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Outlineoftalk
Estimatingtheimportanceofhostgeneticsingut
microbiotacomposition
Usinghostgeneticvariationtostudyhostgutmicrobiome
interactions.
1.Maternalseeding
2.Diet
3.Genetics
4.Age
5.Antibiotics
6.Disease
TheHybridMouseDiversityPanel(HMDP)
About100commerciallyavailable,
highlydiverseinbredstrainsofmice
Sequencedordenselygenotyped
Sufficientlypoweredforhigh
resolutionassociationmapping
Usefulforgenebyenvironment
studies
Gutmicrobiotain200men5070yearsofagefromKuopio,Finland
HybridMouseDiversityPanel:113mousestrains(males)
Membersofaninbredstraintendtosharemicrobiomecomposition
Strains
(Diet)
BUB
(Chow)
BXA14
(Chow)
BXD15
(HF)
NON
SEA SWR
MA
(HF) (chow) (chow) (HF)
Heritability: Thefractionofvarianceofatraitthatis
explainedbygenetics.
Heritability: Thefractionofvarianceofatraitthatis
explainedbygenetics.
r
Phenotype similarity
Phenotype similarity
Genetic similarity
Xby descent)
(identity
Genetic similarity
Correlation coefficient r
Phenotype similarity
Phenotype similarity
Heritability: Thefractionofvarianceofatraitthatis
explainedbygenetics.
Genetic similarity
(identity by descent)
Heritability h2
Genetic similarity
(identity by descent)
TheinbredstrainsoftheHMDParerelatedtoone
another,havingbeenderivedfromapoolofpetmice
about100yearsago.
Genealogy of
inbred strains
Heritabilityofgutmicrobiotabasedonmousediversitypanel
Phyla
Avg.Frequency(%)
Heritability(%)
Actinobacteria
0.49
60
Bacteroidetes
43
62
Firmicutes
48
67
Proteobacteria
0.43
32
Tenericutes
0.73
40
Verrucomicrobia
7.3
56
Heritabilityestimatedusingmicrobiotacompositionandgenotypesof110
inbredstrainsofmice,employingalinearmixedmodelassumingadditive
geneticeffects.
(2016)
Hostdependentregulationofgutmicrobiota
Sex hormones:
One way the host controls gut microbiota
Gonadectomy (GDX) experiments in strain C57BL/6J
Genebydietinteractionsofgutmicrobiota
Chow
HighFat/
HighSucrose
HighFat/
Cholesterol
HMDPstrainsin
sameorderinall
plots
Outlineoftalk
Estimatingtheimportanceofhostgeneticsingut
microbiotacomposition
Usinghostgeneticvariationtostudyhostgutmicrobe
interactions.
Genomewideassociationstudy:
Locicontrollinggutmicrobiotainmice
Lrrk2
Nr2f2
Tle4
Lrrc19
60
0
BxH20/KccJ
AXB19b/PgnJ
BXD68/RwwJ
CXB12/HiAJ
C3H/HeJ
BXD50/RwwJ
CXB13/HiAJ
CXB6/ByJ
SWR/J
BXD87/RwwJ
CxB3/ByJ
BXD55/RwwJ
BxA4/PgnJ
BXD45/RwwJ
AXB19/PgnJ
BXD49/RwwJ
BXA24/PgnJ
BxD1/TyJ
BXD84/RwwJ
BXD86/RwwJ
BxD12/TyJ
BxD38/TyJ
CXB11/HiAJ
BXD48/RwwJ
BXD13/TyJ
BXD75/RwwJ
BxA16/PgnJ
AxB19a/PgnJ
BUB/BnJ
MA/MyJ
BXD56/RwwJ
DBA/2J
BXD85/RwwJ
BxD5/TyJ
CxB7/ByJ
AxB6/PgnJ
BXD61/RwwJ
BxD19/TyJ
C57BLKS/J
BXH19/TyJ
BXD73/RwwJ
BXH8/TyJ
SM/J
BXD20/TyJ
NOD/ShiLtJ
CXB4/ByJ
BTBR T<+> tf/J
BXD40/TyJ
RIIIS/J
C57BL/6J
BXD64/RwwJ
BXD62/RwwJ
BxA11/PgnJ
BXD79/RwwJ
LP/J
BXD27/TyJ
BXH6/TyJ
BALB/cJ
BxA7/PgnJ
BXD71/RwwJ
BXD14/TyJ
BXD21/TyJ
BXA14/PgnJ
A/J
BXD43/RwwJ
BXD74/RwwJ
FVB/NJ
BxH22/KccJ
AxB15/PgnJ
NON/SHiLtJ
BXD66/RwwJ
SEA/GnJ
AxB4/PgnJ
BXD70/RwwJ
CBA/J
BXD51/RwwJ
BXD6/TyJ
BXD32/TyJ
AXB10/PgnJ
PL/J
NZW/LacJ
BxH9/TyJ
BxA8/PgnJ
BXD24/TyJ-Cep290<rd16>/J
BXD69/RwwJ
BxD31/TyJ
BXA2/PgnJ
BXD34/TyJ
BXD44/RwwJ
BXD9/TyJ
BXA1/PgnJ
BXD60/RwwJ
KK/HlJ
50
40
30
20
10
6-8 mice/strain
Microbiotaassociationswithmetabolictraitsinmice
Taxa
Trait
P value
Akkermansia
muciniphila
Insulin
HOMA-IR
Body Fat % - 8 wks
Triglycerides
Food Intake
Insulin
HOMA-IR
Glucose
Body Fat % - 8 wks
Insulin
HOMA-IR
Body Fat % - 8 wks
4.57E-06
1.51E-04
9.02E-04
8.49E-03
1.45E-04
8.16E-05
2.20E-02
4.27E-03
1.12E-06
Oscillospira spp.
Ruminococcus
gnavus
Roseburia spp.
4.68E-06
4.09E-04
1.04E-06
Heat-killed Akk
5
4
killed_Akk
Females
Akk
3
2
1
0
beforediet
diet 2.5
wks
a er 4 wks
er HF/
Start
2.5
wks
4 awks
HS
HF/HS
Akk m.
AXB19 males
Akk
Body fat increase (g)
AXB19 females
8
7
6
5
4
3
2
1
0
Heat-killed Akk
Akk
before diet
diet 2.5
wkswks
a er 4 wks
er HF/
Start
2.5
4 awks
HF/HS
HS
Akk m.
Akk
killed_Akk
Males
Body fat
80
100
20
0
H
FA
kk
50
H
F
10
40
H
F
20
H
F
-A
kk
TC mg/dl
150
60
TG mg/dl
30
H
F
200
H
F
-A
kk
Body Fat %
40
Glucose metabolism
***
***
20
1000
H
F
-A
kk
0
H
F
0
H
F
-A
kk
2000
40
H
F
-A
kk
100
3000
H
F
200
60
HOMA-IR
300
Insulin pg/ml
4000
H
F
Glucose mg/dl
400
Summary
In a controlled environment host genetics contributes
importantly to gut microbiota.
The relationship between host genetics, diet and the gut
microbiome is complex.
Host genetics can be used as a tool to study host-microbiota
interactions.
Welfare:
Oversight
Training
Respect
SystemsGenetics:Apopulationbasedapproach
Disease
Thanks to:
Elin Org
Margarete Mehrabian
Brian Parks
Jennifer Lang
Simon Hui
Brian Bennett
Stanley Hazen (Cleve. Clinic)
Rob Gunsalus (UCLA)
Eleazar Eskin (UCLA)
Markku Laakso (Finland)
Rob Knight (UCSD)
Federico Rey (Wisconsin)
Mappinggenesforgutmicrobiotataxa:Akk.mucinophila
rs33129247
Igf1r
68
Nr2f2
69
70
Positiononchr7(Mb)
71
Mappinggenesforgutmicrobiotataxa:Akk.mucinophila
rs33129247
Igf1r
68
Nr2f2
69
70
71
Positiononchr7(Mb)
Experimentinprogress
I. Establishment
II. Mixing
(3 wks)
(8 wks)
III. Recovery
10
C57BL/6J
C57BL/6J
(13 wks)
20
C57BL/6J
C57BL/6J-MIX
MIX
BTBRT+tf/J-MIX
BTBRT+tf/J
BTBRT+tf/J
BTBRT+tf/J
(28 wks)
Animal welfare
OfficeofAnimalResearchOversight
WorkswiththeUCLAIACUC
ARC(ChancellorsAnimalResearchCommittee
Assurecompliancewith:
AAALACaccreditation(since1976)
PublicHealthServicePolicies
OfficeofLaboratoryAnimalWelfare(OLAW)
USDepartmentofAgriculture
AnimalWelfareAct