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The Developmental Role of Agouti in Color Pattern Evolution

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Animal color patterns can affect fitness in the wild; however, little is known about the mechanisms that control their formation and subsequent evolution. We took advantage of two locally camouflaged populations of Peromyscus mice to show that the negative regulator of adult pigmentation, Agouti, also plays a key developmental role in color pattern evolution. Genetic and functional analyses showed that ventral-specific embryonic expression of Agouti establishes a prepattern by delaying the terminal differentiation of ventral melanocytes. Moreover, a skin-specific increase in both the level and spatial domain of Agouti expression prevents melanocyte maturation in a regionalized manner, resulting in a novel and adaptive color pattern. Thus, natural selection favors late-acting, tissue-specific changes in embryonic Agouti expression to produce large changes in adult color pattern.
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DOI: 10.1126/science.1200684
, 1062 (2011);331 Science , et al.Marie Manceau
The Developmental Role of Agouti in Color Pattern Evolution
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and ARC-1057448). We thank J. Polston, First Chief of
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thank the Northern Land Use Research, Inc., for field
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Supporting Online Material
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SOM Text
Figs. S1 to S5
Table S1 and S2
References
13 December 2010; accepted 26 January 2011
10.1126/science.1201581
The Developmental Role of Agouti
in Color Pattern Evolution
Marie Manceau,
1,2
Vera S. Domingues,
1,2
Ricardo Mallarino,
1
Hopi E. Hoekstra
1,2
*
Animal color patterns can affect fitness in the wild; however, little is known about the mechanisms
that control their formation and subsequent evolution. We took advantage of two locally camouflaged
populations of Peromyscus mice to show that the negative regulator of adult pigmentation, Agouti,
also plays a key developmental role in color pattern evolution. Genetic and functional analyses
showed that ventral-specific embryonic expression of Agouti establishes a prepattern by delaying
the terminal differentiation of ventral melanocytes. Moreover, a skin-specific increase in both
the level and spatial domain of Agouti expression prevents melanocyte maturation in a regionalized
manner, resulting in a novel and adaptive color pattern. Thus, natural selection favors late-acting,
tissue-specific changes in embryonic Agouti expression to produce large changes in adult color pattern.
Variation in pigment type (i.e., color) and
distribution (i.e., color pattern) can have
a profound impact on the fitness of or-
ganisms in the wild (1). In vertebrates, several
genes involved in pigment type switching (2,3)
and those necessary for proper pigment pattern-
inginmice(4,5)andfish(4,6,7) have been de-
scribed; however, such work has focused on
laboratory mutants rather than natural variation.
Therefore, the molecular factors responsible for
color pattern formation and evolution (i.e., the genes
and developmental processes targeted by selec-
tion) remain poorly understood in wild vertebrates.
We took advantage of the striking color pat-
tern variation in natural populations of deer mice
(genus Peromyscus). Mainland mice (P. polionotus
subgriseus) inhabit oldfields with dark soil and
have the most common color pattern observed in
vertebrates: a dark dorsum and light ventrum
1
Department of Organismic and Evolutionary Biology,
Harvard University, Cambridge, MA 02138, USA.
2
Museum
of Comparative Zoology, Harvard University, Cambridge,
MA 02138, USA.
*To whom correspondence should be addressed. E-mail:
hoekstra@oeb.harvard.edu
Fig. 1. (Aand B) Mainland
and beach mice differ in coat
color pattern, which provides
camouflage in their respec-
tive habitats (inset shows lo-
calsoilsample).(Cand D)
Position of the boundary
between the dorsal region,
comprising banded and black
hairs, and ventral region, com-
prising bicolored or white
hairs, in mainland and beach
mice (black dashed lines).
DM, dorsal midline; n=5
for each subspecies. Error bars
indicate SEM. (Eand F)The
position of the dorsoventral
boundary is established be-
fore birth (1-day-old pups).
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(Fig. 1A). Beach mice (P. p. leucocephalus), which
have recently colonized the light-colored sand
dunes of Floridas Gulf Coast, have evolved adap t-
ive differences in color (i.e., lighter overall pigmen-
tation) and pattern (i.e., absence of pigmentation
on the face, flanks, and tail) relative to their main-
land ancestors (Fig. 1B) (8,9).
We characterized these differences in adult
pigment pattern of mainland and beach mouse
subspecies by classifying hair into four distinct
types according to the distribution of pigments
along individual hairs and quantifying the pro-
portion of each type along the dorsoventral axis
(10). Although both subspecies have all types of
hair, their distribution differs: The dorsal region,
which has black and banded hairs, is reduced in
beach mice (i.e., the dorsoventral boundary is
shifted upward) and the hairs in their ventral re-
gion entirely lack pigments, whereas mainland
mice have bicolored ventral hairs (i.e., melanic base,
unpigmented tip) (Fig. 1, C and D). These sub-
specific differences in pigment pattern are visible at
birth (Fig. 1, E and F), which indicates that they
are established during embryonic development.
Mutations in three genetic loci explain most
of the pigment variation in adult pelage between
beach and mainland mice (11). We focused on
the locus containing the candidate pigmentation
gene Agouti because in laboratory mice, ventral
Agouti expression is necessary for the establish-
ment of dorsoventral differences in pigmentation
(5,1214). Although the developmental mech-
anism through which Agouti acts to establish these
color differences remains unclear, it may contrib-
ute to color pattern evolution in natural populations.
We used a genetic approach to confirm that
Agouti is a causal gene responsible for color
pattern differences between beach and mainland
mice (Fig. 2A and fig. S1) (10). Because there
were no differences in Agouti protein sequence
between beach and mainland mice (11), we mea-
sured the allele-specific expression of Agouti in
the two tissues, skin and testis, where it is ex-
pressed in Mus (15). We found that Agouti ex-
pression is higher in the ventral skin of beach
mice relative to mainland mice (Fig. 2B). In F
1
hybrids, the beach mouse (light) allele shows
significantly higher expression than the mainland
(dark) allele (factor of ~17, P= 0.01, one-tailed
Studentsttest; Fig. 2B). This expression level
difference is replicated but smaller in dorsal skin
(factor of ~4, P= 0.015, one-tailed Studentst
test; fig. S2). By contrast, no Agouti expression
differences were detected in the testes (Fig. 2C).
These data show that mutation(s) in Agouti are
cis-acting and likely involve a skin-specific reg-
ulatory element.
To determine the specific effects of these
Agouti expression differences on color pattern,
we generated Peromyscus individuals homozy-
gous for the light allele of Agouti (Agouti LL)and
dark alleles at the two other implicated pigment
loci (10). Adult Agouti LL mice displayed both
an upward shift in the dorsoventral boundary and
white ventral hairs (Fig. 2, D and E, and fig. S2),
thereby partly recapitulating the derived color pat-
tern of wild beach mice. Because these differences
are apparent at birth (fig. S2), changes in Agouti
expression pattern contribute to changes in pig-
ment pattern through developmental modifications.
We next described typical stages of Pero-
myscus development (fig. S3) and compared
the embryonic expression patterns of dark and
light Agouti alleles. In embryos from mainland
mice, Agoutis expression was restricted to the
ventral half of the dermis in early developmental
stages (Fig. 3, A and B) and to the ventral dermis
and hair follicles at fetal stages (Fig. 3, C and D).
Thus, Agoutis expression domain is tightly cor-
related with the light-colored ventrum in adult
skin. This suggests that the color pattern is spa-
tially determined early in embryonic development
by a prepattern established by Agouti.Bycom-
parison, in Agouti LL embryos, the ventral expres-
sion of Agouti showed an upward shift (Fig. 3F)
that corresponds to the dorsal displacement of
the pigment boundary observed in adult mice. In
Fig. 2. (A) Fine-scale mapping of the causal locus in Peromyscus by quantitative trait loci (QTL) (left) and
recombinant breakpoint analyses (right). (Band C) Quantitative polymerase chain reaction (qPCR)
analyses of Agouti mainland (dark) and beach (light) allele transcript levels in the ventral skin and testes
of mainland mice, beach mice, and their F
1
hybrids (n= 3 to 6 for each strain) (2^ct is the inferred
difference in transcript level of Agouti relative to the control gene b-actin). (D)Coatcolorpatternof
Agouti LL mice. (E) Pigment of ventral hairs and position of dorsoventral (DV) boundary in mainland,
beach, and Agouti LL mice. DM, dorsal midline; n= 5 for each strain. Error bars indicate SEM.
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addition, ventral Agouti expression was significant-
ly higher in Agouti LL than in mainland embryos
[by a factor of ~4.9 at embryonic day 12 (E12) and
by a factor of ~4.4 at E14, P=0.03andP=0.003,
respectively; one-tailed Studentsttests] (Fig. 3, I
and J); these differences were allele-specific
(fig. S2) and correlated with the presence or ab-
sence of adult pigmentation in the ventrum.
These findings suggest that modifications in the
embryonicprepattern defined by Agouti contrib-
ute to color pattern evolution in beach mice.
In vitro studies suggested that Agouti may
also cause melanocyte dedifferentiation by down-
regulating pigment cellspecific genes (1618).
We tested how Agouti expression changes af-
fected melanocyte behavior in vivo by comparing
the distribution and maturation of melanocytes
during Peromyscus embryogenesis. We used
Trp2 (also known as Dct) and Trp1, two enzymes
consecutively expressed in melanocytes during
both their migration in the dermis and maturation
in hair follicles, as markers of early and late
differentiation, respectively (19). In both main-
land and Agouti LL E14 embryos, Trp2
+
melano-
cytes had colonized the entire embryonic dermis
(fig. S4), which demonstrates that the formation
of dorsoventral color differences and the evolu-
tion of the novel color pattern are not caused by
changes in melanocyte migration. By contrast,
fully differentiated (Trp1
+
) melanocytes were re-
stricted to a dorsal region complementary to the
ventral domain of Agouti expression (Fig. 3, K
and L, and fig. S5), which suggests that their
distribution early in development is restricted by
the extent of Agouti expression.
During late fetal stages, Trp2
+
cells success-
fully colonized hair follicles in the dorsum, but in
the ventrum they were confined to the dermis
(fig. S4) and were fewer in number and prolif-
erated less (fig. S6); therefore, melanocyte dif-
ferentiation and proliferation were impaired in
this region. Dorsal Trp1
+
melanocyte behavior
in Agouti LL fetuses was similar to that observed
in mainland mice (Fig. 3, M and O). However, in
the ventrum, Trp1
+
melanocytes were present but
did not reach the epidermal compartment or hair
follicles, as they did in mainland fetuses (Fig. 3,
N and P), and thus remained similar in distribu-
tion to less mature (Trp2
+
) melanocytes (fig. S4).
These results suggest that increased ventral ex-
pression levels of Agouti repress the terminal
differentiation of ventral melanocytes and their
colonization into the epidermis, and that this is
the developmental mechanism by which the
absence of pigmentation in the beach mouse
ventrum and flanks evolved.
To functionally test Agoutis embryonic role
in vivo,we took advantage of a natural strain of
Peromyscus (non-Agouti,NA) in which a large
deletionintheAgouti locus results in a loss of
function (20). NA mice, as in Mus musculus
Agouti mutants (21), displayed no visible pat-
terning, with a homogeneously black color (Fig.
4A) present at birth (Fig. 4B). This observation
confirms that Agouti is necessary for establishing
color pattern in Peromyscus. The melanocytes in
NA embryos expressed both Trp2 and Trp1 in the
ventral dermis (Fig. 4D and fig. S7), and, at fetal
stages, Trp1
+
cells localized in the hair follicles
(Fig. 4F) to produce pigments (fig. S8) similar to
dorsal melanocytes (Fig. 4E), whereas Trp2 ex-
pression was no longer detectable (fig. S7). These
results, consistent with previous in vitro studies
(17,18), clearly demonstrate in vivo that Agouti
represses the terminal maturation of Trp1
+
/Trp2
+
melanocytes in the ventral embryonic skin.
To further understand Agoutis function during
development, we used ultrasound-assisted retro-
viral infection in utero to ectopically express
Agouti in the hair follicles of mainland embryos
(22). Embryos collected 10 days after injection
Fig. 3. (Ato H) In situ hybridization against Agouti in mainland (top) and Agouti LL (bottom)
embryos. Agouti expression is shown at E12 and E14 in the dermis of embryos; arrowheads
indicate the dorsal limit of Agouti expression in mainland (brown) and Agouti LL (orange)
embryos. Tissue sections show Agouti expression in the ventral and dorsal skin and hair follicles of
E22 fetuses. Enlargements correspond to the areas outlined by rectangles. (Iand J)Relative
Agouti transcript levels at E12 and E14 in the dorsal and ventral regions of mainland and Agouti
LL embryos quantified by qPCR. (Kto P) Distribution of melanocytes (arrowheads) stained with
antibody to Trp1 (in white) along the dorsoventral axis in transverse sections at E14 (schemes
based on embryos in fig. S5) and E22 relative to the future position of the dorsoventral pigment boundary (dotted lines). (Qand R) Relative proportions of Trp1
+
melanocytes within the dermal or the epidermal compartments at E22. Error bars indicate SEM. nt, neural tube; n, notochord; end, endoderm; ect,
ectoderm; d, dermis; ep, epidermis.
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(10) displayed a robust ectopic expression of
Agouti in all neural-derived GFP
+
(green fluo-
rescent proteinpositive) cell lineages, including
melanocytes and epidermal cells of the hair
follicle wall (Fig. 4, G to L). GFP
+
melanocytes
were detected in both the dorsal and ventral
parts of the fetal skin (Fig. 4,G and J), con-
firming that Agouti does not interfere with dorsal-
ventral melanocyte migration. In the dorsum,
many Trp1
+
melanocytes were present in hair
follicles infected with viruses containing control
GFP only (Fig. 4, H and O), whereas their
numbers decreased in mice infected with the
virus expressing Agouti (Fig. 4, K to O). This
finding confirms that higher expression of Agouti
prevents melanocytes from undergoing terminal
differentiation in the epidermis.
Our results indicate that the level and extent
of Agouti expression during development affects
adult color pattern by modulating the degree of
repression of a terminal step in melanocyte dif-
ferentiation. In mainland mice, where Agouti is
expressed at low levels in the ventrum, ventral
melanocyte differentiation is delayed, which leads
to the formation of partially pigmented (bicolored)
hairs (fig. S8). In beach mice, changes in Agouti
expression contribute to the evolution of their
novel and adaptive color pattern. Specifically, in
Agouti LL individuals, the expression of Agouti
in a new spatial domain causes an upward shift in
the pigment boundary, and an increase in its ex-
pression level completely prevents ventral melano-
cyte maturation, leading to an absence of pigment
production in ventral hairs.
Although Agoutis role in adult pigmentation
and its pleiotropic effects on obesity (2,3,23)have
been well described, our study has identified a de-
velopmental mechanism through which the region-
specific expression of Agouti controls the distribution
of pigments across the body. Here, Agouti establishes
an embryonic prepattern that subsequently evolved
through skin-specific changes to Agouti expression,
whichinturnaffectthelatestagesofpigmentcell
differentiation, thereby minimizing pleiotropy in
two ways. Because some minimally pleiotropic
developmental loci might constitute hotspots
for morphological evolution (2427), one may
speculate that even small changes in Agouti ex-
pression during embryogenesis contribute to the
establishment of more complex vertebrate pig-
ment patterns.
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A. Abzhanov, and C. Tabin for technical assistance; G. Barsh
for helpful discussions; V. Hearing for antibodies to
Trp1/Trp2; and C. Desplan, C. Tabin, A. Abzhanov,
C. Linnen, and J. Gros for comments on the manuscript. In
situ hybridizations on sections and in utero injections were
conducted in the Abzhanov and Tabin/Cepko laboratories,
respectively. Supported by the Portuguese Foundation
for Science and Technology (V.S.D.) and by NSF grant
DEB-0919190 (H.E.H.).
Supporting Online Material
www.sciencemag.org/cgi/content/full/331/6020/1062/DC1
Materials and Methods
Figs. S1 to S8
Tables S1 and S2
References
19 November 2010; accepted 25 January 2011
10.1126/science.1200684
Fig. 4. (A) Adult non-Agouti (NA) Peromyscus mice have a homogeneously
black coat. (B) Lack of dorsoventral color difference is visible at birth. (Cto F)
Dorsal and ventral views of NA skins at E14 and E22 stained with a Trp1
antibody (arrowheads). (Gto L) Transgenic expression of murine leukemia
retroviruses (MLVs) coding for the nuclear GFP-only or the Peromyscus Agouti
gene with the nuclear GFP are shown in whole-mount embryos or transverse
views of dorsal GFP
+
hair follicles stained with GFP (in green) and Trp1 (in red).
In (I) and (L), robust ectopic expression of Agouti is detected in dorsal hair
follicles infected with the GFP/Agouti virus but is absent from the control, GFP
+
,
dorsal hair follicles. (Mand N) Dorsal and ventral hair follicles (stained with the
nuclei marker Dapi in blue) containing typical numbers of Trp1
+
melanocytes (in
green). (O)PercentageofGFP
+
hair follicles (HF) containing 0, 1, 2, or >3 Trp1
+
cells for the control (left) and the GFP/Agouti (right) viruses. d, dermis; ep,
epidermis.
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... Color patterns like the orange blotch of guppies, the stripes of zebras, and the eyespots on peacock's tails result from regional differences in number and properties of pigment cells and in synthesis and deposition of pigments. For instance, several studies revealed that regulatory variation in Agouti signaling protein (Asip/asip1, gene name in tetrapods/teleosts), a member from Agouti gene family that can inhibit Mc1r activity, is underlay changes in dorsa-ventral patterning of vertebrates by inhibiting melanin synthesis and/or decreasing melanophore number in ventral areas (Manceau et al. 2011, Linnen et al. 2013, Ceinos et al. 2015. On the other hand, Asip has been also linked to stripe-interstripe patterning in rodent and galliform, where high expression in the light areas between melanic stripes might locally inhibit dark pigmentation and thereby shaping the pattern (Mallarino et al. 2016, Haupaix et al. 2018. ...
... Chapter III of this thesis focusing on the evolutionary history of Agouti gene family, a notable gene family that plays crucial roles in the evolution of vertebrate color patterns (Manceau et al. 2011, Haupaix et al. 2018, Kratochwil et al. 2018. By comparing the gene expression between and within species, Chapter III demonstrates the functional conservation and divergence of the Agouti gene family facilitated the evolution of color patterns in teleost fishes. ...
... The teleost-specific agrp2 (Fig. S.I.3) is a strong candidate gene for stripes because its paralogs have been previously associated with pigmentation phenotypes (Zhang et al. 2010, Manceau et al. 2011, Ceinos et al. 2015. To test for agrp2 expression differences between nonstriped (Pnye) and striped (Hsau) Lake Victoria cichlids, we performed quantitative polymerase chain reaction (qPCR; Fig. I.2D and Fig. S.I.5) on a number of adult tissues, including skin (supplementary text). ...
... Beach mouse subspecies on Florida's Gulf and Atlantic coasts have independently evolved light coloration from a dark-colored mainland ancestor (21). Previous work identified three genomic regions involved in differences between Gulf coast beach mice and mainland mice (22), in which two pigment genes have thus far been implicated: the Melanocortin-1 receptor [Mc1r (19)] and the Agouti signaling protein [ASIP (23)]. The interaction between Mc1r and Agouti mediates the switch from dark (eumelanin) to light pigment (pheomelanin) production in mammals (24)(25)(26). ...
... We then inserted this sequence upstream of a minimal promoter and lacZ reporter gene (Fig. 4C). Given the currently limited transgenic techniques available for Peromyscus, the resulting construct was injected into embryos of Mus (strain FVB/NJ), and embryos were collected at embryonic stage (E) 14.5, a time point when Agouti expression plays a key role in the establishment of pigment prepatterns in both Mus and Peromyscus (23). Of the 14 embryos with independent genomic integrations of the lacZ construct (verified by PCR), we observed consistent lacZ expression in the skin of eight embryos, although expression was spatially variable across embryos ( Fig. 4D and SI Appendix, Fig. S5). ...
Article
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Identifying the genetic basis of repeatedly evolved traits provides a way to reconstruct their evolutionary history and ultimately investigate the predictability of evolution. Here, we focus on the oldfield mouse ( Peromyscus polionotus ), which occurs in the southeastern United States, where it exhibits considerable color variation. Dorsal coats range from dark brown in mainland mice to near white in mice inhabiting sandy beaches; this light pelage has evolved independently on Florida’s Gulf and Atlantic coasts as camouflage from predators. To facilitate genomic analyses, we first generated a chromosome-level genome assembly of Peromyscus polionotus subgriseus . Next, in a uniquely variable mainland population ( Peromyscus polionotus albifrons ), we scored 23 pigment traits and performed targeted resequencing in 168 mice. We find that pigment variation is strongly associated with an ∼2-kb region ∼5 kb upstream of the Agouti signaling protein coding region. Using a reporter-gene assay, we demonstrate that this regulatory region contains an enhancer that drives expression in the dermis of mouse embryos during the establishment of pigment prepatterns. Moreover, extended tracts of homozygosity in this Agouti region indicate that the light allele experienced recent and strong positive selection. Notably, this same light allele appears fixed in both Gulf and Atlantic coast beach mice, despite these populations being separated by >1,000 km. Together, our results suggest that this identified Agouti enhancer allele has been maintained in mainland populations as standing genetic variation and from there, has spread to and been selected in two independent beach mouse lineages, thereby facilitating their rapid and parallel evolution.
... These results support the hypothesis that divergent natural selection is acting on cis mechanisms that regulate ecomorph-specific shifts in gene expression and transcriptional modification in Lake Masoko A. calliptera. More specifically, given that cis regulatory changes accumulate preferentially over time 29,31,32,[75][76][77] , and that cisregulatory divergence is shown to increase linearly with divergence time 78 , the high levels of cis-regulatory divergence observed here in such a young species pair (less than 1,000 years old) suggests that cis-mechanisms are a major driver of radiation within this cichlid lineage. ...
... We found that 728 (10%) of the genes exhibiting divergent expression regimes between benthic and littoral ecomorphs were regulated by at least one expression or splicing cis-regulatory QTL (Fig. 3). Given that cis regulatory changes accumulate preferentially over time 29,31,32,[75][76][77] , and that cis-regulatory divergence is shown to increase linearly with divergence time 78 , the high levels of cisregulatory divergence observed here in such a young species pair suggests that cismechanisms are a major driver of radiation within this cichlid lineage. Moreover, we found that both expression and splicing cis-regulatory variants were associated with more highly differentiated genomic regions, implicating cis mechanisms as important targets of natural selection during the early stages of ecological speciation. ...
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Rapid ecological speciation along depth gradients has taken place independently and repeatedly in freshwater fishes. While the extent of genomic divergence between ecomorphs is often well understood, the molecular mechanisms facilitating such rapid diversification are typically unclear. In Lake Masoko, an East African crater lake, the cichlid Astatotilapia calliptera has diverged into shallow littoral and deep benthic ecomorphs with strikingly different jaw structures within the last 1,000 years. Using genome-wide transcriptome data from jaw tissue, we explore two major regulatory transcriptional mechanisms, expression and splicing QTL variants and examine their contribution to differential gene expression underpinning functional phenotypes. We identified 7,550 genes with significant differential expression between ecomorphs, of which 4.2% were regulated by cis-regulatory expression QTLs, and 6.4% were regulated by cis-regulatory splicing QTLs. There were also strong signals of divergent selection of differentially expressed genes that showed divergent regulation from expression, splicing or both QTL variants, including genes associated with major jaw plasticity and adaptation networks, adaptive immune system response, and oxidoreductase processes. These results suggest that transcriptome plasticity and modification have important roles during early-stage ecological speciation and demonstrate the role of regulatory-variants as important targets of selection driving ecologically-relevant divergence in gene expression that is associated with adaptive diversification.
... The number of caudal vertebrae is established in utero (Fig. S5). Therefore, to aid in the prioritization of potentially causative genes and to better understand the developmental pathways likely to be important in establishing the vertebra number difference between these ecotypes, we first performed RNA-seq on tail bud tissue spanning the period in which tail somites are forming ("early", E12.5 to "late", E15.5, which correspond to E10.5 and E13.5 in Mus musculus; Theiler 1989, Manceau et al. 2011, Davis & Keisler 2016 to identify genes that are differentially expressed, even at low levels, between ecotypes (forest, n = 18; prairie, n = 17). In a multidimensional scaling analysis, these samples clustered strongly both by ecotype (forest/prairie) and by stage (early/late tail segmentation) (Fig. S6A). ...
... from each ecotype. Because Peromyscus mice experience postpartum estrus (Dewsbury 1979), we set the date of conception as the birth date of a female's last litter and then confirmed these ages using a developmental time series of Peromyscus (Manceau et al. 2011, Davis & Keisler 2016. ...
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Variation in the size and number of axial segments underlies much of the diversity in animal body plans. Here, we investigate the evolutionary, genetic, and developmental mechanisms driving tail-length differences between forest and prairie ecotypes of deer mice ( Peromyscus maniculatus ). We first show that long-tailed forest mice perform better in an arboreal locomotion assay, consistent with tails being important for balance during climbing. The long tails of these forest mice consist of both longer and more caudal vertebrae than prairie mice. Using quantitative genetics, we identify six genomic regions that contribute to differences in total tail length, three of which associate with vertebra length and the other three with vertebra number. For all six loci, the forest allele increases tail length, consistent with the cumulative effect of natural selection. Two of the genomic regions associated with variation in vertebra number contain Hox gene clusters. Of those, we find an allele-specific decrease in Hoxd13 expression in the embryonic tail bud of long-tailed forest mice, consistent with its role in axial elongation. Additionally, we find that forest embryos have more presomitic mesoderm than prairie embryos, and that this correlates with an increase in the number of neuromesodermal progenitors (NMPs), which are modulated by Hox13 paralogs. Together, these results suggest a role for Hoxd13 in the development of natural variation in adaptive morphology on a microevolutionary timescale. HIGHLIGHTS In deer mice, the long-tailed forest ecotype outperforms the short-tailed prairie ecotype in climbing, consistent with the tail’s role in balance. Long tails are due to mutations on distinct chromosomes that affect either length or number of caudal vertebrae. QTL mapping identifies Hox clusters, one gene of which – Hoxd13 – shows low allele-specific expression in the embryonic tail bud of forest mice. Forest mouse embryos have a larger presomitic mesoderm (PSM), likely mediated by a larger progenitor population (NMPs) and lower Hoxd13 levels.
... Beach mouse subspecies on Florida's Gulf and Atlantic coasts have independently evolved light coloration from a dark-colored mainland ancestor (21). Previous work identified three genomic regions involved in differences between Gulf coast beach mice and mainland mice (22), in which two pigment genes have thus far been implicated: the Melanocortin-1 receptor [Mc1r (19)] and the Agouti signaling protein [ASIP (23)]. The interaction between Mc1r and Agouti mediates the switch from dark (eumelanin) to light pigment (pheomelanin) production in mammals (24)(25)(26). ...
... We then inserted this sequence upstream of a minimal promoter and lacZ reporter gene (Fig. 4C). Given the currently limited transgenic techniques available for Peromyscus, the resulting construct was injected into embryos of Mus (strain FVB/NJ), and embryos were collected at embryonic stage (E) 14.5, a time point when Agouti expression plays a key role in the establishment of pigment prepatterns in both Mus and Peromyscus (23). Of the 14 embryos with independent genomic integrations of the lacZ construct (verified by PCR), we observed consistent lacZ expression in the skin of eight embryos, although expression was spatially variable across embryos ( Fig. 4D and SI Appendix, Fig. S5). ...
Preprint
Identifying the genetic basis of repeatedly evolved traits provides a way to reconstruct their evolutionary history and ultimately investigate the predictability of evolution. Here, we focus on the oldfield mouse (Peromyscus polionotus), which occurs in the southeastern United States, where it exhibits considerable coat-color variation. Dorsal coats range from dark brown in mice inhabiting mainland habitat to near white on the white-sand beaches of the southeastern US, where light pelage has evolved independently on Florida's Gulf and Atlantic coasts as an adaptation to visually hunting predators. To facilitate genomic analyses in this species, we first generated a high-quality, chromosome-level genome assembly of P. polionotus subgriseus. Next, in a uniquely variable mainland population that occurs near beach habitat (P. p. albifrons), we scored 23 pigment traits and performed targeted resequencing in 168 mice. We find that variation in pigmentation is strongly associated with a ~2 kb region approximately 5 kb upstream of the Agouti-signaling protein (ASIP) coding region. Using a reporter-gene assay, we demonstrate that this regulatory region contains an enhancer that drives expression in the dermis of mouse embryos during the establishment of pigment prepatterns. Moreover, extended tracts of homozygosity in this region of Agouti indicate that the light allele has experienced recent and strong positive selection. Notably, this same light allele appears fixed in both Gulf and Atlantic coast beach mice, despite these populations being separated by >1,000km. Given the evolutionary history of this species, our results suggest that this newly identified Agouti enhancer allele has been maintained in mainland populations as standing genetic variation and from there has spread to, and been selected in, two independent beach mouse lineages, thereby facilitating their rapid and parallel evolution.
... Likewise, beach mice match their surroundings through a lighter shade and color primarily on the back. This adaptation is mediated by changes in the level and pattern of Agouti expression within NCC derived cells, which alters the distribution and maturation of melanocytes [126], and a single amino acid change in Mc1r that decreases eumelanin biosynthesis [127]. ...
Article
Vertebrates have some of the most complex and diverse features in animals, from varied craniofacial morphologies to colorful pigmentation patterns and elaborate social behaviors. All of these traits have their developmental origins in a multipotent embryonic lineage of neural crest cells. This “fourth germ layer” is a vertebrate innovation and the source of a wide range of adult cell types. While others have discussed the role of neural crest cells in human disease and animal domestication, less is known about their role in contributing to adaptive changes in wild populations. Here, we review how variation in the development of neural crest cells and their derivatives generates considerable phenotypic diversity in nature. We focus on the broad span of traits under natural and sexual selection whose variation may originate in the neural crest, with emphasis on behavioral factors such as intraspecies communication that are often overlooked. In all, we encourage the integration of evolutionary ecology with developmental biology and molecular genetics to gain a more complete understanding of the role of this single cell type in trait covariation, evolutionary trajectories, and vertebrate diversity.
... Mundy and Kelly suggested that mutations in ASIP coding region were not involved in color changes among closely related primate species 32 . Allele-specific expression of ASIP in body part has been found to be responsible for color pattern differences in mice 33 . We speculate that expression and regulatory differences at ASIP might play an important role in pattern variation in Sulawesi macaques. ...
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Coat color is often highly variable within and between animal taxa. Among hundreds of pigmentation-related genes, melanocortin-1 receptor (MC1R) plays key roles in regulating the synthesis of the dark eumelanin and the red–yellow pheomelanin. The six species of macaques that inhabit Sulawesi Island diverged rapidly from their common ancestor, M. nemestrina. Unlike most macaques, Sulawesi macaques commonly have a dark coat color, with divergence in shade and color pattern. To clarify the genetic and evolutionary basis for coat color in Sulawesi macaques, we investigated the MC1R sequences and functional properties, including basal cAMP production and α-MSH-induced activity in vitro. We found fixed non-synonymous substitutions in MC1R in each species. Furthermore, we found that six species-specific variants corresponded with variation in agonist-induced and basal activity of MC1R. Inconsistent with the dark coat color, four substitutions independently caused decreases in the basal activity of MC1R in M. hecki, M. nigra, M. tonkeana, and M. ochreata. Selective analysis suggested MC1R of M. nigra and M. nigrescens underwent purifying selection. Overall, our results suggest that fixed differences in MC1R resulted in different functional characteristics and might contribute to divergence in color among the six Sulawesi macaque species.
... Genetic analyses indicate that corin is a suppressor of the agouti pathway in coat color specification, and that this function requires the protease activity of corin [45,75]. Consistently, Corin has been identified as one of the three major pigmentation genes in beach mice in the Gulf and Atlantic Coasts of the United States [76]. ...
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Atrial natriuretic peptide (ANP) is a crucial element of the cardiac endocrine function that promotes natriuresis, diuresis, and vasodilation, thereby protecting normal blood pressure and cardiac function. Corin is a type II transmembrane serine protease that is highly expressed in the heart, where it converts the ANP precursor to mature ANP. Corin deficiency prevents ANP activation and causes hypertension and heart disease. In addition to the heart, corin is expressed in other tissues, including those of the kidney, skin, and uterus, where corin-mediated ANP production and signaling act locally to promote sodium excretion and vascular remodeling. These results indicate that corin and ANP function in many tissues via endocrine and autocrine mechanisms. In heart failure patients, impaired natriuretic peptide processing is a common pathological mechanism that contributes to sodium and body fluid retention. In this review, we discuss most recent findings regarding the role of corin in non-cardiac tissues, including the kidney and skin, in regulating sodium homeostasis and body fluid excretion. Moreover, we describe the molecular mechanisms underlying corin and ANP function in supporting orderly cellular events in uterine spiral artery remodeling. Finally, we assess the potential of corin-based approaches to enhance natriuretic peptide production and activity as a treatment of heart failure.
Article
Whole tissue RNASeq is the standard approach for studying gene expression divergence in evolutionary biology and provides a snapshot of the comprehensive transcriptome for a given tissue. However, whole tissues consist of diverse cell types differing in expression profiles, and the cellular composition of these tissues can evolve across species. Here, we investigate the effects of different cellular composition on whole tissue expression profiles. We compared gene expression from whole testes and enriched spermatogenesis populations in two species of house mice, Mus musculus musculus and M. m. domesticus, and their sterile and fertile F1 hybrids, which differ in both cellular composition and regulatory dynamics. We found that cellular composition differences skewed expression profiles and differential gene expression in whole testes samples. Importantly, both approaches were able to detect large-scale patterns such as disrupted X chromosome expression although whole testes sampling resulted in decreased power to detect differentially expressed genes. We encourage researchers to account for histology in RNASeq and consider methods that reduce sample complexity whenever feasible. Ultimately, we show that differences in cellular composition between tissues can modify expression profiles, potentially altering inferred gene ontological processes, insights into gene network evolution, and processes governing gene expression evolution. This article is protected by copyright. All rights reserved
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Unusual behavior has been noted in Paramisgurnus dabryanus loaches, which have been seen to float on the water, both on aquafarms and laboratories. Animal behavior usually reflects adaptation to the environment, but this “floating” behavior undoubtedly increases the risk of being predated. In order to understand the ecological significance, we first studied the basic characteristics of this behavior. The floating loaches showed five typical characteristics: (1) They floated more at night than during the day, (2) They mainly floated for a short time (< 30 s), (3) The gill respiration frequency decreased significantly (P < 0.05), (4) The proportion of floating fish gradually increased with water temperature (P < 0.05), (5) Juvenile P.dabryanus floated for the first time approximately 14 dph, which coincided with the period when the intestine tract penetrated through and they began to breathe with it.
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To examine the effects of coat-color genes on the proliferation and differentiation of mouse epidermal melanocytes, we cultured epidermal, cell suspensions derived from neonatal skins of C57BL/10JHir (black) and its congenic mice carrying agouti, brown, albino, dilute, and pink-eyed dilution genes in a serum-free medium supplemented with dibutyryl adenosine 3',5'-cyclic monophosphate. The proliferative rates of agouti, brown and dilute black melanocytes were similar to that of black melanocytes, while those of albino and pink-eyed black melanocytes were about one-half of that of black melanocytes. The morphology of albino and pink-eyed black melanocytes, though nonpigmented, was similar to black melanocytes; namely, dendritic, polygonal or epithelioid. Dilute black melanocytes also possessed the similar morphology, whereas their melanosomes were accumulated in the perinuclear region. Dopa-melanin depositions after dopa reaction in brown and dilute black melanocytes were greater than in black and agouti melanocytes. Although dopa-melanin depositions were not observed in albino melanocytes, about 8% of pink-eyed black melanocytes were positive to dopa reaction. Silver depositions after combined dopa-premelanin reaction in agouti, brown and dilute black melanocytes were similar to that in black melanocytes. Although albino melanocytes were devoid of silver depositions, about 25% of pink-eyed black melanocytes were positive to the reaction. Pyrrole-2,3,5-tricarboxylic acid (PTCA, degradation product of eumelanin) contents in agouti and dilute black melanocytes were slightly lower than in black melanocytes, while that in brown melanocytes was reduced to one-third. In contrast, PTCA contents in albino and pink-eyed black melanocytes were reduced to less than 0.5%. Aminohydroxyphenylalanine (AHP, degradation product of pheomelanin) contents did not differ among these melanocytes. These results suggest that the coat-color genes exert their influences on the proliferation and differentiation of mouse epidermal melanocytes by affecting tyrosinase activity, melanosome maturation and transport, and eumelanin synthesis.
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Convergence--the independent evolution of the same trait by two or more taxa--has long been of interest to evolutionary biologists, but only recently has the molecular basis of phenotypic convergence been identified. Here, we highlight studies of rapid evolution of cryptic coloration in vertebrates to demonstrate that phenotypic convergence can occur at multiple levels: mutations, genes and gene function. We first show that different genes can be responsible for convergent phenotypes even among closely related populations, for example, in the pale beach mice inhabiting Florida's Gulf and Atlantic coasts. By contrast, the exact same mutation can create similar phenotypes in distantly related species such as mice and mammoths. Next, we show that different mutations in the same gene need not be functionally equivalent to produce similar phenotypes. For example, separate mutations produce divergent protein function but convergent pale coloration in two lizard species. Similarly, mutations that alter the expression of a gene in different ways can, nevertheless, result in similar phenotypes, as demonstrated by sister species of deer mice. Together these studies underscore the importance of identifying not only the genes, but also the precise mutations and their effects on protein function, that contribute to adaptation and highlight how convergence can occur at different genetic levels.
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The light color of mice that inhabit the sandy dunes of Florida's coast have served as a textbook example of adaptation for nearly a century, despite the fact that the selective advantage of crypsis has never been directly tested or quantified in nature. Using plasticine mouse models of light and dark color, we demonstrate a strong selective advantage for mice that match their local background substrate. Further our data suggest that stabilizing selection maintains color matching within a single habitat, as models that are both lighter and darker than their local environment are selected against. These results provide empirical evidence in support of the hypothesis that visual hunting predators shape color patterning in Peromyscus mice and suggest a mechanism by which selection drives the pronounced color variation among populations.
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Identifying the molecular basis of phenotypes that have evolved independently can provide insight into the ways genetic and developmental constraints influence the maintenance of phenotypic diversity. Melanic (darkly pigmented) phenotypes in mammals provide a potent system in which to study the genetic basis of naturally occurring mutant phenotypes because melanism occurs in many mammals, and the mammalian pigmentation pathway is well understood. Spontaneous alleles of a few key pigmentation loci are known to cause melanism in domestic or laboratory populations of mammals, but in natural populations, mutations at one gene, the melanocortin-1 receptor (Mc1r), have been implicated in the vast majority of cases, possibly due to its minimal pleiotropic effects. To investigate whether mutations in this or other genes cause melanism in the wild, we investigated the genetic basis of melanism in the rodent genus Peromyscus, in which melanic mice have been reported in several populations. We focused on two genes known to cause melanism in other taxa, Mc1r and its antagonist, the agouti signaling protein (Agouti). While variation in the Mc1r coding region does not correlate with melanism in any population, in a New Hampshire population, we find that a 125-kb deletion, which includes the upstream regulatory region and exons 1 and 2 of Agouti, results in a loss of Agouti expression and is perfectly associated with melanic color. In a second population from Alaska, we find that a premature stop codon in exon 3 of Agouti is associated with a similar melanic phenotype. These results show that melanism has evolved independently in these populations through mutations in the same gene, and suggest that melanism produced by mutations in genes other than Mc1r may be more common than previously thought.
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Ever since the integration of Mendelian genetics into evolutionary biology in the early 20th century, evolutionary geneticists have for the most part treated genes and mutations as generic entities. However, recent observations indicate that all genes are not equal in the eyes of evolution. Evolutionarily relevant mutations tend to accumulate in hotspot genes and at specific positions within genes. Genetic evolution is constrained by gene function, the structure of genetic networks, and population biology. The genetic basis of evolution may be predictable to some extent, and further understanding of this predictability requires incorporation of the specific functions and characteristics of genes into evolutionary theory.
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The melanocortin-1 receptor (MC1R) is a key regulator of pigmentation in mammals and is tightly linked to an increased risk of skin cancers, including melanoma, in humans. Physiologically activated by alpha-melanocyte stimulating hormone (alphaMSH), MC1R function can be antagonized by a secreted factor, agouti signal protein (ASP), which is responsible for the lighter phenotypes in mammals (including humans), and is also associated with increased risk of skin cancer. It is therefore of great interest to characterize the molecular effects elicited by those MC1R ligands. In this study, we determined the gene expression profiles of murine melan-a melanocytes treated with ASP or alphaMSH over a 4-day time course using genome-wide oligonucleotide microarrays. As expected, there were significant reductions in expression of numerous melanogenic proteins elicited by ASP, which correlates with its inhibition of pigmentation. ASP also unexpectedly modulated the expression of genes involved in various other cellular pathways, including glutathione synthesis and redox metabolism. Many genes up-regulated by ASP are involved in morphogenesis (especially in nervous system development), cell adhesion, and extracellular matrix-receptor interactions. Concomitantly, ASP enhanced the migratory potential and the invasiveness of melanocytic cells in vitro. These results demonstrate the role of ASP in the dedifferentiation of melanocytes, identify pigment-related genes targeted by ASP and by alphaMSH, and provide insights into the pleiotropic molecular effects of MC1R signaling that may function during development and may affect skin cancer risk.
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During the last Ice Age, a thousand-mile-wide land bridge connected Siberia and Alaska, creating the region known as Beringia. Over twelve thousand years ago, a procession of large mammals and the humans who hunted them crossed this bridge to America. Much of the Russian evidence for this migration has until now remained largely inaccessible to American scholars. American Beginnings brings together for the first time in one volume the most up-to-date archaeological and palaeoecological evidence on Beringia from both Russia and America. "An invaluable resource. . . . It will no doubt remain the key reference book for Beringia for many years to come."—Steven Mithen, Journal of Human Evolution "Extraordinary. The fifty-six contributors . . . represent the most prominent American and Russian researchers in the region."—Choice "Publication of this well-illustrated compendium is a great service to early American and especially Siberian Upper Paleolithic archaeology."—Nicholas Saunders, New Scientist "This is a great book . . . perhaps the greatest contribution to the archaeology of Beringia that has yet been published. . . . This is the kind of book to which archaeology should aspire."—Herbert D.G. Maschner, Antiquity
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Molecular genetic analysis of phenotypic variation has revealed many examples of evolutionary change in the developmental pathways that control plant and animal morphology. A major challenge is to integrate the information from diverse organisms and traits to understand the general patterns of developmental evolution. This integration can be facilitated by evolutionary metamodels-traits that have undergone multiple independent changes in different species and whose development is controlled by well-studied regulatory pathways. The metamodel approach provides the comparative equivalent of experimental replication, allowing us to test whether the evolution of each developmental pathway follows a consistent pattern, and whether different pathways are predisposed to different modes of evolution by their intrinsic organization. A review of several metamodels suggests that the structure of developmental pathways may bias the genetic basis of phenotypic evolution, and highlights phylogenetic replication as a value-added approach that produces deeper insights into the mechanisms of evolution than single-species analyses.