1. pets
2. cats

COMMENTARY
Pigment Cell Melanoma Res.
Tabby pattern genetics – a whole new breed of cat
Chris Kaelin1,2 and Greg Barsh1,2
1
Department of Genetics, Stanford University, Stanford, CA, USA
HudsonAlpha Institute for Biotechnology, Huntsville, AL, USA
e-mail: [email protected]
2
doi: 10.1111/j.1755-148X.2010.00723.x
Much of what we know about pigment cell biology comes
from studying laboratory mice, yet the conservation of
gene action and interaction across domesticated animals,
including horses, cattle, pigs, and dogs, is firm evidence
that most aspects of color variation are conserved in
mammals. The domestic cat, however, is a special case in
which variation within and among breeds exhibits a fascinating glimpse into an entirely new area of color variation
as exemplified by tabby patterns. Periodic patterns with
color markings spaced at non-random intervals are common in nature and evident in all major mammalian orders
– stripes on chipmunks, reticulated markings on giraffes
and hyenas, tail rings on lemurs, and, of course, tabby
stripes on domestic cats. The similar nature but diverse
manifestation among these patterns suggests they are
formed by a conserved, adaptable, and largely unexplored
mechanism. Periodic patterns are conspicuously missing
from the laboratory mouse, but the cat stands out as a
unique genetic model in which recent work from Eizirik
et al. (2010) provides new genetic insight.
Domestic cats have four distinct and heritable coat patterns – ticked, mackerel, blotched, and spotted – that are
collectively referred to as tabby markings (Figure 1).
These patterns are a composite of two features: (i) a light
background component resulting from individual hairs
with a subapical light-colored band and (ii) a superimposed darker component resulting from unbanded
hairs. The ticked phenotype refers to the absence of any
superimposed pattern, leaving only the banded or ‘ticked’
background color. Mackerel, blotched, and spotted phenotypes describe variations of the tabby pattern, in which
the darker component forms either periodic vertical
stripes (mackerel), whorls (blotched), or leopard-like spots
(as in the Ocicat or Egyptian mau breeds of domestic
cats). The periodicity of tabby markings distinguishes
them in a fundamental way from other characteristic but
randomly displayed markings, such as the tricolor patches
on a calico cat or the black spots on a Dalmatian. These
random patterns arise from events that are stochastically
initiated (like inactivation of an X chromosome in females
or survival of a melanocyte cluster) but stably maintained,
either through epigenetic mechanisms as with X inactivation, or a developmental process, as with a limited winª 2010 John Wiley & Sons A/S
dow for neural crest migration. By contrast, periodic
patterns must arise from a mechanism that is specifically
programed to be spatially constrained.
What are the molecules and cells that underlie tabby
patterns? A genetic approach to this question began
nearly a century ago when Phineas Whiting described
three tabby ‘banding factors’, noting a simple pattern of
inheritance for each: ticked is dominantly inherited relative to mackerel and blotched, whereas blotched is
recessively inherited relative to ticked or to mackerel
(Whiting, 1918). Whiting posited a single locus (T ) with
three alleles – ticked (T a), mackerel (T +), and blotched
(t b). That view has now been revised by the recent
work of Eizirik et al. (2010), who applied a genome-wide
panel of molecular markers to pedigrees segregating
the different coat color patterns, and thereby discovered
that two loci were involved in determining the difference between ticked, mackerel, and blotched patterns
(Figure 1). In this modern view of cat pattern genetics,
the Tabby locus determines the type of pattern, with
the TaM (Mackerel) allele dominant to the Tab (Blotched )
allele, while a second locus, now known as Ticked,
determines the absence or presence of pattern, with
the Ti A allele dominant to the Ti+ allele. The nomenclature has become complicated; similar to Eizirik et al.
(2010), we use lower case roman to describe the
Phenotype
Genotype
Ticked
Tabby
Ticked
TiA/Ti+
or
TiA/TiA
any
genotype
Mackerel
Ti+/Ti+
TaM/Tab
or
TaM/TaM
Blotched aka
“Classic Tabby”
Ti+/Ti+
Tab/Tab
Spotted
Ti+/Ti+
TaM/Tab
or
TaM/TaM
Figure 1. The four characteristic tabby coat patterns in domestic
cats, with corresponding genotypes at the Ticked and Tabby loci,
as determined by Eizirik et al. (2010). All cat images by Helmi Flick.
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Commentary
phenotypes and ⁄ or underlying processes, e.g. tabby,
ticked, mackerel, and blotched, and capitalized italics to
refer to the loci and ⁄ or alleles, e.g. Tabby, Ticked, Mackerel, and Blotched. As described later, the allele of
Ticked associated with the presence of pattern is probably ancestral, and thus designated Ti +, while the allele
of Ticked associated with the absence of pattern, as in
Abyssinian cats, therefore Ti A, is probably derived.
Strategies to identify the Tabby and Ticked genes are
discussed further in the following paragraphs, but before
doing so, it may be helpful to consider what types
of developmental and cellular mechanisms might be
involved. Eizirik et al. (2010) suggest that mammalian
coat patterns are formed by two distinct processes: (i) a
‘spatially oriented’ mechanism that establishes a prepattern in the skin and (ii) a ‘pigmentation-oriented’ mechanism that regulates expression of pigmentary genes in
response to the prepattern. Building on this idea, we propose that distinct ‘spatially oriented’ and ‘pigmentationoriented’ mechanisms provide an appealing conceptual
framework to explain why coat patterns occur commonly
but not ubiquitously in mammals. Perhaps, a complex,
‘spatially oriented’ mechanism developed prior to or early
in mammalian evolution, and diverged to give rise to various types of prepatterns. In contrast, a ‘pigmentationoriented’ mechanism could have occurred independently
several times during mammalian evolution. In other
words, white and black stripes on a zebra might depend
on the same ancient prepattern as do yellow and black
stripes on a tiger, but the specific pigmentary genes that
interpret the prepattern could be completely different.
Most ideas about spatial prepatterns in large animals
stem from the mathematical work of Alan Turing on reaction–diffusion processes, which have applications not
only in biology but also in chemistry and physics. Interaction of two diffusible substances to yield predictable and
periodic patterns during skin development forms the
basis for theoretical work that could explain a large range
of mammalian coat patterns (Bard, 1981). Practically
speaking, melanoblasts constitute only a small fraction of
the cell population in the developing skin, and therefore
seem an unlikely substrate for propagating a reaction–
diffusion signal. (Furthermore, tabby stripes occasionally
appear to cross areas of skin devoid of melanocytes.)
Instead, a putative ‘spatially oriented’ mechanism seems
more likely to be mediated by fibroblasts and ⁄ or keratinocytes in the developing skin, in which widely expressed
components of a reaction–diffusion system come to
delimit prepattern boundaries. Genetic variants affecting
this process—perhaps alleles of the Tabby gene—could
change the shape and ⁄ or location of the boundaries,
thereby giving rise to stripes or blotches (Figure 2).
What about a ‘pigmentation-oriented’ mechanism in
tabby striping? Dark areas in a patterned animal, whether
stripes, spots, or blotches, are caused by conversion of a
light band to a darker surrounding color on individual hairs.
At first glance, prime candidates for this phenomenon are
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A
Skin development
Hair follicle cycling
Postnatal
Prenatal
Spatially-oriented
mechanism
Pigmentation-oriented
mechanism
Ticked
Tabby
B
and/or
Spotted
(TaM/TaM)
Blotched
(Tab/Tab)
Broken mackerel
(TaM/Tab)
Blotched
(Tab/Tab)
50% blotched
(Tab/Tab)
50% mackerel - spotted
(TaM/Tab)
Figure 2. A, Model for Tabby and Ticked gene action in pattern
formation. A ‘spatially oriented’ developmental mechanism, likely
based on reaction–diffusion, establishes a prepattern that is later
read out by a ‘pigmentation-oriented’ mechanism. Eizirik et al.
(2010) posit that Tabby functions in the former process, while
Ticked could function in either process. B, Summary of results
obtained by Eizirik et al. (2010), which suggests that homozygosity
for Blotched (Tab ⁄ Tab) is not permissive for spotting gene(s) action.
the paracrine signaling molecule Agouti protein and its target the melanocortin 1 receptor (Mc1r), which controls
the temporal production of eumelanin and pheomelanin
during hair growth. However, the persistence of tabby
markings in cats with an Agouti loss-of-function mutation
(a ⁄ a) is strong evidence that Agouti does not mediate pattern formation in domestic cats. These ‘ghost’ tabby
markings are sometimes visible on young, non-agouti cats
as darker patterns on a black background. In fact, nonagouti cats can be orange in color because of mutation of
the as-yet-unidentified gene sex-linked orange, and in this
background, persistence of tabby stripes on a non-agouti
background is even more pronounced (Searle, 1968).
Recent evidence also points away from Mc1r as a candidate for mediating tabby stripes. Peterschmitt et al.
(2009) report that amber coat color in Norwegian forest
cats is caused by an Mc1r loss-of-function and, furthermore, that tabby markings on amber cats appear solid
black on an otherwise amber background. The idea that
tabby markings persist when either Agouti or Mc1r signaling is disrupted leaves an intriguing alternative hypothesis
– that an as-yet-unidentified signaling system, with the
capacity to override the pigment-type switching pathway,
can regulate melanogenesis in response to a ‘spatially oriented’ prepattern. If so, identification of the Ticked gene
might reveal a novel set of inputs that affect pigment cell
behavior (Figure 2).
Eizirik et al. (2010) suggest that Tabby may be a component of the ‘spatially oriented’ mechanism, because
Tabby alleles change the shape of the pattern, and that
Ticked may be a component of either mechanism,
because the loss of the pattern could result from disrupª 2010 John Wiley & Sons A/S
Commentary
tion of either the ‘spatially oriented’ mechanism or the
‘pigmentation-oriented’ mechanism (Figure 2). Using
linkage mapping in pedigree individuals, they identify
discrete genomic intervals for both genes, containing 40
and 16 genes, respectively. There are no ‘smoking gun’
candidate genes in either interval, which is bad news
for those hoping for a quick and simple answer, but
good news to those hoping to apply pigmentary variation to fundamental questions in developmental biology.
Besides stripes and blotches, how (and why) do
related patterns arise, such as cheetah spots or leopard
rosettes? Part of the answer could involve hybridization.
A famous example is the ‘liger’, the offspring of a male
lion and female tiger, whose coat pattern is distinct
from either tiger stripes or the rosettes characteristic of
juvenile lions, and might best be described as ‘broken
mackerel’. Amazingly, Eizirik et al. (2010) describe an
analogous situation in domestic cats, in which a cross
between true-breeding spotted and blotched cats produced ‘broken mackerel’ patterns that were intermediate
between stripes and spots (Figure 2). Genetics in ligers is
difficult, but when Eizirik et al. (2010) backcrossed their
broken mackerel F1 animals to blotched cats, they
observed an equal ratio of blotched and non-blotched
cats. The non-blotched cats, however, displayed a range
of patterns extending from fully striped to fully spotted.
Thus, while the genetic architecture of spotting remains
elusive, we learn something about the interaction of
spots, stripes, and whorls from this cross – in the appropriate genetic background, stripes are converted to
spots, but whorls are not. This selective pattern conversion indicates that a spotting gene (or genes) is capable
of interacting with TaM but not Tab.
Molecular identification of Ticked, Tabby, and spotting
gene(s) should be rewarding to the evolutionary as well as
the developmental biologist, because mechanisms
homologous to those in tabby cats seem likely to generate the stripes, spots, and intricate rosette patterns that
distinguish the 37 extant species of wild cats. Their recent
evolutionary divergence (within the last 12 million
years), well-characterized phylogenetic relationships, and
range of species-specific coat patterns make the larger
cat family an attractive model for comparative genomics
once the patterning genes in domestic cats are identified.
Going forward, a population-based mapping strategy
provides an attractive approach for narrowing the Ticked
and Tabby candidate intervals. In fact, cat populations
have been recognized for a long time as being particularly amenable to such approaches. In two studies published more than 50 years ago, the British geneticist
A.G. Searle compared traits of ‘alley cat’ populations in
different parts of the world where he spent time as a
professor (Searle, 1949, 1959). He noted equal ratios of
blotched and mackerel but very few ticked cats in London, whereas, in Malaya, Singapore, he noted equal
ratios of ticked and mackerel cats but very few blotched
cats. Searle took the skewed distributions of tabby patª 2010 John Wiley & Sons A/S
terns as evidence that (i) cats descended from a mackerel-patterned ancestor (the presumed wild ancestors of
domestic cats, Felis silvestris or Felis lybica, are both
striped) and that (ii) ticked and blotched alleles were
derived after cat domestication in different parts of the
world. Placed in context of the present study, the Ti A
and Tab alleles represent derivative variants at their
respective loci, and the regions surrounding the causative mutations should be defined by reduced allelic variation relative to ancestral alleles.
Of course, the ultimate goal is not only to identify coat
pattern genes but also to learn how they function. The
laboratory mouse, with an array of well-characterized
pigmentation mutants and a robust toolkit for genetic
manipulation, remains the ideal mammalian model for
studying gene function. If a ‘spatially oriented’ mechanism is conserved across mammalian species, then engineering a striped or spotted mouse might require simply
engaging the right ‘pigmentation-oriented’ pathway.
Such a strategy does not seem so impractical, considering that the striped African mouse (Rhabdomys pumilio),
a close relative of the laboratory mouse, is…well striped.
The recent work by Eizirik et al. (2010) was motivated
by the longstanding interest and focus of O’Brien and
colleagues on the domestic cat as a model genetic system and builds on more than a decade of comparative
cytogenetics, radiation hybrid maps, BAC libraries, and,
more recently, next-generation sequencing for SNP discovery. Lagging a few years behind the domestic dog,
genetic and genomic resources for the cat are now
coming on line and promise molecular exploration of
frontiers in developmental and evolutionary biology that
have been widely admired but poorly understood.
Acknowledgement
The authors thank Helmi Flick for providing the cat photographs.
References
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