genet. 15, 422–431 (2007).
pubmed: 17290275
doi: 10.1038/sj.ejhg.5201785
Campos-Rodríguez, R. et al. Stress modulates intestinal secretory immunoglobulin A. Front. Integr. Neurosci. 7, 86 (2013).
pubmed: 24348350
pmcid: 3845795
doi: 10.3389/fnint.2013.00086
Zallocco, L. et al. Salivary proteome changes in response to acute psychological stress due to an oral exam simulation in university students: Effect of an olfactory stimulus. Int. J. Mol. Sci. 22, 4925 (2021).
doi: 10.3390/ijms22094295
Levchenko, A. et al. NRG1, PIP4K2A, and HTR2C as potential candidate biomarker genes for several clinical subphenotypes of depression and bipolar disorder. Front. Genet. 11, 936 (2020).
pubmed: 33193575
pmcid: 7478333
doi: 10.3389/fgene.2020.00936
Hill, S. Y., Jones, B. L. & Haas, G. L. Suicidal ideation and aggression in childhood, genetic variation and young adult depression. J. Affect. Disord. 276, 954–962 (2020).
pubmed: 32745832
doi: 10.1016/j.jad.2020.07.049
pmcid: 7484359
Zhang, J.-P. et al. Pharmacogenetic associations of antipsychotic drug-related weight gain: A systematic review and meta-analysis. Schizophr. Bull. 42, 1418–1437 (2016).
pubmed: 27217270
pmcid: 5049532
doi: 10.1093/schbul/sbw058
Li, J., Hashimoto, H. & Meltzer, H. Y. Association of Serotonin2c receptor polymorphisms with antipsychotic drug response in schizophrenia. Front. Psychiatry 10, 58 (2019).
pubmed: 30828307
pmcid: 6384235
doi: 10.3389/fpsyt.2019.00058
Way, B. M., Brown, K. W., Quaglia, J., McCain, N. & Taylor, S. E. Nonsynonymous HTR2C polymorphism predicts cortisol response to psychosocial stress II: Evidence from two samples. Psychoneuroendocrinology 70, 142–151 (2016).
pubmed: 27211696
doi: 10.1016/j.psyneuen.2016.04.022
Avery, B. M. & Vrshek-Schallhorn, S. Nonsynonymous HTR2C polymorphism predicts cortisol response to psychosocial stress I: Effects in males and females. Psychoneuroendocrinology 70, 134–141 (2016).
pubmed: 26787298
doi: 10.1016/j.psyneuen.2015.12.023
Bhat, S. S. et al. Disruption of the IL1RAPL1 gene associated with a pericentromeric inversion of the X chromosome in a patient with mental retardation and autism. Clin. Genet. 73, 94–96 (2008).
pubmed: 18005360
doi: 10.1111/j.1399-0004.2007.00920.x
Montani, C. et al. The X-linked intellectual disability protein IL1RAPL1 regulates dendrite complexity. J. Neurosci. 37, 6606–6627 (2017).
pubmed: 28576939
pmcid: 6596553
doi: 10.1523/JNEUROSCI.3775-16.2017
Lam, M. et al. Comparative genetic architectures of schizophrenia in East Asian and European populations. Nat. Genet. 51, 1670–1678 (2019).
pubmed: 31740837
pmcid: 6885121
doi: 10.1038/s41588-019-0512-x
Pizzo, R., Lamarca, A., Sassoè-Pognetto, M. & Giustetto, M. Structural bases of atypical whisker responses in a mouse model of CDKL5 deficiency disorder. Neuroscience 445, 130–143 (2020).
pubmed: 31472213
doi: 10.1016/j.neuroscience.2019.08.033
Weaving, L. S. et al. Mutations of CDKL5 cause a severe neurodevelopmental disorder with infantile spasms and mental retardation. Am. J. Hum. Genet. 75, 1079–1093 (2004).
pubmed: 15492925
pmcid: 1182143
doi: 10.1086/426462
Raghavan, N. S. et al. Prepubertal ovariectomy exaggerates adult affective behaviors and alters the hippocampal transcriptome in a genetic rat model of depression. Front. Endocrinol. 8, 373 (2017).
doi: 10.3389/fendo.2017.00373
Raudvere, U. et al. g:Profiler: A web server for functional enrichment analysis and conversions of gene lists (2019 update). Nucleic Acids Res. 47, W191–W198 (2019).
pubmed: 31066453
pmcid: 6602461
doi: 10.1093/nar/gkz369
Gunturkun, M. H. et al. GeneCup: mine PubMed for gene relationships using custom ontology and deep learning. Cold Spring Harbor Lab. https://doi.org/10.1101/2020.09.17.297358 (2021).
doi: 10.1101/2020.09.17.297358
Molendijk, M. L. & de Kloet, E. R. Coping with the forced swim stressor: Current state-of-the-art. Behav. Brain Res. 364, 1–10 (2019).
pubmed: 30738104
doi: 10.1016/j.bbr.2019.02.005
Redei, E. E. et al. Pilot validation of blood-based biomarkers during pregnancy and postpartum in women with prior or current depression. Transl. Psychiatry 11, 68 (2021).
pubmed: 33479202
pmcid: 7820442
doi: 10.1038/s41398-020-01188-4
Kim, P. et al. Rat reduced complexity model of oxycodone self-administration and stress responsiveness. Virtual NIDA Genetics and Epigenetics Consortium Meeting (2021).
Supernat, A., Vidarsson, O. V., Steen, V. M. & Stokowy, T. Comparison of three variant callers for human whole genome sequencing. Sci. Rep. 8, 17851 (2018).
pubmed: 30552369
pmcid: 6294778
doi: 10.1038/s41598-018-36177-7
Brouard, J.-S., Schenkel, F., Marete, A. & Bissonnette, N. The GATK joint genotyping workflow is appropriate for calling variants in RNA-seq experiments. J. Anim. Sci. Biotechnol. 10, 44 (2019).
pubmed: 31249686
pmcid: 6587293
doi: 10.1186/s40104-019-0359-0
Ramdas, S. et al. Extended regions of suspected mis-assembly in the rat reference genome. Sci. Data 6, 39 (2019).
pubmed: 31015470
pmcid: 6478900
doi: 10.1038/s41597-019-0041-6
Nishimura, T. et al. Role of the PAR-3-KIF3 complex in the establishment of neuronal polarity. Nat. Cell Biol. 6, 328–334 (2004).
pubmed: 15048131
doi: 10.1038/ncb1118
Nguyen-Dumont, T., Pope, B. J., Hammet, F., Southey, M. C. & Park, D. J. A high-plex PCR approach for massively parallel sequencing. Biotechniques 55, 69–74 (2013).
pubmed: 23931594
doi: 10.2144/000114052
Krzywinski, M. et al. Circos: An information aesthetic for comparative genomics. Genome Res. 19, 1639–1645 (2009).
pubmed: 19541911
pmcid: 2752132
doi: 10.1101/gr.092759.109