Neurogenomic insights into paternal care and its relation to territorial aggression - Bell Lab
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ARTICLE
https://doi.org/10.1038/s41467-019-12212-7 OPEN
Neurogenomic insights into paternal care and its
relation to territorial aggression
Syed Abbas Bukhari1,2,3, Michael C. Saul1,6, Noelle James 4, Miles K. Bensky5, Laura R. Stein3,7,
Rebecca Trapp3,8 & Alison M. Bell1,3,4,5
1234567890():,;
Motherhood is characterized by dramatic changes in brain and behavior, but less is known
about fatherhood. Here we report that male sticklebacks—a small fish in which fathers
provide care—experience dramatic changes in neurogenomic state as they become fathers.
Some genes are unique to different stages of paternal care, some genes are shared across
stages, and some genes are added to the previously acquired neurogenomic state. Com-
parative genomic analysis suggests that some of these neurogenomic dynamics resemble
changes associated with pregnancy and reproduction in mammalian mothers. Moreover,
gene regulatory analysis identifies transcription factors that are regulated in opposite
directions in response to a territorial challenge versus during paternal care. Altogether these
results show that some of the molecular mechanisms of parental care might be deeply
conserved and might not be sex-specific, and suggest that tradeoffs between opposing social
behaviors are managed at the gene regulatory level.
1 Carl R. Woese Institute for Genomic Biology, University of Illinois, Urbana Champaign, 1206 Gregory Drive, Urbana, IL 61801, USA. 2 Illinois Informatics Institute,
University of Illinois, Urbana Champaign, 616 E. Green St., Urbana, IL 61820, USA. 3 Department of Evolution, Ecology and Behavior, University of Illinois,
Urbana Champaign, 505 S. Goodwin Avenue, Urbana, IL 61801, USA. 4 Neuroscience Program, University of Illinois, Urbana Champaign, 505 S. Goodwin
Avenue, Urbana, IL 61801, USA. 5 Program in Ecology, Evolution and Conservation Biology, University of Illinois, Urbana Champaign, 505 S. Goodwin Avenue,
Urbana, IL 61801, USA. 6Present address: Jackson Labs, 600 Main St., Bar Harbor, ME 04609, USA. 7Present address: Department of Biology, University of
Oklahoma, 730 Van Vleet Oval, Room 314, Norman, OK 73019, USA. 8Present address: Department of Biological Sciences, Purdue University, 915 W. State
St., West Lafayette, IN 47907, USA. Correspondence and requests for materials should be addressed to A.M.B. (email: alisonmb@illinois.edu)
NATURE COMMUNICATIONS | (2019)10:4437 | https://doi.org/10.1038/s41467-019-12212-7 | www.nature.com/naturecommunications 1ARTICLE NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-019-12212-7
I
n many species, parents provide care for their offspring, which Moreover, the basic building blocks of parental care are ancient
can improve offspring survival. There is fascinating diversity and deeply conserved in vertebrates13. For example, the hormone
in the ways in which parents care for their offspring, from prolactin was named for its essential role in lactation in mam-
infant carrying behavior in titi monkeys, poison dart frogs and mals, but had functions related to parental care in fishes long
spiders to provisioning of offspring in burying beetles and before mammals evolved14. Growing evidence for deep homology
birds1,2. The burden of parental care does not always land of brain circuits related to social behavior15–18 suggests that the
exclusively on females; in some species both parents provide care diversity of parental care among vertebrates is underlain by
and in others males are solely responsible for care. changes in functionally conserved genes operating within similar
Our understanding of the molecular and neuroendocrine basis neural circuits19.
of parental care has been largely influenced by studies in mam- In this study, we track the neurogenomic dynamics of the
mals, where maternal care is the norm. In mammals, females transition to fatherhood in male stickleback fish by measuring
experience cycles of estrus, pregnancy, child birth and lactation as gene expression (RNA-Seq) in two brain regions containing
they become mothers, all of which are coordinated by hormones. nodes within the social behavior network, diencephalon and tel-
While maternal care is often primed by hormonal and physio- encephalon. Gene expression in experimental males is compared
logical changes related to embryonic or fetal development, the across five different stages (nest, eggs and three time points after
primers for paternal behavior are likely to be more subtle, such as hatching) and relative to a control group. In this species, fathers
the presence of eggs or offspring3,4. Despite this subtlety, there is are solely responsible for the care of the developing offspring, and
growing evidence that males can also experience changes in male sticklebacks go through a predictable series of stages as they
physiology and behavior as they become fathers, some of which become fathers, from territory establishment and nest building to
resemble changes in mothers5. For example, men experience mating, caring for eggs, hatching and caring for fry20.
increased oxytocin6 and a drop in testosterone7 following the In addition to providing care, parents must be vigilant to
birth of a child. Indeed, a recent study in burying beetles showed defend their vulnerable dependents from potential predators or
that the neurogenomic state of fathers when they are the sole other threats. Tradeoffs between parental care and territory
providers of care closely resembles the neurogenomic state of defense have been particularly well studied in the ecological lit-
mothers8. erature, e.g.21, and parental care and territorial aggression
There is taxonomic diversity in the specific behavioral mani- represent the extremes on a continuum of social behavior—from
festations of care, but all care-giving parents go through a pre- strongly affiliative to strongly aversive. Therefore, an additional
dictable series of stages as they become mothers or fathers, from goal of this study is to compare and contrast the neurogenomics
preparatory stages prior to fertilization (e.g. territory establish- of paternal care with the neurogenomic response to a territorial
ment and nest building) to the care of developing embryos (e.g. challenge. As parental care and territorial aggression are social
pregnancy, incubation), to care of free-living offspring (e.g. pro- behaviors and both utilize circuitary within the social behavior
visioning of nestlings, lactation, etc). Each stage is characterized network in the brain15–17, we expect to observe similarities
by a set of behaviors and events, and the transition to the next between parental care and a territorial challenge at the molecular
stage depends on the successful completion of the preceding stage level. However given their position at opposite ends of the con-
e.g. ref. 9. The temporal ordering of stages, combined with our tinuum of social behavior, along with neuroendocrine tradeoffs
understanding of the neuroendocrine dynamics of reproduc- between them22, here we test the hypothesis that opposition
tion10, prompts at least three non-mutually exclusive hypotheses between parental care and territorial aggression is reflected at the
about how we might expect gene expression in the brain to molecular and/or gene regulatory level.
change over the course of parental care. First, because each stage Altogether results suggest that some of the molecular
is characterized by a particular set of behaviors, each stage might mechanisms of parental care are deeply conserved and are not
have a unique neurogenomic state associated with it (the unique sex-specific, and suggest that tradeoffs between opposing social
hypothesis). Second, some of the demands of parenting remain behaviors are managed at the gene regulatory level.
constant across stages, e.g. defending a nest site, therefore we
might expect to see the signal of a preceding stage to persist into
subsequent stages (the carryover hypothesis), resulting in shared Results
genes among stages, especially between stages close together in Neurogenomic dynamics of paternal care. There were dramatic
the series. Finally, extending the reasoning further, and con- neurogenomic differences associated with paternal care. A large
sidering that parents must pass through one stage before pro- number of genes—almost 10% of the transcriptome—were dif-
ceeding to the next, genes associated with one stage might be ferentially expressed between the control and experimental
added to the previous stage as a parent proceeds through the groups over the course of the parenting period (Fig. 1a, Supple-
stages (the additivity hypothesis, an extension of the carryover mentary Data 1). Within each stage, a comparable number of
hypothesis).Whether changes that occur at the neurogenomic genes were up- and down-regulated. There were significant gene
level can be mapped on to behaviorally defined (as opposed to expression differences between the control and experimental
endogenously defined) stages of parental care is unknown. groups within both brain regions; relatively more genes were
Moreover, we know little about whether there are genes that differentially expressed in diencephalon.
conform to a unique, carryover or additive pattern across stages Functional enrichment analysis of the differentially expressed
of care. These hypotheses provide a novel conceptual framework genes (DEGs) suggests that paternal care requires changes in
for improving our understanding of parental care at the mole- energy metabolism in the brain along with modifications of
cular level, and could serve as a model for studying other life immune system and transcription. Genes associated with the
events that comprise a series of behaviorally defined stages, e.g. immune response were down-regulated in both brain regions and
stages of territory establishment, stages of pair-bonding, stages of during most stages relative to the control group. Genes associated
dispersal, etc. with energy metabolism and the adaptive component of the
Unlike mammals, paternal care is relatively common in fishes: immune response were upregulated in telencephalon. Genes
of the fishes that display parental care, 80% of them provide some associated with the stress response were downregulated in both
form of male care, therefore fish are good subjects for under- brain regions around the day of hatching. Genes associated with
standing the molecular orchestrators of paternal care11,12. energy metabolism were downregulated as the fry emerged
2 NATURE COMMUNICATIONS | (2019)10:4437 | https://doi.org/10.1038/s41467-019-12212-7 | www.nature.com/naturecommunicationsNATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-019-12212-7 ARTICLE
a Diencephalon Telencephalon
c Diencephalon Telencephalon
5 galn
4
200 3
2
1
Genes
0
3 galr1
2
−200
1
Up
Down
Expression (log CPM)
Nest Eggs Early Mid Late Nest Eggs Early Mid Late 3 pgr
b 2
Diencephalon Telencephalon
Up Down Up Down 1
Energy Immune Adaptive Immune
metabolism immune 0
response response
Nest response
6
esr1
Energy Immune Immune 5
Eggs metabolism response response
4
Immune 3
Stress response, Immune
Early Transport response energy response 2
metabolism
10.0 oxt
Cell Adaptive Immune
Biosynthesis communication immune response,energy 7.5
Mid & gene & regulation response metabolism,
expression of metabolism stress response 5.0
Immune response, 2.5
Adaptive
metabolism,
Late immune
Metabolism cellular transport, 0.0 Exp Con
response
ion homeostasis
Nest Eggs Early Mid Late Nest Eggs Early Mid Late
Fig. 1 Neurogenomic dynamics of paternal care. a The number of up- and down-regulated differentially expressed genes (DEGs) at each stage of paternal
care in diencephalon and telencephalon. b Summary of GO-terms that were enriched in up- and down-regulated genes at each stage in the two brain
regions. c The expression profile of candidate genes related to maternal care (galanin, galanin receptor 1, progesterone, estrogen receptor 1, oxytocin)
across stages, with expression in the two brain regions plotted relative to the appropriate circadian control group; data points represent individual samples
with means and s.e.m. indicated. Statistical significance of these genes was assessed as a pairwise contrast between a stage and its control (see
Supplementary Data 1 for full list of genes; source data are in GEO GSE134508) using negative binomial distribution with generalized linear models in
edgeR. Boxes surround means that are statistically different between the control and experimental condition within the stage.
(Fig. 1b, Supplementary Data 2). The expression profile of cutoff for differential expression in another stage (false negatives),
particular candidate genes related to parental care are in Fig. 1c, we followed an empirical approach (as in23). We kept the cutoff
with statistically significant differences between the control and for DEGs at the focal stage at FDR < 0.01 and relaxed the FDR
experimental condition within a stage indicated. Altogether these threshold on the other stages (Supplementary Fig. 1). This
patterns suggest that paternal care involves significant neuroge- procedure was repeated for each stage and in each brain region
nomic shifts in stickleback males. separately. This analysis produced—with high statistical con-
fidence—lists of DEGs that are unique to each stage (Fig. 2a),
consistent with the “unique” hypothesis.
Change and stability of neurogenomic state across stages. We Next, we assessed the extent to which genes were shared among
used these data to assess evidence for three non-mutually exclu- different stages of paternal care by testing whether the number of
sive hypotheses about how neurogenomic state might change overlapping DEGs between stages was greater than expected
across stages of parental care. According to the unique hypoth- using a hypergeometric test. Consistent with the carryover
esis, there is a strong effect of stage on brain gene expression and hypothesis, within each brain region, the number of overlapping
little to no overlap among the genes associated with different DEGs between stages was statistically much greater than expected
stages. To evaluate this hypothesis we tested whether there were by chance (Supplementary Data 3), and stages that are close
DEGs that were unique to each stage, i.e. not shared with other together in the series shared more DEGs compared to stages that
stages. We generated lists of genes that were differentially are further apart (Fig. 2b, Supplementary Fig. 2).
expressed between the control and experimental group at each These results suggest that there are genes whose signal persists
stage within each brain region. Then, we excluded the DEGs that across stages of care. We then evaluated the possibility that each
were shared between stages in order to identify unique genes to new stage triggers a neurogenomic response which persists into
each stage. To increase confidence that the unique genes are truly subsequent stages, i.e. that genes associated with one stage are
unique to each stage, i.e. that they didn’t just barely passed the added to the previous stage as a parent proceeds through the
NATURE COMMUNICATIONS | (2019)10:4437 | https://doi.org/10.1038/s41467-019-12212-7 | www.nature.com/naturecommunications 3ARTICLE NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-019-12212-7
a Unique - Diencephalon b Telencephalon
Diencephalon
Nest Eggs Early Mid Late
Late
Nest
25
Mid
Eggs
Early
Nest
30
Eggs Eggs
Early
Early
9
Nest Mid
Mid
Nest Eggs Early Mid Nest Eggs Early Mid
c Added shared - Diencephalon Added shared - Telencephalon
Nest Eggs Early Mid Late Nest Eggs Early Mid Late
Nest
Nest
123
177
Eggs
Late
23
3
Early
8
Unique - Telencephalon
Nest
Log (fold change)
21
–2 –1 0 1 2
Eggs
235
2
Early
Eggs
8
58
Early
Mid
26
3
Mid
Late
32
60
Fig. 2 Change and stability of neurogenomic state across stages of parental care. a There were DEGs that were only differentially expressed during one
stage. Shown is a heat map depiction of the expression profile of the genes that were “unique” to each stage, showing how they were regulated in other
stages, separated by stage and by brain region. b The statistical significance of the pair-wise overlap between stages within each brain region. The size of
the circle is proportional to the significance of the p-value (hypergeometric test FDR) of the overlap, such that large circles indicate smaller p-values. Note
that the stages closest to the focal stage tended to share more DEGs compared to stages further apart in the series. c DEGs that were added to a stage and
were also differentially expressed in subsequent stages. Shown is a heat map depiction of the added shared genes for each stage, separated by brain region,
showing how they were regulated across stages. Red = upregulated, blue = downregulated. Numbers on the heat maps indicate the number of genes in
each heat map. Source data are in GEO GSE134508
stages. According to this hypothesis, when a parent is caring for overlap with subsequent stages, therefore except for the “nest
eggs in their nest, for example, the “egg” genes are added to the added shared genes”, each of the added shared genes from the
previously activated “nest” genes, and so on, in an additive previous stage(s) were subtracted from the focal stage’s added
fashion. To examine this statistically, for each stage, we identified shared genes (Supplementary Fig. 3). This process generated four
genes that: (1) were differentially expressed during the stage of sets of added shared genes: genes that were differentially
interest; (2) were not differentially expressed during any of the expressed during the nest stage and were also differentially
preceding stages; (3) were also differently expressed in a expressed during at least one subsequent stage (“nest added
subsequent stage, hereafter referred to as "added shared genes". shared genes”), genes that were differentially expressed during the
Only genes added during a new stage were used to test for their egg stage and were also differentially expressed during at least one
4 NATURE COMMUNICATIONS | (2019)10:4437 | https://doi.org/10.1038/s41467-019-12212-7 | www.nature.com/naturecommunicationsNATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-019-12212-7 ARTICLE
subsequent stage but not during the nest stage (“egg added shared experience across stages of maternal care, we leveraged a recent
genes”), and so on. dataset where brain gene expression was compared across a series
This analysis revealed genes that became differentially of pregnancy and post-partum stages in mice (Supplementary
expressed as males proceeded through different stages of paternal Data 5)31. Similar to stickleback fathers, there were both unique
care and ROAST24 analysis found that the added shared genes and added shared DEGs across different stages of pregnancy and
remained differentially expressed in subsequent stages in a postpartpum in mouse mothers. We then tested if the enduring
statistically significant manner (Supplementary Data 4). This (added shared genes) and transient (unique) changes in
suggests, for example, that there was a transcriptional signal of neurogenomic state that were experienced in stickleback fathers
eggs which persisted after the egg stage. To see if the genes that were similar to the enduring and transient signals of pregnancy
were added and which persisted over time were similarly and the postpartum period in mouse mothers. Specifically, we
regulated across subsequent stages of paternal care, we examined compared mouse and stickleback added shared genes within the
the expression profiles of the added shared genes at each stage appropriate orthogroup (Supplementary Data 6). For example, we
and tested if the direction of regulation was consistent across compared 356 stickleback added shared genes within 90
stages. This analysis revealed that added shared genes were indeed orthogroups in diencephalon and 838 mouse added shared genes
similarly regulated across stages (Supplementary Data 4, Fig. 2c). within 265 orthogroups in hypothalamus and found that they
For example, added shared genes that were upregulated in males shared 14 orthogroups. In order to test whether those 14 shared
with nests were also upregulated during subsequent stages, orthogroups is greater than expected due to chance, we employed
especially during stages close to the nesting stage. To investigate a Monte Carlo based permutation approach. We did not use a
this further, we calculated the probability that all genes within a regular hypergeometric test or regular permutation test here (at
set of added shared genes were expressed in the same direction the orthogroup level) because each orthogroup contains more
due to chance, i.e. either consistently up- or down-regulated. than one gene in both the stickleback and mouse genomes, and
Then, we counted the number of genes within each set of added some of those genes were differentially expressed and others were
shared genes that were concordantly expressed. We found that not. Instead, we sampled the gene sets (e.g. 356 and
the number of concordantly expressed genes was greater than 838 genes in diencephalon/hypothalamus) repeatedly (105) and
expected by chance (diencephalon χ2 = 1859, P < 1e-6, telence- with replacement from both species’ universes and counted the
phalon χ2 = 146, df = 2, P < 1e-4). For example, 172 of the 235 overlaps at the orthogroup level. This overlap was then tested
genes in the nest added shared genes in diencephalon were against the observed overlap to compute p-values, which are
concordantly expressed across stages, much higher than the highly significant (Fig. 3, note that the overlap never reaches 14
expected 15 genes due to chance. The concordant expression orthogroups). Added shared genes in stickleback and mouse
pattern across stages suggests that an added shared gene serves a include BDNF (a candidate gene related to anxiety, stress and
similar function in different stages. depression32) and a regulator of G protein receptors RGS3
(related to insulin metabolism33). We followed the same
procedure for the unique genes and did not find any evidence
Pathways are not sex-specific and are deeply conserved. Some of of sharing between the two species. For example, there were 33
the candidate genes associated with female pregnancy and unique genes in four orthogroups in mouse hypothalamus and
maternal care were differentially expressed in different stages of 244 unique genes in 54 orthogroups stickleback diencephalon
paternal care in sticklebacks (Fig. 1c). For example, in mammals, with no overlap between them (Supplementary Data 6).
levels of progesterone, estrogen and their receptors increase Altogether, the differential expression of candidate genes
during pregnancy and then subside after childbirth. A similar related to maternal care along with the deep homology of the
pattern was observed in the diencephalon of male sticklebacks: enduring signal of care across stages (added shared genes) suggest
both estrogen receptor (esr1) and progesterone receptor (pgr) that some of the neurogenomic shifts that occur during paternal
were upregulated during early hatching and then subsided care in a fish are deeply conserved and are not sex-specific.
(Fig. 1c). Oxytocin (and its teleost homolog isotocin) plays an
important role in social affiliation and parental care in mammals6
and fish19,25–28. Oxytocin (oxt) was upregulated in diencephalon Parenting and aggression tradeoffs at the molecular level. To
when male sticklebacks were caring for eggs in their nests, and better understand how different social demands are resolved in the
upregulated in telencephalon mid-way through the hatching brain, we compared these data to a previous study on the neuro-
process (Fig. 1c). genomic response to a territorial challenge in male sticklebacks34,
Genes that have been implicated in infanticide during parental which measured brain gene expression 30, 60 or 120 min after a 5
care in mammals were also differentially expressed in stickle- min territorial challenge. The two experiments studied behaviors at
backs, where egg cannibalism is common. Galanin—a gene the opposite ends of a continuum of social behavior: paternal care
implicated with infanticidal behavior in mice29—was highly provokes affiliative behavior while a territorial challenge provokes
expressed in diencephalon (which includes the preoptic area) aggressive behavior, and the challenge hypothesis originally posited
during the nest, eggs and early hatching stages. However, the that patterns of testosterone secretion reflects tradeoffs between
galanin receptor gene was downregulated during the middle to parental care and territory defense, assuming that testosterone is
late hatching stages in both brain regions (Fig. 1c). Furthermore, incompatible with parental care in males22. Subsequent studies have
the progesterone receptor—which mediates aggressive behavior shown that testosterone is not always inhibitory of parental care35,
toward pups in mice30—gradually declined in both brain regions and that a territorial challenge activates gene regulatory pathways
as hatching progressed, and its level was lowest when all the fry that do not depend on the action of testosterone36. Regardless of the
were hatched (Fig. 1c). Up-regulation of galanin during the egg specific neuromodulators or hormones, a mechanistic link between
stage and down-regulation of progesterone receptor during the parental care and territory defense is likely to operate through the
hatching stage could reflect how male sticklebacks inhibit social behavior network in the brain because most nodes of this
cannibalistic behavior while providing care. network express receptors for neuromodulators and hormones that
To test if the neurogenomic changes that we observed in are involved with both parental care and aggression37. Therefore we
stickleback fathers across stages, e.g. unique and added shared used these data to assess whether there is commonality at the
genes, are similar to the neurogenomic changes that mothers molecular level between aggression and paternal care. For example,
NATURE COMMUNICATIONS | (2019)10:4437 | https://doi.org/10.1038/s41467-019-12212-7 | www.nature.com/naturecommunications 5ARTICLE NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-019-12212-7
a b
HEarly
HEarly
HLate
HLate
PC14
PC16
PC14
PC16
PP10
PP10
HMid
HMid
Eggs
Eggs
Nest
Nest
PP1
PP3
PP1
PP3
EOG091G0Y2U | stmn4l | Stmn4 EOG090B0052 | acaca | Acacb
EOG090B03S5 | cpne3 (1 of 4) | Cpne2 EOG090B01VP | gria3b | Gria2
EOG090B028A | il6st | Il6st EOG091G0BDG | si:ch211−196h16.12 | Rgs3
EOG090B00HH | MYH3 | Myh7 EOG090B0COB | bdnf | Bdnf
EOG090B00HH | MYH3 | Myh13 EOG090B0EU9 | cldn7a | Cldn1
EOG090B00HH | MYH3 | Myh2 EOG090B0IGX | spen | Spen
EOG090B0K1Y | vamp2 | Vamp1 EOG090B0IOF | ndufa7 | Ndufa7
EOG090B0DS7 | cnih2 | Cnih3 EOG090B01AP | b4galnt3b | B4galnt3
EOG090B02QF | prkca | Prkcb
EOG090B0ACR | sox19a | Sox3
EOG090B0COB | bdnf | Bdnf –Log(fdr)
EOG090B0D45 | adcyap1a | Adcyap1 8
6
EOG090B00XG | sall3a | Sall3 4
EOG090B01WI | VAV3 (1 of 2) | Vav3 2
Fig. 3 DEGs associated with shared orthogroups. Color represents the significance of differential expression between the control and experimental group (p
values (−log(fdr)) across the five conditions in stickleback (left) and the five conditions in mouse (right). a shows the significance of DEGs within
14 shared orthogroups between diencephalon in stickleback and hypothalamus in mouse. b shows the significance of DEGs within nine shared orthogroups
between telencephalon in stickleback and hippocampus in mouse. Source data are in GEO GSE134508
a b Paternal care
Territorial challenge
Territorial challenge A
Territorial
B
challenge
30 60 120
Time (minutes)
Paternal care Nest Eggs Hatch * F F
U F
F F U 566 177 1941
F
C U F E
D
~1–7 ~5 Paternal care
Time (days)
c ENSGACG00000008417
ENSGACG00000010788
ENSGACG00000009215
ENSGACG00000013094
ENSGACG00000018137
ENSGACG00000002226
ENSGACG00000018434
ENSGACG00000014160
ENSGACG00000011629
ENSGACG00000001106
ENSGACG00000009027
ENSGACG00000011918
ENSGACG00000000451
ENSGACG00000009792
ENSGACG00000005610
ENSGACG00000001556
ENSGACG00000013707
ENSGACG00000011930
klf12a
ENSGACG00000002490 ENSGACG00000009569
ENSGACG00000017185
ENSGACG00000016169
ENSGACG00000020423
ENSGACG00000010416 ENSGACG00000014064
ENSGACG00000006930
ENSGACG00000017053
ENSGACG00000009609 ENSGACG00000002343
ENSGACG00000008991
ENSGACG00000001392
ENSGACG00000000450
ENSGACG00000011142
ENSGACG00000006332
ENSGACG00000005256
ENSGACG00000009291 ENSGACG00000000702
ENSGACG00000006913
ENSGACG00000016553
ENSGACG00000017694
ENSGACG00000018563
ENSGACG00000003199
ENSGACG00000014419
ENSGACG00000002352
ENSGACG00000020202 ENSGACG00000015883
ENSGACG00000004004
ENSGACG00000005270 ENSGACG00000015121
ENSGACG00000012218
ENSGACG00000012399
ENSGACG00000002865
ENSGACG00000012886
ENSGACG00000001338 ENSGACG00000004346 ENSGACG00000018829
ENSGACG00000005959
CRX
ENSGACG00000018704
ENSGACG00000013846
ENSGACG00000009264
ENSGACG00000017069
ENSGACG00000008062
ENSGACG00000017836
ENSGACG00000001289
ENSGACG00000001886
ENSGACG00000005714 ENSGACG00000008170
ENSGACG00000008977
ENSGACG00000014764
ENSGACG00000002462
ENSGACG00000014962 ENSGACG00000002791
ENSGACG00000006671 ENSGACG00000004057
ENSGACG00000019323
ENSGACG00000001188
ENSGACG00000010691
ENSGACG00000006675 ENSGACG00000017170
ENSGACG00000007277
ENSGACG00000004014
ENSGACG00000006256
ENSGACG00000016510 ENSGACG00000013235
ENSGACG00000017407 ENSGACG00000004124 ENSGACG00000017239 ENSGACG00000015171
ENSGACG00000000703
ENSGACG00000003477
ENSGACG00000013679
ENSGACG00000000718
ENSGACG00000017221 ENSGACG00000019442
ENSGACG00000014622
ENSGACG00000012208 ENSGACG00000006654
ENSGACG00000002286 ENSGACG00000018033
ENSGACG00000007585 ENSGACG00000001508
ENSGACG00000016677 ENSGACG00000001900
ENSGACG00000014887 ENSGACG00000003067 ENSGACG00000012802
ENSGACG00000001664 ENSGACG00000017959 ENSGACG00000006028
ENSGACG00000003192
ENSGACG00000006773
ENSGACG00000010350 ENSGACG00000014426 ENSGACG00000016988
ENSGACG00000005558 ENSGACG00000010211
ENSGACG00000007625 ENSGACG00000005793
ENSGACG00000003839
ENSGACG00000016678 ENSGACG00000006252 ENSGACG00000011864 ENSGACG00000020776
ENSGACG00000015660 ENSGACG00000016021
ENSGACG00000015671 ENSGACG00000010287
ENSGACG00000016316 ENSGACG00000015391
ENSGACG00000017345
ENSGACG00000003017 ENSGACG00000013854
ENSGACG00000000412 ENSGACG00000016681 ENSGACG00000000314
ENSGACG00000010270
ENSGACG00000002874 ENSGACG00000016249 ENSGACG00000012956
ENSGACG00000009422
ENSGACG00000007934 ENSGACG00000011301 ENSGACG00000002787
ENSGACG00000017900
ENSGACG00000010179 ENSGACG00000002334
ENSGACG00000018546 ENSGACG00000017612
ENSGACG00000015123 ENSGACG00000006547
ENSGACG00000001981 ENSGACG00000006479
ENSGACG00000017287 ENSGACG00000015130 ENSGACG00000001998
ENSGACG00000016811
ENSGACG00000020357 ENSGACG00000006779 ENSGACG00000019917
ENSGACG00000000801 ENSGACG00000015964
ENSGACG00000018497
ENSGACG00000000615
ENSGACG00000010875 ENSGACG00000017723
ENSGACG00000016516 ENSGACG00000013904
ENSGACG00000018547
ENSGACG00000010639
ENSGACG00000003679 ENSGACG00000008338 ENSGACG00000020178
ENSGACG00000003778
ENSGACG00000020582 ENSGACG00000016445
ENSGACG00000011827 ENSGACG00000016370 ENSGACG00000018022 ENSGACG00000016420
ENSGACG00000016253 ENSGACG00000008155 ENSGACG00000010123
ENSGACG00000008358 ENSGACG00000015381 ENSGACG00000014047
ENSGACG00000002422 ENSGACG00000019148
ENSGACG00000003937 ENSGACG00000004123
ENSGACG00000020017 ENSGACG00000020127 ENSGACG00000005455
ENSGACG00000017184
ENSGACG00000006886 ENSGACG00000012744 ENSGACG00000007705
ENSGACG00000003289
ENSGACG00000004437 ENSGACG00000008646
ENSGACG00000017121
ENSGACG00000017360
mef2aa
ENSGACG00000012788
ENSGACG00000019075 ENSGACG00000014245 ENSGACG00000005592
ENSGACG00000008673 ENSGACG00000008957
ENSGACG00000018521 ENSGACG00000008212 ENSGACG00000003189
ENSGACG00000020840
ENSGACG00000017207
ENSGACG00000012737
ENSGACG00000009241
ENSGACG00000012301
ENSGACG00000004207
ENSGACG00000017359 ENSGACG00000003369 ENSGACG00000010707
ENSGACG00000014580
ENSGACG00000010624
ENSGACG00000001398
ENSGACG00000018939 ENSGACG00000015748
ENSGACG00000015844
ENSGACG00000016368 ENSGACG00000006481
ENSGACG00000009761
ENSGACG00000013465 ENSGACG00000006960
ENSGACG00000003412
ENSGACG00000015051
ENSGACG00000004080 ENSGACG00000006996
ENSGACG00000020743 ENSGACG00000003919 ENSGACG00000017881
ENSGACG00000019036 ENSGACG00000010518 ENSGACG00000015259
ENSGACG00000012602 ENSGACG00000020277
ENSGACG00000003833
ENSGACG00000019125 ENSGACG00000015618 ENSGACG00000011021
ENSGACG00000010229
ENSGACG00000002357
ENSGACG00000019080
ENSGACG00000002425
ENSGACG00000017483 ENSGACG00000014002
ENSGACG00000007667
ENSGACG00000019187 ENSGACG00000018139
ENSGACG00000015232 ENSGACG00000015840
ENSGACG00000017372
ENSGACG00000007481 ENSGACG00000003615 ENSGACG00000020416
ENSGACG00000016924 ENSGACG00000001539 ENSGACG00000017255
ENSGACG00000019888
ENSGACG00000010365 ENSGACG00000011348 ENSGACG00000004568
ENSGACG00000016232 ENSGACG00000016904
ENSGACG00000014782
ENSGACG00000013917 ENSGACG00000007885
ENSGACG00000004910
ENSGACG00000009006
ENSGACG00000010912 ENSGACG00000017128 ENSGACG00000008918
ENSGACG00000009905
ENSGACG00000016078 ENSGACG00000002622
ENSGACG00000011974
ENSGACG00000002720
ENSGACG00000008787 ENSGACG00000010085
ENSGACG00000014846 ENSGACG00000001434
ENSGACG00000011743 ENSGACG00000000628
ENSGACG00000011967 ENSGACG00000005508 ENSGACG00000003888 ENSGACG00000012138
ENSGACG00000003340 ENSGACG00000006916 ENSGACG00000003215
ENSGACG00000012219
ENSGACG00000006736
ENSGACG00000001509
ENSGACG00000001883 ENSGACG00000006581
ENSGACG00000006792
ENSGACG00000005402
ENSGACG00000008077 ENSGACG00000009438
ENSGACG00000010953 ENSGACG00000014983 ENSGACG00000006272
ENSGACG00000018040 ENSGACG00000012203 ENSGACG00000008113
ENSGACG00000007835
ENSGACG00000009306 ENSGACG00000002573
ENSGACG00000017245
ENSGACG00000003505 ENSGACG00000013146
ENSGACG00000000411
ENSGACG00000019783
ENSGACG00000007821
ENSGACG00000008778 ENSGACG00000017193 ENSGACG00000007827 ENSGACG00000006101
ENSGACG00000007122 ENSGACG00000016074
ENSGACG00000019027
ENSGACG00000010356 ENSGACG00000006572 ENSGACG00000019986
ENSGACG00000003431
ENSGACG00000012933 ENSGACG00000006082 ENSGACG00000004668
ENSGACG00000009385 ENSGACG00000000898 ENSGACG00000004873 ENSGACG00000008890
ENSGACG00000001754 ENSGACG00000001291 ENSGACG00000001295
ENSGACG00000005227
ENSGACG00000019298
ENSGACG00000014381 ENSGACG00000012028
ENSGACG00000010570
ENSGACG00000014728 ENSGACG00000014621 ENSGACG00000004757 ENSGACG00000009355
ENSGACG00000007721 ENSGACG00000019448 ENSGACG00000008279
ENSGACG00000014727
ENSGACG00000011137 ENSGACG00000017458
nfixa
ENSGACG00000017597
ENSGACG00000020394
ENSGACG00000008216 ENSGACG00000004570
ENSGACG00000009959 ENSGACG00000002708
ENSGACG00000014281 ENSGACG00000007991
ENSGACG00000015372
ENSGACG00000014838 ENSGACG00000015958
ENSGACG00000013182 ENSGACG00000011932
ENSGACG00000017225
ENSGACG00000013605
ENSGACG00000010970
ENSGACG00000015747 ENSGACG00000008947
ENSGACG00000001665 ENSGACG00000015386
ENSGACG00000005822
ENSGACG00000013353
ENSGACG00000009797
ENSGACG00000002228 ENSGACG00000008402 ENSGACG00000007776 ENSGACG00000006863
ENSGACG00000011084
ENSGACG00000011995 ENSGACG00000006392
ENSGACG00000015734 ENSGACG00000003513
ENSGACG00000012516 ENSGACG00000012157 ENSGACG00000014163
ENSGACG00000005058
ENSGACG00000003813
ENSGACG00000017176 ENSGACG00000008329
ENSGACG00000018910 ENSGACG00000017369 ENSGACG00000019611
ENSGACG00000004088
ENSGACG00000018854
ENSGACG00000019340 ENSGACG00000005966
ENSGACG00000008405
ENSGACG00000017885
ENSGACG00000009794 ENSGACG00000008792
ENSGACG00000004399 ENSGACG00000004914 ENSGACG00000010700 ENSGACG00000011793
ENSGACG00000009888 ENSGACG00000007443
ENSGACG00000020076 ENSGACG00000017882
ENSGACG00000013512 ENSGACG00000012436
ENSGACG00000011762 ENSGACG00000007335
ENSGACG00000018364 ENSGACG00000012867
ENSGACG00000013069
ENSGACG00000007641
ENSGACG00000008199 ENSGACG00000004154 ENSGACG00000011207 ENSGACG00000007319
ENSGACG00000015979
ENSGACG00000014720
ENSGACG00000014766
ENSGACG00000003160
ENSGACG00000015271
ENSGACG00000014579 ENSGACG00000017017 ENSGACG00000018664
ENSGACG00000019462 ENSGACG00000014202
ENSGACG00000015990
ENSGACG00000006854 ENSGACG00000017015
ENSGACG00000010385 ENSGACG00000010079
ENSGACG00000009821
ENSGACG00000015648
ENSGACG00000005950
ENSGACG00000014009 ENSGACG00000020406
ENSGACG00000013387 ENSGACG00000018709
ENSGACG00000019789
ENSGACG00000002014
ENSGACG00000007995
ENSGACG00000002778
ENSGACG00000001065 ENSGACG00000016538
ENSGACG00000007843
ENSGACG00000017305
ENSGACG00000020307 ENSGACG00000014956
ENSGACG00000009115 ENSGACG00000007968 ENSGACG00000002995
ENSGACG00000007617 ENSGACG00000018855
ENSGACG00000013900
ENSGACG00000004655 ENSGACG00000002824 ENSGACG00000008491
ENSGACG00000016661 ENSGACG00000014290
neurod1
ENSGACG00000014234 ENSGACG00000006049
ENSGACG00000007978 ENSGACG00000009373 ENSGACG00000010820
ENSGACG00000016858
ENSGACG00000014616 ENSGACG00000007197 ENSGACG00000014591
ENSGACG00000009671 ENSGACG00000008541
ENSGACG00000008752 ENSGACG00000013764
ENSGACG00000014859
ENSGACG00000020890 ENSGACG00000016713
ENSGACG00000010864 ENSGACG00000007196
KLF7
ENSGACG00000003033 ENSGACG00000020297 ENSGACG00000002430
ENSGACG00000000498 ENSGACG00000020171
ENSGACG00000020135
ENSGACG00000020583 ENSGACG00000005648
ENSGACG00000010481
ENSGACG000000