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State of cat genomics

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Our knowledge of cat family biology was recently expanded to include a genomics perspective with the completion of a draft whole genome sequence of an Abyssinian cat. The utility of the new genome information has been demonstrated by applications ranging from disease gene discovery and comparative genomics to species conservation. Patterns of genomic organization among cats and inbred domestic cat breeds have illuminated our view of domestication, revealing linkage disequilibrium tracks consequent of breed formation, defining chromosome exchanges that punctuated major lineages of mammals and suggesting ancestral continental migration events that led to 37 modern species of Felidae. We review these recent advances here. As the genome resources develop, the cat is poised to make a major contribution to many areas in genetics and biology.
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State of cat genomics
Stephen J. O’Brien
1
, Warren Johnson
1
, Carlos Driscoll
1
, Joan Pontius
2
,
Jill Pecon-Slattery
1
and Marilyn Menotti-Raymond
1
1
Laboratory of Genomic Diversity, National Cancer Institute, Frederick, MD 21702, USA
2
Laboratory of Genomic Diversity, Basic Research Program, SAIC-Frederick, Inc., NCI-Frederick, Frederick, MD 21702, USA
Our knowledge of cat family biology was recently
expanded to include a genomics perspective with the
completion of a draft whole genome sequence of an
Abyssinian cat. The utility of the new genome infor-
mation has been demonstrated by applications ranging
from disease gene discovery and comparative genomics
to species conservation. Patterns of genomic organiz-
ation among cats and inbred domestic cat breeds have
illuminated our view of domestication, revealing linkage
disequilibrium tracks consequent of breed formation,
defining chromosome exchanges that punctuated major
lineages of mammals and suggesting ancestral conti-
nental migration events that led to 37 modern species of
Felidae. We review these recent advances here. As the
genome resources develop, the cat is poised to make a
major contribution to many areas in genetics and
biology.
Introduction
Cats and their wild progenitors have existed for a long time
– fossil records suggest they first appeared 35 million
years ago (MYA). Although the great saber-tooth tigers of
those times have long been extinct, modern cats are des-
cended from a midsize cat that existed 10–11 MYA [1–3].
Humans seem to be fascinated with the feline species – a
rich literature and artistic imagery of lions, tigers, chee-
tahs and leopards testifies to this – and domestic cats rank
among the world’s most venerated companion animals.
Our affection toward cats, complemented by accounts of
cats’ behavior and biology, has resulted in their contri-
bution to a diverse range of disciplines (ranging from
disease to conservation studies) that are suitable for
genetic and genomic enquiry. For example, cats, like dogs,
enjoy extensive veterinary medical surveillance (second
only to human medicine) and have 250 genetic diseases
analogous to human disorders [4–8]. Feline infectious
agents offer powerful natural models to human diseases
including HIV-AIDS [feline immunodeficiency virus
(FIV)], SARS (feline coronavirus-FCoV), avian influenza,
neurotropic viruses [canine distemper virus (CDV)] and
cancers [feline leukemia virus-feline sarcoma virus (FeLV/
FeSV)] [5–16]. Cats are a domesticated representative of
the Felidae family, which includes some of the most suc-
cessful, but now the most threatened, predator species on
earth [1,2,17].
With a rapidly growing literature on cat behavior,
coat colors, reproductive advances and breed development,
the domestic cat is poised to benefit from the recently
completed draft whole genome sequence of an Abyssinian
cat named Cinnamon [8,18]. Cats present a powerful model
in development, physiology and neuroscience (some of
which are listed in Table 1). Here we review the insights
achieved from the cat genome sequence and discuss the
wealth of knowledge about genomic organization that is
being shown through comparative genomics. Furthermore,
we trace the natural history of the wild cats, discuss the
origins of cat domestication and review the many aspects of
cats that make them a useful animal ‘model’ for human
diseases and for comparative genomics.
Developing and applying a whole genome sequence
for cats
The study of feline genetics had its roots in early gene-
mapping strategies using linkage and physical mapping
approaches [19–22]. Over the past few decades, several
important biological and informatics resources required
for genetic investigations in cats were developed. The
resources are comparable to those developed in other
genome projects and include the following: (i) somatic cell
and radiation hybrid panels used to build a framework
physical map of comparative anchor tagged sequence (C-
ATS) markers for cats [19,23–28]; (ii) three large cat pedi-
grees used to build a cat linkage map [29–32]; (iii) several
genomic libraries (BAC, PAC, cosmid and fosmid) for gene
discovery and genome assembly validation [33–35] and (iv)
finished DNA sequence of three subregions of the cat
genome [i.e. FLA, the major histocompatibility complex
(3.3 Mbp), mitochondrial DNA and counterpart nuclear
mitochondrial DNA (mtDNA; numt) sequence; and 30
Mbp of the ENCODE Project cat genome sequence
(http://www.genome.gov/10005107,[33–40]). The appli-
cation of these important tools led to significant advances
in cat genetics including gene discovery and regional gene
annotation and to anticipation for a whole genome
sequence.
In 2005, the cat was included in a selection of 24
mammals for whole genome sequencing by National
Human Genome Research Institute, to facilitate interpret-
ation of the finished human genome sequence. The species
were chosen to capture the evolutionary divergence across
the 4500 living species of mammals initially with a ‘light’
(i.e. twofold) genome coverage [18,41]. The principal
criteria for selecting these species were (i) to discover short
conserved sequence regions among mammals that would
include gene regulatory motifs; (ii) to provide a platform for
reconstruction of ancestral genomes that preceded the
divergence nodes of the mammalian radiations and
(iii) to stimulate the development and application of new
Review
Corresponding author: O’Brien, S.J. (obrien@ncifcrf.gov).
268 0168-9525/$ see front matter . Published by Elsevier Ltd. doi:10.1016/j.tig.2008.03.004
animal models for human medicine and biology. In
2006, the whole genome sequence of a female Abyssinian
cat named Cinnamon was determined by Agencourt
Bioscience (http://www.agencourt.com); Abyssinian cats
are the most inbred, making genome assembly easier. A
consortium of scientists assembled, mapped and annotated
the cat genome sequence using a comparative approach
that involved cross-reference to NCBI-annotated genome
assembles of six index mammals (human, chimpanzee,
mouse, rat, dog and cow) [8]. For details of the annotation
strategy and highlights of genomic features that were
discovered, see Box 1.
About 327 037 single nucleotide polymorphism (SNP)
variants were heterozygous in Cinnamon’s genome, and a
sampling of 200 SNPs validated 85% of them as being
variable in additional domestic cats from various breeds.
Cinnamon’s genomic history was molded by three episodes
of historic inbreeding; the original domestication event for
cats (10 000 years ago), Abyssinian breed formation and
disease (rdAc) pedigree establishment [42,43]. Her genome
is a patchwork of short regions of SNP homozygosity inter-
spersed with regions of heterozygosity (more than one SNP
per 600 bp), perhaps a reflection of historic inbreeding. In
total, there are 275 alternating homozygous/heterozygous
segments in Cinnamon’s genome, with 57% of her genome
being largely homozygous. Similar alternating homozygous
genome segments occur in dogs, likely for the same reason
[44].
Indeed, the potential of cat phenotypic and medical
surveillance in the genomic era is beginning to be realized.
Currently there are 38 cat genes for which mutational
variants responsible for feline metabolic diseases or for
morphological phenotypes are described [8]. This includes
18 hereditary diseases, where the mutation in cat occurs in
the homologous gene to the analogous human syndrome.
The single exception, spinal muscular atrophy (SMA), a
leading cause of human infant mortality, involved a large
140-kb deletion of the LIX1 gene in the cat model [45]. The
LIX1 gene is located on chromosome A1 within 25 cm
(Mbp) of the SMN1 gene, whose human homolog carries
causal mutations in 97% of human SMA patients. In
addition, the resolution of the molecular genetic bases of
ten coat color (or hair length) variants now establishes cats
as important species for study of pigmentation, hair de-
velopment and ocular albinism [8,21,31,46–51].
Recently, the NHGRI Committee for the Annotation of
the Human Genome promoted the cat to an additional
sixfold genome coverage, due to be completed in late
Table 1. The cat as a useful model species
Application Evidence
Medical models of
human diseases
There is a rich literature of veterinary disease in cats; >250 hereditary diseases in cats are analogous to human genetic
diseases. Eighteen of these have a known gene mutation in cats suitable for pathogenesis and therapeutic study
[4–8,32].
Infectious agents Cats have well-described models for several deadly human viral diseases, notably HIV-AIDS-feline immunodeficiency
virus, which is endemic in 14 free ranging species of Felidae including domestic cats [11]. Cats also harbor feline
leukemia virus and feline sarcoma virus, which have laid groundwork for oncogene discoveries and a virulent model
for SARS, feline coronavirus, and many others [10–16].
Neuroscience and
physiology
Cat are traditional subjects for neurophysiology studies that have led to important insight on ocular and neural
physiological processes [43,45,97–102].
Behaviors Cats have many curious behaviors associated with nurturing, defense, allusiveness and tameness that seem to have
genetic influences. Social organization in lions and in domestic cats seems to involve co-adaptation of behavior and
reproductive strategies [5,88].
Reproduction The reproductive physiology of cats is relatively advanced; for example, artificial insemination, in vitro fertilization,
embryo transfer, chineric embryos and nuclear cloning have been performed in cats. Promising advances have
occurred in embryonic stem cell isolation, leading to hopes of gene knockouts and gene replacement in laboratory
settings.
Domestication The process of cat domestication represents one of the more fascinating natural experiments. It seems to have
happened in a single locale in the Fertile Crescent when humans began agriculture. Cat domestication has led to the
growth of 600 million domestic cats worldwide. The adaptive aspects of this process in genetic terms await resolution
[42].
Breed development Approximately 68 certified cat breeds current exist; most are younger than a few hundred years. Each was selected
artificially for appearances and behavior, raising the question of what was selected and how well [5,88].
Coat-color variation The cat breeds are fixed in different combinations for some 12 coat color genes that have been described and tracked
in pedigrees. Resolution of their genetic bases will lead not only to more precise breed improvement but also to a
better understanding of pigmentation, hair development and ocular albinism. We know the basis for ten coat color hair
length genes, but others (such as Orange) remain elusive [31,46–51,88].
Forensic
development
Cats have led the way in establishing the legal precedent for introduction of short tandem repeat–based cat individual
identification of hairs and other biospecimens found at crime scenes. Cats hairs are easily picked up, so suspects with
cats or dogs can implicate themselves through their pets [91,103,104].
Felidae evolution,
adaption and natural
history
The cat family Felidae has shown much in the application of sophisticated tools of molecular evolution to phylogeny
reconstruction. Multidisciplinary interpretation of felid phylogeny, geography, paleontology and geology has allowed
inference around their historic continental migrations and origins [1,2,17].
Comparative
genomics
The highly conserved synteny of the cat genome map with that of human, dolphin and other mammal species has
given us a glimpse of the ancestral genome organization of all mammals. Recent sequence analyses of cat and other
mammal genomes are beginning to reveal a view of the pattern of genome organization that has punctuated the
mammalian radiations [8,22,60].
Felidae
conservation
Humans’ fascination with the cat species has produced a plethora of ecological and behavioral descriptions of the
plight of the many endangered Felidae species. Genetics in conservation became widely accepted with the finding of
the cheetahs’ genetic uniformity and progressed to studies on leopards, pumas, tigers, wildcats, lynxes and other free-
ranging species [17].
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269
2008 [18]. The planned supplement of SNP discovery using
‘light’ resequence coverage of 30 cats from ten cat breeds
assures a large store of SNPs and short tandem repeats
(STRs) suitable for gene association discovery using SNP
genotyping arrays. The decay of linkage disequilibrium
(LD) already measured among 24 cat breeds predicts that
a SNP genotypic array including 45 000 evenly placed
SNPs is appropriate for gene association discovery in cats,
similar to the approach successfully applied to dogs
[8,44,52,53]. However, cats have shorter LD stretches than
dogs (because they were domesticated more recently than
dogs; see below) and require three times more SNPs for
gene association studies. We anticipate that these efforts
will lead to the discovery of 2 million new SNPs, which will
aid the development of an eagerly awaited genotype array
chip of 80 000–100 000 SNPs, suitable for genome-wide
association studies. The dog genome sequence led to scores
of new gene discoveries [44,52,53]; the availability of these
promising cat genome resources portends that cat
advances should be close behind.
Comparative genome organization in mammals
Cat genomics has benefited from and also played a key role
in the emerging field of comparative genomics. The earliest
comparisons of gene order in mammalian chromosomes
revealed long stretches of conserved synteny between
human chromosomes and homologous chromosome seg-
ments in developing gene maps of mouse, cat and cow
[9,19,54,55]. Conserved syntenic region homologies be-
tween mammal species were confirmed by precise G-band-
ing pattern identities across chromosome arms and in
some cases over entire chromosomes [20,56,57]. These
large segments of chromosome homology were explicitly
defined by florescent in situ hybridization (FISH) or
chromosome painting, whereby metaphase chromosomes
of various mammals were decorated by flow-sorted and
fluorescent-labeled whole chromosome probes [9,22,58,59].
Chromosome painting studies gave us the first look at
the details of genome rearrangements that characterized
the divergence of mammals. With the caveat that intra-
chromosomal rearrangements (inversions) were invisible
by these methods, a paradigm emerged that chromosomal
exchange followed a dichotomous mode in different mam-
mal groups [22,58]. In most lineages, a low or ‘default’ rate
was observed where species groups displayed few translo-
cation exchanges, on the order of one new rearrangement
every 10–15 MY (exemplified by cat, human, dolphin, pig
and other species). These default (slow or conserved)
lineages were in sharp contrast to lineages whose chromo-
somes were reshuffled extensively (examples of reshuffled
lineages were gibbons, new world monkeys, murid rodents,
canids and ursids) [22,56–58]. The global reorganization in
reshuffled lineages was three to five times more extensive
than was seen in the slower ‘default’ lineages for inexplic-
able reasons.
Assembled whole genome sequences, including the cat
genome, have allowed the detection of intrachromosomal
inversions, because 100 000 conserved sequence block
(CSB) markers of homology between species (see Box 1)
enabled an extremely high-density genome resolution of
conserved syntenic segments [8,60,61]. Using sophisti-
cated breakpoint parsimony algorithms [genome re-
arrangements in man and mouse (GRIMM) synteny and
multiple genome rearrangement algorithm (MGR)] [62–
64] that resolved the breakpoint coordinates joining 500
homologues synteny blocks [HSBs; previously called smal-
lest combined evolutionary unit segments (SCEUS);
Figure 1], the paradigm of dichotomous rates of genome
exchange was unseated [8,26]. The wrinkle came from the
occurrence of numerous intrachromosomal rearrangements
but at different tempos in the slow default translocation
lineages versus the reshuffled lineages (Figure 1). A pre-
liminary analysis of six species genome sequences showed
that lineages with few translocation exchanges display
considerably more intrachromosomal inversions, whereas
species with reshuffledand increased translocations showed
fewer inversions (Table 2). The total number of transloca-
tions plus inversions is similar in all lineages, becausein the
slow ‘default’ lineages (human and cat), inversions are
increased, whereas in the shuffled translocation-rich
lineages (murids and dogs), inversions are infrequent. It
almost seems that interchromosomal and intrachromoso-
mal exchanges are compensating in different lineages.
Additional fascinating observations have emerged
from comparing available mammal species genomes [60].
First, the overall rates of chromosome exchanges within
Box 1. Annotation of the cat whole genome sequence
Here we give an overview of the strategy and main conclusions from
the cat genome sequence study; full details can be found in Ref. [8].
The ‘light’ (1.9-fold coverage) of Cinnamon was assembled, mapped
and annotated using a comparative approach to finished whole
genomes sequence/maps of six mammals (human, chimpanzee,
mouse, rat, dog and cow). Briefly, 8 027 672 sequence reads (84%
plasmid and 16% fosmid) were assembled to 817 956 overlapping
contigs and 217 790 scaffolds using the ARACHNE and PHUSION
genome assembly algorithms [93–95]. The contigs were aligned to
the index mammals’ sequence maps and anchored with 1682
ordered markers from the cat radiation–hybrid map, assuming that
the order of reciprocal best match (RBM) sequences between the
radiation hybrid (RH) anchor markers for cats was the same as for a
their dog and human counterparts. The cat genome sequence is
accessible on a web-based genome sequence browser, GARFIELD
http://lgd.abcc.ncifcrf.gov [8,96], which includes the following
annotated features:
o 817 956 contigs and 217 790 scaffolds across 2.7 Gbp of cat
genome sequence
o definition and mapping of >1 million RBM alignments between
cat and six index mammals, revealing a set of 133 499 conserved
sequence blocks (CSBs) present in all seven genomes. CSBs and
RBMs were used to annotate cat genes and homologous synterny
blocks (HSBs)
o identification of 20 285 cat genes based on alignment and
conserved syntenic orthology with orthologous genes in index
mammals
o sequence, iteration and mapping of cat repeat sequence families
o detection and mapping of 201 microRNA loci
o definition of 2814 HSBs across six index mammal genomes
o detection of previously undiscovered nuclear mitochondrial DNA
(numt) sequences distributed across cat chromosomes
o description of undiscovered endogenous retroviral sequences
and phylogenetic lineages, ten times more abundant than
previously known FeLV and RD114 endogenous retroviral
sequences
o detection of 327 037 single nucleotide polymorphisms, 34 850
deletion insertion polymorphisms and 200 177 short tandem
repeat (or microsatellite) loci
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270
mammalian orders have increased (more than tenfold)
since the Cretaceous–Tertiary boundary (65 MYA),
coincident with the advancement and diversification of
most mammalian orders at the time. Second, 20% of
chromosome breakpoint regions defined by comparative
alignments were not only reused more than once during
mammalian evolution, but the reused sites are clustered
nonrandomly around centromeres. Third, chromosomal
breakpoints defined between mammals show a marked
enrichment in gene density compared with the genome-
wide average; they seem to cluster in gene-rich areas.
Fourth, primate-defined breakpoints (translocation and
inversion) occur in regions of human segmental dupli-
cations, suggesting that such local aneuploidy plays a part
in chromosomal exchange. Finally, evolutionary break-
points in mammal lineages seem to coincide with break-
points that occur in human cancers, suggestive of a
common underlying mechanism.
These conclusions emerged from comparisons of species
that have a whole genome sequence and a dense radiation
hybrid (RH) map. The inferences must be affirmed by
future comparisons, particularly with the additional 24
species selected for whole genome sequence [18]. The
puzzle is not completely solved, but the prospect of richer
whole genome sequence data across mammals in the future
holds high anticipation for both resolving the effective
chromosomal dynamics and also for inferring the genome
organization of the ancestral bears, felids, at other mam-
mal groups in high definition.
Genomic natural history of the world’s cats
Nestled in the genome of every individual are cryptic
footprints of historic episodes encountered by their
ancestral progenitors. The emerging field of genomic
archeology (or genomic prospecting) aims to mine the
ancient DNA sequence to enable better interpretation
of the divergence, migration and demographic pertur-
bations that occurred in the silence of prehistory
[65–68]. The cat family Felidae – an assemblage of 37
successful predatory carnivore species on five continents
(Figure 2) – provides a cogent example of how genomic
data can complement geographic, paleontological and
geologicalaspectstocharacterizeaspeciesgroups
natural history [1,2] (Figure 3).
The first step in reconstructing cat origins was to estab-
lish a robust molecular phylogeny, which informed the
hierarchical relationship and divergence nodes that define
the Felidae radiation. This was accomplished by selecting
35 cat genes (a total of 22 789 bp chosen from autosomal,
mitochondrial, X- and Y-linked loci) that were sequenced in
all cat species [1]. Available tree-building algorithms con-
verged on a phylogenetic tree on which the nodes could be
dated with a dozen well-calibrated fossils. The earliest
predecessor of living cats, Pseudaelurus, lived in Eurasia
during the Miocene and spawned the Asian ancestor of
modern cats 11 MYA. Molecular phylogeny defined eight
principal Felidae lineages (Figure 3), descended from
major Miocene divergence events that form the axiom
for Felidae genus recognition [69]. Armed with robust
and high resolution molecular phylogeny, the fossil-cali-
brated dates for the branches, the current and historic
locations of cat species and a record of global sea level
changes and continental movements, we postulated a
plausible sequence of 11 historic felid migrations to explain
available data [1,2]. This scenario describes our current
understanding of how cats came to be (Figure 3).
Table 2. Counting ancestral translocations and inversions (breakpoints) that discriminate the genome of cat from index mammals
Counts Number of chromosome breakpoint events in comparing cat to
Human Chimpanzee Mouse Rat Dog
Breakpoints (BP) 135 136 256 258 100
Translocations 29 29 110 106 58
Inversions 106 107 146 152 42
Translocation:inversion 0.27 0.27 0.75 0.70 1.38
BP/MY 0.71 0.74 1.36 1.4 0.89
a
The number of interchromosomal exchanges (translocations) between the genome of cat versus primates is two to five times lower than that of cat versus ‘shuffled’ taxa
mouse, rat and dog, whereas intrachromosomal exchanges (inversions) are fourfold higher in cat versus primates than translocations. This difference is apparent in low
translocation:inversion ratios in cat-primate versus cat-rodent or cat-dog, and results in a balanced overall rate (BP/MY) among all comparisons (see Refs. [8,26,60]).
Figure 1. Homologous synteny blocks (HSBs) relative to cat chromosomes B4 and X defined by conserved sequence blocks across six index mammalian species’ genome
sequences [8,26,60]. HSBs reflect the chromosome segments that are retained across divergent mammals, allowing one to reconstruct the chromosome exchanges and
breakpoint that punctuate genome organization throughout the mammalian radiation (see main text and Table 2 for more details).
Review Trends in Genetics Vol.24 No.6
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The first split from the Pseudaelurus occurred 10.8
MYA in Asia, producing the five great roaring cats of the
genus Panthera (lion, tiger, leopard, jaguar and snow
leopard) and the earliest offshoot (the two clouded leopard
species). Interestingly, a novel species of clouded leo-
pards, Neofelis diardi, the first new Felidae species
described in a century, was defined recently on the basis
of genomic analysis [70,71]. A second major separation,
also in Asia, led to the Bornean bay cat lineage, a group
that evolved, speciated and currently resides in Southeast
Asia. The next divergence and first intercontinental
migration founded the caracal lineage, three African
cat species whose progenitors crossed into Africa 6–10
MYA (migration route A; Figure 3). During the Miocene,
sea levels were 60 m below current levels such that
Africa and the Arabian Peninsula were connected by land
bridges across the Red Sea, facilitating the first felid
migration to Africa. During the same period, cats dis-
persed across Asia and traversed the Bering Straits to
Alaska (migration route B; Figure 3). The earliest pro-
genitors of three subsequent cat lineages, (the ocelot, lynx
and puma) were found in North America. Thus, cats were
present in Asia, Europe, Africa and North America. Sub-
sequently the sea levels rose, separating the continents;
the changing habitats of the now ‘isloated’ cats contrib-
uted to the evolution of new cat species we are familiar
with today.
A dynamic evolutionary process in North America
produced the lynx and puma lineages 8.0 and 7.2 million
years ago, respectively, to generate pumas, jaguarundi,
American cheetahs, three lynx species and bobcats, species
whose fossil remains in American deposits affirm their
Western Hemisphere origins. Eurasian lynx species’ pro-
genitors and American cheetahs would later migrate back
to Asia during the Pliocene (3–4 MYA) when the sea levels
dropped once more (migration route D; Figure 3).
Toward the end of the Pliocene (2–3 MYA), the oceans
receded once again, and the North and South American
continents were connected by the Isthmus of Panama.
North American cat species were able to migrate south
via the Isthmus of Panama (migration route C; Figure 3),
where they encountered a continent with no placental
carnivores (i.e. no bears, dogs, cats, skunks) [72,73]. South
America had been isolated from northern land masses for
tens of millions of years (since Australia, Africa and South
American parted from the southern supercontinent
Gondwanaland >100 MYA). Several marsupial species,
including a few successful carnivorous varieties, had
evolved in South America. These carnivorous marsupials
were no match for the newly arrived cats [72,73]. Out-
competed in their habitat and ecological niches, nearly all
marsupials were quickly replaced by migrant carnivores
such as the cats from the ocelot lineage, a divergent group
of seven feline species that survive in South America.
Figure 2. Geographic distribution and Latin names for the 37 living species of the Felidae family. All these species except domestic cats are considered threatened or
endangered by the conservation organization of the world.
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Contemporaneous with the cats arrival in South America,
North American dogs took the empty southern continent as
a terrific opportunity to exploit. New South American
Canidae (dog family) species rapidly evolved and, similar
to the Felidae, they would display a wide breadth of
morphological and physiological adaptations [44,74].
More recently, cheetahs and pumas became extinct in
North America, after the last ice age 12 000 years ago. A
major Pleistocene extinction of mammals eliminated 40
species of mammals from North America, including 75% of
the large vertebrates living there [75,76]. Mammoths,
mastodons, dire wolves, massive short-faced bears, giant
ground sloth, American lions, saber-tooth cats, puma and
cheetahs abruptly disappeared from North America. Much
earlier, ancestral populations of cheetahs living in Asia
would migrate to Africa where they survive today. Pumas
avoided complete annihilation as some had moved to South
America and returned to North America many generations
later (migration route E; Figure 3)[77]. The other large
mammal species would never return. The series of
migration events needs to be confirmed by more extensive
paleontological and geographical precision in the future; if
it is, it would provide one of the most detailed accounts of
natural history dispersal for any mammalian species
group.
Origins of cat domestication
The next act in the cat’s journey, from the wild to human
settlements, occurred 10 000 years ago in Southwest
Asia. At that time, a handful of diminutive cat species
intermingled within dense forests of the Mediterranean
basin: jungle cat, desert cat and a ubiquitous wildcat
species, Felis silvestris, which had three recognized wildcat
subspecies – F. silvestris silvestris (European wildcat),
F.s. ornata.(Middle Eastern wildcat) and F.s. lybica (Asian
and Near Eastern wildcat). From one of these progenitors,
perhaps the most successful experiment in cat natural
history began – that of cat domestication.
A recent phylogeographic study of wildcats and
domestic cats (N = 979) from three continents (Figure 4)
Figure 3. Molecular phylogeny of Felidae [1,2]. The branching hierarchy of the cat family as discerned from an analysis of 30 genes from members of each species. Modern
cat species assort into eight lineages, each representing a close relative relationship among species within each group. The time scale is imputed from several dates of
fossils that define certain portions of the tree (arrows). The geological periods during the 11 million year interval of cat evolution are presented beside the time scale. The
global sea levels relative to current sea level are shown in meters. Arrows A–E depict five imputed ancestral migration routes discussed in text that we infer were traversed
by ancestors of modern cat species.
Review Trends in Genetics Vol.24 No.6
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used 36 STR loci and 2604 bp of mitochondrial DNA to
resolve subspecies structure of F. silvestris and their
relationship to domestic cats [42]. Although it was well
known that modern wildcat populations often include
ongoing admixture of domestic cats and wildcats [42,78
81], subspecies-specific nuclear and mtDNA lineages in each
population were clearly resolved. For example, in sub-
Saharan Africa, two versions of mtDNA genotypes were
apparent (domestic and African wildcat; beige and blue
pie charts, respectively, in Figure 4). The derivative mol-
ecular phylogeny for five geographically distinct subspecies
(F.s. silvestris, F. cafra, F.s. ornata, F.s.lybica and F.s. bieti)
were monophyletic and well resolved using both mtDNA
sequence (Figure5a) and composite STR genotypes [42].The
analysis also showed that a large assemblage of domestic
cats from across the globe (including 112 fancy breed cats)
had genotypes that were indistinguishable from the
clades defined by the Near East subspecies F.s. lybica.
Furthermore, a STRUCTURE-based population genetic
analysis identified a discrete population of wildcats from
the Near East (Israel, United Arab Emirates and Saudi
Arabia; Figure 5b) that probably reflects the ancestral
founder population for the world’s domestic cats.
The oldest known archaeological deposits that show co-
occurrence of cat and human remains date to 9500 years
ago in Cyprus [82], some 5000–6000 years before the
ancient Egyptian civilization existed, which had been
thought to be the site of cat domestication [83–86]. Alter-
natively, the combined genomic archaeological data seem
to point to a domestication event in the Near East around
the same time as the first agricultural village settlements
in the Fertile Crescent (10 000 years ago).Perhaps the
Figure 4. The current range of Felis silvestris and areas of sample collection are shown [42]. The colored regions reflect the location of capture of individuals with different
short tandem repeat and mitochondrial DNA (mtDNA) clade genotypes (defined in the bottom left). mtDNA haplotype frequencies are indicated in pie charts specifying the
number of specimens carrying each mtDNA haplotype clade. Domestic cats, F. s. catus, are distributed world wide and overwhelmingly carry Clade IV mtDNA haplotypes
(beige). The inset on the right shows the current and historic range of F. silvestris subspecies on the basis of traditional morphology-based taxonomy. The Chinese desert
cat is considered a wildcat subspecies, F. silvestris bieti as supported by data presented in Ref. [42].
Review Trends in Genetics Vol.24 No.6
274
Figure 5. Resolving the origins of cat domestication. (a) Phylogenetic tree of mitochondrial DNA sequence (minimum evolution/neighbor joining phylogram of 2604 bp of the
genes NADH5 andNADH6) of 176 haplotypes discerned from 742 catssampled across the range of the domestic cat, European,Asian and African wildcat,Chinese desert cat and
sand cat. Trees created from Bayesian, maximum likelihood (ML) and maximum parsimony (MP) methods result in identical topologies for clade groupings. Confidence/
bootstrap values [Bayes/MP/ML/minimum evolution (ME)] are basedon 1000 iterations and areadjacent to nodes. The numberof single nucleotide differences is indicatedin red
below the corresponding branch. Clade designations and number of individuals is indicated in parentheses after the corresponding common name and taxonomic trinomial.
Beige Clade IV bearing mtDNA haplotypes are found among domestic cats, inwild potentially admixed populations in Europe,Asia, or Africa (see Figure 4) and in Near Eastern
wildcats (see main text for further details). Nodes A–E are mtDNA lineages occurring in moderndomestic cats that they retain fromtheir wildcat forbearers, F.s. lybica;seetext.
(b) STRUCTURE-based populations resolved 851 cats intoseveral wildcat groups, three domestic cat groups and one group (brown) that included both domestic cats and Near
East wildcats [42,92].y-axis represent Q-value, the percent representation of resolved populations (colors) within each individual (listed on x-axis) [42,92].
Review Trends in Genetics Vol.24 No.6
275
wild cats made themselves useful to early farmers by
dispatching rodents from the early grain stores.
Evidence suggests that cats were probably domesticated
on multiple occasions in separate locations, because at
least five much older (>100 000 years old) mtDNA lineages
were found in extant domestic cats (Clades A–E in
domestic cat cluster in Figure 5a). From the Near East
origins of domestication, subsequent gradual movements
of cats with their human companions would spread
domestic cats across the globe. The 600 million domestic
cats alive today comprise the only Felidae species (Felis
catus) that is not considered to be threatened or endan-
gered by the world’s conservation bodies [87].
By the time of the industrial revolution (late 18th–early
19th century), pet cat owners were selectively mating their
pet tabbies to produce fancy breeds. The American Cat
Fanciers Association (http://www.acfacats.com) and the
International Cat Association (http://www.tica.org) cur-
rently recognize 68 official cat breeds, from Maine Coon,
Siamese, Persian to Korat; all of their roots can be traced to
the origins of human and feline civilization in the Fertile
Crescent.
Figure 6. Phylogenetic neighbor-joining tree (a) of individuals from 38 cat breeds based on distance matrices generated from proportion of shared alleles algorithm (Dps)
from composite genotypes [83]. Bootstrap support for branches that are supported in >60% of 100 replicates are indicated. The asterisk indicates a group of breeds that was
derived completely or in part from Southeast Asian ancestors. The histogram (b), generated from STRUCTURE analysis of 1040 cats, shows the proportion of each
individual’s genome that originated from 22 populations [83,92]. The numbers in colored blocks refer to 22 distinct cluster groups that were resolved. Some populations are
composed of multiple breeds [83].
Review Trends in Genetics Vol.24 No.6
276
Modern cat breeds derive from the earliest fancy
breeds (Siamese, Persian, Korat, Egyptian Mau, Manx,
Turkish Angora and others) established around the 17th
century to the most recent (American Curl, Selkirk Rex,
Singapora) established during the late 20th century [88].
A comprehensive SNP and STR survey of 38 cat breeds
(27 individuals per breed, 1040 cats in total) revealed
only modest phylogenetic and population genetic
partitions caused by the recent timing of breed initiation
and (unlike dog breeds) the allowable intercrossing be-
tween certain breeds in recent generations [89,90].None-
theless, there is a recognizable and diagnostic population
structure that permitted confirmation of 96% breed
assignment on the basis of a forensic panel of ten highly
informative, tetra-nucleotide STR loci [91].InFigure 6,
we present a phylogenetic topology of 34 cat breeds based
on composite STR genotype, population genetic–based
STRUCTURE algorithm output of the same individuals.
The results provide a genomic view of the slight but
useful genetic differentiation among modern breeds of
domestic cats [89,90].
Concluding remarks and future perspectives
Humans’ fascination with cats seems to have spread to the
science and genetic community. We have attempted to
highlight here some of the genetic advances that provide
new opportunities for better understanding cat biology
and the evolutionary processes that created this exqui-
sitely successful group of predators. The tools have appli-
cations in every aspect of cat biology, and it is exhilarating
for us to witness the invigoration of science potential for
the species.
Whether pursuing genetic diseases, behavior or species
conservation, the cat has provided powerful examples and
lessons of evolutionary, developmental and adaptive pro-
cesses. We anticipate a bright future for the cat’s entry
among the company of major animal models of genetic
biology.
Acknowledgements
Work in our laboratory is funded in whole or in part with federal funds
from the National Cancer Institute, National Institutes of Health, under
Contract N01-CO-12400. The content of this publication does not
necessarily reflect the views or policies of the Department of Health
and Human Services, nor does mention of trade names, commercial
products or organizations imply endorsement by the U.S. Government.
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