The potential of integrating human and mouse discovery platforms to advance our understanding of cardiometabolic diseases

  1. Aaron W Jurrjens
  2. Marcus M Seldin
  3. Corey Giles
  4. Peter J Meikle
  5. Brian G Drew  Is a corresponding author
  6. Anna C Calkin  Is a corresponding author
  1. Baker Heart and Diabetes Institute, Australia
  2. Central Clinical School, Monash University, Australia
  3. Department of Biological Chemistry and Center for Epigenetics and Metabolism, University of California, Irvine, United States
  4. Baker Department of Cardiometabolic Health, University of Melbourne, Australia
  5. Baker Department of Cardiovascular Research Translation and Implementation, La Trobe University, Australia
2 figures and 3 tables

Figures

Illustrative overview of Hybrid Mouse Diversity Panel (HMDP) study designs utilised for the investigation of cardiometabolic diseases and related traits.

Interventions include transgenic expression of the human apolipoprotein (APO)E*3-Leiden and the human cholesteryl ester transferase protein (CETP) transgenes with concomitant feeding of an atherosclerosis promoting western diet (Ath-HMDP; red) (Bennett et al., 2015), feeding of a high-fat, high-sucrose diet (HF/HS-HMDP; yellow) (Parks et al., 2013), induction of isoproterenol (iso)-induced HF (HF-HMDP; green) (Rau et al., 2015), and 30 days of voluntary wheel running (Ex-HMDP; blue) (Moore et al., 2019). Created with BioRender.com.

Benefits of integrating human and mouse datasets for biological discovery.

Created with BioRender.com.

Tables

Table 1
Human genetic and multi-omics resources for cardiometabolic traits.
ResourcePopulationTissue(s)*Genetic and omics data*Primary phenotypesLink
METSIM
METabolic Syndrome In Men Study
n=10,197 Finnish males, aged 45–73Subcutaneous adipose tissue
  • Medical history

  • Clinical and metabolic traits

  • Cardiovascular disease risk factors

  • Medication usage

  • Oral glucose tolerance test (Stancáková et al., 2009)

Reviewed in Laakso et al., 2017
MAGNet
Myocardial Applied Genomics Network
n=177 cases and n=136 controls for heart failure; collected during transplantCardiac tissue
  • Cardiomyopathy classification

https://www.med.upenn.edu/magnet/
STARNET
Stockholm-Tartu Atherosclerosis Reverse Networks Engineering Task study
n=600 cases and n=250 controls for CAD; individuals undergoing open-thoracic surgeryAortic root, mammary artery, liver, subcutaneous fat, visceral fat, skeletal muscle, whole blood
  • Clinical and biomedical traits

  • Medical history

  • Medication usage

  • Preoperative angiographic assessment of CAD

  • History of CAD and stroke

http://starnet.mssm.edu/
GTEx
Genotype-Tissue Expression project
n=948 donors, aged 21–70; Biospecimens collected <24 hr post-mortem54 tissue types
  • Medical history

  • Disease risk factors

  • Cause of death

https://gtexportal.org/
UKB
UK Biobank
~500,000 individuals of European descent from the UK; with longitudinal follow-up on some subsetsBlood, urine, and saliva sampleshttps://www.ukbiobank.ac.uk/
CARDIoGRAMplusC4D
Coronary ARtery DIsease Genome-wide Replication and Meta-analysis plus The Coronary Artery Disease study
n=63,746 cases and n=130,681 controls for CAD or MI--http://www.cardiogramplusc4d.org/
BHS
Busselton Health Study
>5000 individuals from Busselton, Western AustraliaPlasma
  • Clinical and biomedical traits

  • Self-reported medical history

https://bpmri.org.au/research/key-projects-studies/busselton-health-study-2.html
MVP
Million Veterans Project
n>900,000 veterans from the United States, aged 50–69Blood
  • Self-reported medical history

  • Electronic health records

https://www.mvp.va.gov
  1. *

    For brevity, a subset of relevant datatypes and key references are provided in this table. We apologise to the investigators whose work could not be cited due to space limitations. See accompanying links and references for additional information.

  2. WGS, whole genome sequencing; WES, whole exome sequencing; SNP, single nucleotide polymorphism; CAD, coronary artery disease; MI, myocardial infarction; CHIP-seq, Chromatin Immunoprecipitation Sequencing; ATAC-Seq, assay for transposase-accessible chromatin using sequencing; RNA-Seq, RNA sequencing; GWAS, genome-wide association study.

Table 2
Common mouse genetic reference panels utilised for the study of cardiometabolic diseases.
Breeding structurePanelDescriptionStrainsAdvantagesConstraints*Application of panels for cardiometabolic-related phenotypes
InbredBXD
C57BL/6J × DBA/2J
Inbred mouse panel derived from intercrosses of C57BL/6J and DBA/2J strains
(Ashbrook et al., 2021) http://www.genenetwork.org
198 strains derived from:
C57BL/6J, DBA/2J
  • Most inbred strains are readily available (i.e. JAX labs)

  • Data available for several thousand phenotypes and >100 omics datasets

  • Large quantity of strains enables enormous mapping power

  • Lower mapping precision and genetic diversity compared to multi-parent populations

  • Less genetic diversity than outbred mice due to homozygosity at each loci

CC
Collaborative Cross
Inbred mouse panel derived from intercrosses between eight progenitor strains
(Collaborative Cross Consortium, 2012)
~100 strains derived from:
A/J, C57BL/6J, 129S1/SvImJ, NOD/ShiLtJ, NZO/H1LtJ, CAST/EiJ, PWK/PhJ, WSB/EiJ
  • Captures a relatively large proportion of the genetic diversity in mice due to being a multi-parent population

  • High genetic diversity; ~45 million segregating SNPs

  • Strains fully genotyped

  • Less genetic diversity than outbred mice due to homozygosity at each locus

HMDP
Hybrid Mouse Diversity Panel
Diverse mouse panel derived from intercrosses of classical and recombinant inbred strains
(Lusis et al., 2016) http://www.genenetwork.org
>130 strains derived from:
C57BL/6J, DBA/2J, A/J, C3H/J, BALBc/J
  • Captures a relatively large proportion of the genetic diversity in mice due to multi-parent ancestry and inclusion of wild-derived strains

  • Less genetic diversity than outbred mice due to homozygosity at each loci

ILSXISSDiverse panel of recombinant inbred mice derived from ILS and ISS progenitor strains
(DeFries et al., 1989) http://www.genenetwork.org
~77 strains derived from:
ILS, ISS;
both of which are in turn derived from: A, AKR, BALB/c, C3H/2, C57BL, DBA/2, Is/Bi and RIII
  • Alternative inbred cross that provides differing foundational strains and therefore diversity.

  • Less genetic diversity than outbred mice due to homozygosity at each loci

F2 HybridHet3
Um-Het3
Heterogenous mouse population mostly used in ageing research
(Nadon et al., 2008) https://www.nia.nih.gov/research/dab/interventions-testing-program-itp
Able to generate unlimited genetically distinct mice, derived from a four-way cross between (BALB/cJ × C57BL6/J) F1 females with (C3H/HeJ × DBA/2J) F1 males
  • F2 offspring are derived from parents with known linkage phase, allowing for the study of parent-of-origin effects

  • Each mouse is genetically unique

  • High allelic variation between F2 offspring

  • The population is reproducible, allowing comparison of genetic and phenotypic data across generations, provided sample sizes are sufficiently large

  • Genotyping is required for each mouse for genetic association studies

OutbredDO
Diversity Outbred
Stocks of genetically unique outbred mice derived from eight CC progenitor strains
(Churchill et al., 2012)
Able to generate unlimited genetically distinct stocks of mice, derived from:
A/J, C57BL/6J, 129S1/SvImJ, NOD/ShiLtJ, NZO/H1LtJ, CAST/EiJ, PWK/PhJ, WSB/EiJ
  • High mapping precision due to extensive allelic diversity

  • Captures ~90% of the genetic diversity in laboratory mice

  • Requires more mice to achieve comparable statistical power to inbred designs

  • Cannot measure intra-strain response to intervention

  • Each mouse requires genotyping for GWA analysis

  1. *

    For brevity, a selection of key phenotypes and references are provided in this table. We apologise to the investigators whose work could not be cited due to space limitations.

  2. NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis; IR, insulin resistance; SNP, single nucleotide polymorphism; GWA, genome-wide association;

Table 3
Select examples of studies that have incorporated human and mouse data for biological discovery.
Cross-species integrationTrait/descriptionCross-species conserved QTL(s), Gene(s), PROTEIN(S), or networks with trait of interestExperimentally validated Gene(s)/PROTEIN(S)*Reference
Human-to-mouse integrationAtherosclerosis/CADPVRL2 (NECTIN-2/CD112)Bennett et al., 2015
Atherosclerosis/CAD12 gene networksAIP, DRAP1, POLR2I, PQBP1Talukdar et al., 2016
Atherosclerosis/CAD and plasma lipids66 genes in aorta and 27 in liver for atherosclerosis
151 genes in liver for plasma lipids
von Scheidt et al., 2017
Biomarker for atherosclerosis/CADGUCY1A3GUCY1A3Kessler et al., 2017
Glucose and lipids in atherosclerosis/CADGlucose and lipid determining gene networkLSSCohain et al., 2021
Atherosclerosis/CAD and cholesterol liver networksMAFFMAFFvon Scheidt et al., 2021
Cross-tissue endocrine factors regulating CAD gene networks42 endocrine factorsEPDR1, FCN2, FSTL3, LBPKoplev et al., 2022
Atherosclerosis/CAD55 genes conserved for atherosclerosis; 14 conserved for other cardiovascular-related traitsRGS19, KPTNLi et al., 2022
Atherosclerosis/CAD and cholesterol liver networksLiver subnetwork consisting of 50 genes, including the key driver gene, ATF3ATF3Bauer et al., 2022
Mouse-to-human integrationBlood pressureUbp1Koutnikova et al., 2009
Diabetes-related traitsSyntenic regions identified for 49 QTLs for gene modules and physiological traitsKeller et al., 2018
Cross-tissue endocrine interactions regulating whole-body metabolismLcn5/LCN6, NotumLcn5/LCN6, Notum, SMOC1, ITIH5, PPBPSeldin et al., 2018
Biomarker for heart failureGPNMBLin et al., 2018
Hepatic fibrosisNine conserved pathwaysHui et al., 2018
Hepatic and plasma lipidomePSMD9Psmd9Parker et al., 2019
Exercise metabolismDnm1lDnm1lMoore et al., 2019
Diabetes-related traitsHunk, Zfp148 (others not reported)Ptpn18, Hunk, Zfp148Keller et al., 2019
Cholesterol metabolism54 genesSesn1Li et al., 2020
NASH/NAFLDL-PK (Pklr)L-PK (Pklr)Chella Krishnan et al., 2021a
NASHUp to 42% or 35% overlap of upregulated or downregulated genes in NASH, depending on mouse strainBenegiamo et al., 2023
  1. *

    For brevity, a selection of key references are provided in this table. We apologise to the investigators whose work could not be cited due to space limitations.

  2. NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis; CAD, coronary artery disease.

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  1. Aaron W Jurrjens
  2. Marcus M Seldin
  3. Corey Giles
  4. Peter J Meikle
  5. Brian G Drew
  6. Anna C Calkin
(2023)
The potential of integrating human and mouse discovery platforms to advance our understanding of cardiometabolic diseases
eLife 12:e86139.
https://doi.org/10.7554/eLife.86139