Genomic analysis of cichlid fish 'natural mutants'.

Abstract

In the lakes of East Africa, cichlid fishes have formed adaptive radiations that are each composed of hundreds of endemic, morphologically stunningly diverse, but genetically extremely similar species. In the past 20 years, it became clear that their extreme phenotypic diversity arose within very short time spans, and that phenotypically radically different species are exceptionally similar genetically; hence, they could be considered to be 'natural mutants'. Many species can be hybridized and, therefore, provide a unique opportunity to study the genetic underpinnings of phenotypic diversification. Comparative large-scale genomic analyses are beginning to unravel the patterns and processes that led to the formation of the cichlid species flocks. Cichlids are an emerging evolutionary genomic model system for fundamental questions on the origin of phenotypic diversity.

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Available online at www.sciencedirect.com
Genomic analysis of cichlid fish ‘natural mutants’
Shigehiro Kuraku and Axel Meyer
In the lakes of East Africa, cichlid fishes have formed adaptive
radiations that are each composed of hundreds of endemic,
morphologically stunningly diverse, but genetically extremely
similar species. In the past 20 years, it became clear that their
extreme phenotypic diversity arose within very short time
spans, and that phenotypically radically different species are
exceptionally similar genetically; hence, they could be
considered to be ‘natural mutants’. Many species can be
hybridized and, therefore, provide a unique opportunity to
study the genetic underpinnings of phenotypic diversification.
Comparative large-scale genomic analyses are beginning to
unravel the patterns and processes that led to the formation of
the cichlid species flocks. Cichlids are an emerging
evolutionary genomic model system for fundamental questions
on the origin of phenotypic diversity.
Address
Lehrstuhl fu ¨r Zoologie und Evolutionsbiologie, Department of Biology,
University of Konstanz, 78457 Konstanz, Germany
Corresponding author: Meyer, Axel (axel.meyer@uni-konstanz.de)
Current Opinion in Genetics & Development 2008, 18:551–558
This review comes from a themed issue on
Genomes and evolution
Edited by Sarah Teichmann and Nipam Patel
Available online 16th December 2008
0959-437X/$ – see front matter
# 2008 Elsevier Ltd. All rights reserved.
DOI 10.1016/j.gde.2008.11.002
Introduction
Cichlid fishes are one of the most well-known models in
evolutionary biology [1–4]. The adaptive radiations of
cichlids in East African lakes (Figure 1) are composed of
several hundred endemic species each that have diversi-
fied within extremely short time spans into phenotypi-
cally astonishingly diverse species flocks. In the case of
Lake Victoria, more than 500 species arose within less
than 100,000 years [5–7]. Since their discovery over 100
years ago, this exuberant diversity of cichlid fish species
swarms has peaked the interest of evolutionary biologist.
The diversity of this group of fishes is so much larger than
that of the other groups of fish that also inhabit the large
East African lakes that ecologists and evolutionary biol-
ogists alike soon began to ask by what evolutionary
mechanisms their diversity arose and how it can be
ecologically maintained. It was even suggested that these
fishes might be defying biological theory [8] and, hence,
their conspicuous diversity was dubbed the ‘cichlid pro-
blem’. Now, it would appear that the unusually diverse
cichlids might end up providing an unusually informative
system in which to study the genetic basis of adaptation
and phenotypic diversification, as well as parallel evol-
ution of phenotypes. The information obtained from the
cichlid system is likely to be of relevance for many groups
of organisms.
What are cichlids? Their phylogeny and
timescale
Cichlids are teleost fishes that belong to the family
Cichlidae. Recently, a molecular phylogenetic analysis
using whole mitochondrial DNA sequences suggested
close relationships of fishes of the families Pomacentridae
(damselfishes) and Embiotocidae (surfperches) with the
Cichlidae [9] (Figure 2). Among teleost species whose
genome sequence is available, medaka is the phyloge-
netic closest one to Cichlidae.
In contrast to relatively young age of the oldest fossil
cichlid (?45 Mya), recent molecular evidence suggests
thatcichlidsarearatherancientfamilythatprobablyhasa
Gondwanan origin [10–15]. Since cichlids are likely to be
well over 100 million years old (Figure 2), they probably
diverged into several ancient lineages quite some time
ago and their diversity might not be all that surprising.
Furthermore, not all lineages of cichlids are especially
species rich or have undergone explosive rates of specia-
tion, even those that are part of the species flock differ in
their speciation rates [16]. One lineage of cichlids clearly
dominates in terms of diversity: the haplochomine
cichlids. They are a rather young lineage of cichlids that
is only ?4 million years of age [17]. It arose as part of the
Lake Tanganyika cichlid species flock, was able to leave
theconfinesofthat lake andthen gaverisetothe adaptive
radiationsofbothLakes
[6,7,18,19] — they are entirely composed of the haplo-
chromine lineage of cichlids (Figure 3). Haplochromines
are the, by far, most species-rich lineage of cichlids with
more than 1800 species that belong to this group of
cichlids alone. This means that about 8% of all know
species of fish belong to this one lineage of cichlids.
MalawiandVictoria
As the case of the haplochromines shows, surely several
factors contribute to the species richness of cichlids. In
the case of the haplochromines factors such as the
habitat (cichlids thrive in lakes much more so than in
rivers), the evolutionof egg-spots on theanal fin in males
in conjunction with the evolution of a maternal mouth-
brooding mating system seems to have contributed to
their speciation and diversification [18,20??]. Maternal
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mouthbrooding limits the number of eggs a female can
incubate which in turn might limit the effective popu-
lation size of species and might thereby, in combination
with their small size and short generation times of these
cichlids, lead to an acceleration of speciation rates. Such
differences in phenotypic traits even among cichlid
lineages highlight which comparisons might be helpful
in determining the relative effects of those traits that
contributed to the diversification and speciation of
cichlids. Then it becomes particularly interesting and
potentially illuminating to investigate the genetic basis
of those phenotypic traits.
Why are there so many cichlids?
Severalkindsofkeyinnovationsthatonlycichlidspossess
have been suggested to provide at least part of the
explanation for their extraordinary evolutionary success.
One of these is their astonishingly precise adaptation to
particular food items and ecological niches. This is
achieved through a hugely flexible oral jaw and dentition
and the evolution of novel arrangements of their phar-
yngeal jaws. Through the combination of the flexibility of
the oral jaw morphology and dentition in combination
with their second jaw, it is assumed that cichlid fishes
have managed [21,22] to exploit many trophic resources
that other fish could not. Therefore, they have managed
to occupy many ecological niches that were not open to
other fish lineages.
But there are several other explanations that have been
offered to explain the evolutionary success of cichlids.
The apt German word for the family Cichlidae is Bunt-
barsch, which translates to colorful perch. The conspic-
uous coloration of cichlids, in many species even females
are almost as colorful as males, except in the haplochro-
mine cichlid lineage, where a pronounced sexual color
dimorphism exists in which females are drab and crypti-
cally colored and only the males show their beautiful
552
Genomes and evolution
Figure 1
Great lakes in East Africa. The map also shows the images of a cichlid species that is endemic to that particular lake.
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colors [18,20??]. In several species it could be shown that
females show preferences for particular color morphs of
males. This has led to the suggestion that sexual selection
in addition to more traditional types of mechanisms of
speciation such as ecological speciation might be one of
themajorforcesofdiversification.Therefore,researchhas
not only focused on studying the genes that underlie jaw
and tooth shape (e.g. [23]), but recent research has also
investigated genes responsible for color pigments and
patterns [24,25], as well as genes involved in vision such
as opsin genes [26??,27?], and gene possibly involved in
fertilization [28]. But, other sensory modalities such as
smellandsoundandbehavioraldifferencesareverylikely
to contribute to mate choice and speciation as well,
although, so far, they have not received as much attention
as genes involved in colorational differences (sender) and
visual pigment genes (receiver).
Other potential peculiarity of cichlid fishes that has been
suggested to contribute their diversity is their purported
propensity for hybridization [29]. Cichlids, possibly more
often than other organisms, might also speciate through
mechanisms other than allopatric speciation. In cichlids,
sympatric speciation has been reported more than once
andtheyareoneofthefewempiricalexampleswherethis
mode of speciation has been widely acknowledged to
occur, at least under certain environmental conditions
[30]. However, it seems safe to suggest that allopatric
speciation, because of the very patchy distribution of
species that are closely associated with particular types
of habitats even in the vast lakes of East Africa, in
combination with limited gene flow — also owing to
the aggression of males and their stable breeding terri-
tories — has made the main contribution to cichlid
species ecomorphological diversity [1–4,19].
Cichlid resources for genomics and
transcriptomics
The investigation of the genetics of phenotypic diversi-
fication and speciation in cichlids has included a number
of methods. Because many of the species of the Lake
Victoria and Lake Malawi cichlid species flocks are
extremely closely related, it is often possible to produce
fertile hybrids between them in laboratory settings.
Hence, candidate gene approaches [31], microarray ana-
lyes [32], and quantitative trait loci (QTL) analyses [33]
allowed the identification of genomic loci or even genes
that appear to strongly contribute to differences in jaw
and tooth shape, and those are species differences that
contribute to ecological adaptation and possibly specia-
tion. Other large-scale sequence resources that will con-
tribute even more in the near future to an increasing
understanding of the phenotype–genotype relationship
are bacterial artificial chromosome (BAC) libraries [34–
36], a number of genetic maps [37,38], and EST studies
[39,40].
In the age of genomics, research on the diversification of
cichlids has moved into large-scale molecular compari-
sons. Currently, a comparative genome project is under-
way at the BROAD Institute of MIT (URL: http://
www.broad.mit.edu/models/tilapia/) that will sequence
the genome of the tilapia at medium high coverage
(7?) and will determine the genomes of three other
Genomic analysis of cichlid Kuraku and Meyer553
Figure 2
Phylogeny and timescale of teleost evolution with emphasis on cichlids and their close relatives. See Azuma et al. [14], for details of divergence times.
The stickleback lineage was shown to have diverged from the Fugu/Tetraodon lineage based on mitochondrial sequences, while nuclear DNA
sequences suggested its closer relationship with medaka and cichlids. TSGD, the teleost-specific genome duplication.
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haplochromine cichlids at low coverage (2?) (Figure 3).
Until those genomic efforts are completed other meth-
odological approaches have been undertaken in an effort
to learn about the genetics of phenotypic differentiation
in cichlid fishes. Such genomic comparisons might also
include more phylogenetically comprehensive compari-
sons among the major fish models such as medaka,
stickleback, and fugu. Most recently a comparison of five
cichlid genomes that were sequenced with a whole shot-
gun approach at low coverage (0.5?) yielded some inter-
esting results nonetheless [41??]. These five species of
Lake Malawi haplochromine cichlids were from as differ-
ent lineages as can be found in this adaptive radiation and
representedhugelydifferentlifestylesand,yet,theywere
genetically more similar than humans of different ethnic
groupsordifferent laboratory strains of zebrafish. Because
of the remarkable genetic homogeneity of cichlids, the
large numbers of genetically extremely similar species of
haplochromine cichlids have long been called natural
experiments or ‘natural mutagenesis screens’. Of the
large sets of single nucleotide polymorphisms (SNPs)
that were collected, about 3–5% show statistical signs
of possibly being associated with candidate genes that
may have experienced positive Darwinian selection and
may warrant further study. Such an approach will be
useful for future genotype–phenotype association studies
where representatives of an entire species flock are used
as a mapping panel.
The genome sizes (haploid nuclear DNA content) of
cichlids range from about 0.9–1.2 pg with some outliers,
while chromosome numbers (2n) seem to vary only from
44 to 48 (Animal genome size databse; URL: http://
www.genomesize.com). These genome sizes and karyo-
types resemble those of closely related families of fishes
and do not suggest anything out of the ordinary for
cichlids. On the basis of the still limited information
on the genomes of cichlids it seems that there are no
drastic change in their basic genomic organization (e.g.
expansion/compaction of genome, whole genome dupli-
cations, number, and diversity of retrotransposons) com-
pared to other lineage of fishes with many fewer species
[42,43]. The evolution of regulatory elements is believed
to be a particularly fast and effective means of very rapid
phenotypic diversification [44??]. Larger, more represen-
tativedatasetsonregulatoryelementsandtheirevolution
in cichlid genomes are still lacking, so it is not clear at this
point as to whether there is anything special happening in
the genomes of cichlids in regard to regulatory evolution.
Thelimitedinformationonthisthathasbeencollectedso
far would appear to suggest that the presence/absence of
putative regulatory elements and even micro-RNA is
variable and that those regulatory mechanisms are
possibly rather quickly evolving, particularly in terms
of neo-functionalization and the complementary fixation
ofregulatoryelementsinduplicatedgenes[45].Thisisan
avenue of research that will probably yield interesting
insights as more comparative genomic sequences and
functional genomic studies of cichlids will be conducted.
Genetics of adaptive traits
Many of the above-mentioned phenotypic features that
are unique to cichlid fishes, namely, morphologies of
craniofacial structures (e.g. lips, jaw-shapes, and tooth-
shapes) and body color variation, can be attributed to the
patterns of differentiation of neural crest cells. In
vertebrate embryos, neural crest cells, that delaminate
from dorsal neural fold, migrate to programmed sites,
where they differentiate into cephalic skeletal element
(e.g. jaws), color pigments such as melanocytes and so on.
In general, neural crest cells strongly contribute to the
554
Genomes and evolution
Figure 3
Phylogenetic tree of East African cichlids. Phylogenetic relationships
are based on Salzburger and Meyer [4]. Vertical lengths of triangles
indicate the numbers of species included in each taxon. Names
and images of species are shown on the right hand side for
those whose genome sequences will be determined. RH, riverine
haplochromine.
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species-specific morphology of craniofacial regions of
vertebrates (e.g. [46]). However, although the molecular
regulatory factors for migration and differentiation of
neural crest cells are relatively well studied, this aspect
of cichlid biology has not been explored sufficiently. The
first developmental studies about jaw and teeth devel-
opment in cichlids through QTL analyses [33,47??]
pointed toward a strong contribution of bone morpho-
genetic protein 4 (bmp4). These types of experimental
approaches that use QTL or association analyses with
genetic maps or entire genomic sequences promise in the
near future to increase our understanding of molecular
genetic basis of the rapid adaptive radiation of this
fascinating group of organisms.
Empty morpho-space and massive parallel
evolution through re-awakening of
developmental programs?
Despitetheimpressivediversityofcichlids,nottheentire
theoretically available ‘morpho-space’ is taken up by
them [48?]. For example, many forms (e.g. very large
predators or eel-shaped ones) that are found in other
families of fish were not invented by cichlids. Further-
more, only some, but not all lineages of cichlids diversi-
fied to a notable degree. Why that should be so is still a
wide open question.
One of the most interesting features of cichlids is that the
diversity of the independent radiations of cichlids is not
Genomic analysis of cichlid Kuraku and Meyer555
Figure 4
Cichlids from Lake Tanganyika (left) and those from Lake Malawi (right) independently evolved similar morphologies in parallel. All Lake Malawi cichlids
are more closely related to each other than to any other species. All Lake Malawi cichlids belong to the haplochromine lineage and are derived from a
species that might have resembled a generalist representative of the Tropheus (second species from above on the left) lineage from Lake Tanganyika.
Shown are from top to bottom Bathybates ferox (left) and Ramphochromis longiceps (right). Tropheus brichardi (left) and Pseudotropheus microstoma
(right). Julidochromis ornatus (left) and Melanochromis auratus (right). Cyphotilapia frontosa (left) and Cyrtocara moorei (right). Lobochilotes labiatus
(left) and Placidochromis milomo (right).
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random, but rather that the same phenotypic solutions to
similar ecological challenges have re-evolved repeatedly
(Figure 4) [17,49,50]. Cichlids provide on one of the hand
textbook examples of exuberant and extremely fast spe-
ciation and phenotypic diversification and on the other
the phylogenetic analyses discovered that a good portion
of this diversity is accompanied by massive parallel evol-
ution in and among these adaptive radiations. This raises
very interesting questions the answer to which is likely to
be of relevance to all organisms and not only cichlids. Did
evolution reuse the same developmental pathways to
come up independently with similar developmental out-
comes or did it find alternative ways to respond to similar
ecologicalchallenges?Ourbetwouldbethatevolutionre-
awakened [51] developmental pathways independently
to come up with similar designs rather than evolved
entirely new alternative genetic and phenotypic solutions
in different lineages. But, at this point this is purely a
guess, as the answers to these open questions are not in
yet and are not easy to get as well.
The recognition that cichlid species flocks also provide a
textbook example of parallel evolution or convergence
opens up very interesting future research directions that
can be addressed only through comparative developmen-
tal and genomic approaches. These are not easy pro-
blems, but this line of research promises to yield
insights into the genetics of phenotypic diversification
that have obvious relevance beyond cichlids.
Conclusions
Clearly, more complex lake environments seem to con-
tribute toorpermitthediversificationofcichlidssincethe
species assemblages in lakes are always much more
species rich than those of riverine communities. But,
not all lineages of cichlids are equally prone to speciate,
the champions being the haplochromine cichlids. This
raises the question as to whether some genomic features
of some or all cichlid lineages predispose them to radiate
and diversify phenotypically. The investigation of the
comparative developmental genetic basis of traits and
genomic comparisons across different lineages and radi-
ations will be necessary to get a handle on the long-
standing ‘cichlid problem’. Comparative genomic infor-
mation within cichlids and comparisons to other fish
genomes are just beginning to be collected. Some efforts
are underway to study changes in expression patterns of
genes, investigations of micro-RNAs [45], retrotranspo-
sons [43], and other aspects of regulatory evolution. The
question as to whether regulatory evolution in cichlids is,
in some way, different, that is more effective, from other
lineages of less species-rich organisms and particularly
conducive to speciation remains open at this point. As
recent work on Hox, ParaHox, and KCNA gene clusters
suggests, the genomes of cichlids do not seem to differ all
that much from those of other fishes [45,52,53]. SNP-
based association studies, and whole genomic scans for
conspicuous methylation patterns might provide some
clues as to whether there is something peculiar in the
genomes of these fishes that would suggest a genomic
contribution to their particularly fast rates of speciation
and phenotypic diversification. Finding a solution to the
‘cichlid problem’ has obvious implications for a deeper
understanding of the genetic basis of phenotypic diversi-
fication that goes beyond a better grasp on cichlid fishes.
Acknowledgements
We thank the University of Konstanz and the Deutsche
Forschungsgemeinschaft for financial support.
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Slettan A, Stern JE, Terai Y, Kocher TD: A second-generation
genetic linkage map of tilapia (Oreochromis spp.). Genetics
2005, 170:237-244.
38. Sanetra M, Henning F, Fukamachi S, Meyer A: A microsatellite-
based linkage map of the cichlid fish, Astatotilapia burtoni,
(Teleostei) and a comparison of genetic architectures among
rapidly speciating cichlids. Genetics in press.
39. Salzburger W, Renn SC, Steinke D, Braasch I, Hofmann HA,
Meyer A: Annotation of expressed sequence tags for
the East African cichlid fish Astatotilapia burtoni and
evolutionary analyses of cichlid ORFs. BMC Genomics
2008, 9:96.
40. Watanabe M, Kobayashi N,Shin-iT, Horiike T, Tateno Y,Kohara Y,
Okada N: Extensive analysis of ORF sequences from two
different cichlid species in Lake Victoria provides molecular
evidence for a recent radiation event of the Victoria species
flock: identity of EST sequences between Haplochromis
chilotes and Haplochromis sp. ‘‘Redtailsheller’’. Gene 2004,
343:263-269.
41.
??
Loh YH, Katz LS, Mims MC, Kocher TD, Yi S, Streelman JT:
Comparative analysis reveals signatures of differentiation
amid genomic polymorphism in Lake Malawi cichlids. Gen Biol
2008, 9:R113.
Using partial (5? coverage) genomic sequences of five species of Lake
Malawi cichlids the authors show that they differ byonly about 0.25%and
identifygenomicregions that might contain differences thatshow signsof
selection and contain genes that might have contributed to species
differences and species.
42. Steinke D, Salzburger W, Braasch I, Meyer A: Many genes in fish
have species-specific asymmetric rates of molecular
evolution. BMC Genomics 2006, 7:20.
43. Volff JN, Korting C, Meyer A, Schartl M: Evolution and
discontinuous distribution of Rex3 retrotransposons in fish.
Mol Biol Evol 2001, 18:427-431.
44.
??
The author develops verbal models of the genetic basis of phenotypic
diversification.
CarrollSB: Evo-Devoand anexpanding evolutionarysynthesis:
a genetic theory of morphological evolution. Cell 2008,
134:25-26.
45. Hoegg S, Boore JL, Kuehl JV, Meyer A: Comparative
phylogenomic analyses of teleost fish Hox gene clusters:
lessons from the cichlid fish Astatotilapia burtoni. BMC
Genomics 2007, 8:317.
46. Taylor KM, LaBonne C: Modulating the activity of neural crest
regulatory factors. Curr Opin Genet Dev 2007, 17:326-331.
47.
??
Albertson RC, Streelman JT, Kocher TD, Yelick PC: Integration
and evolution of the cichlid mandible: the molecular basis of
alternate feeding strategies. Proc Natl Acad Sci U S A 2005,
102:16287-16292.
Genomic analysis of cichlid Kuraku and Meyer557
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Using crosses between two different Lake Malawi cichlid species, the
authors use a QTL approach to identify the number and size of the effect
of particular genomic regions and identify potential genes that might be
responsible for particular differences in tooth shape.
48.
?
Clabaut C, Bunje PM, Salzburger W, Meyer A: Geometric
morphometric analyses provide evidence for the adaptive
character of the Tanganyikan cichlid fish radiations. Evolution
Int J Org Evolution 2007, 61:560-578.
Using a combination of morphometic and phylogenetic analysis, the
authors analyze the patterns of diversification of the Lake Tanganyika
cichlid adaptive radiation. They investigate similarities and differences
within and among tribes of that species flock.
49. Stiassny MLJ, Meyer A: Cichlids of the Rift Lakes. Sci Am 1999,
280:64-69.
50. Kocher TD, Conroy JA, McKaye KR, Stauffer JR: Similar
morphologies of cichlid fish in lakes Tanganyika and Malawi
are due to convergence. Mol Phylogenet Evol 1993, 2:158-165.
51. Meyer A: Homology and homoplasy: the retention of genetic
programmes. In Homolgoy. Edited by Bock GR, Cardew G. John
Wiley & Sons Ltd.; 1999:141-157.
52. Siegel N, Hoegg S, Salzburger W, Braasch I, Meyer A:
Comparative genomics of ParaHox clusters of teleost fishes:
gene cluster breakup and the retention of gene sets following
whole genome duplications. BMC Genomics 2007, 8:312.
53. Hoegg S, Meyer A: Phylogenomic analyses of KCNA gene
clusters in vertebrates: why do gene clusters stay intact? BMC
Evol Biol 2007, 7:139.
558
Genomes and evolution
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