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Genome Res. Nov 2007; 17(11): 1675–1689.
PMCID: PMC2045150

Initial sequence and comparative analysis of the cat genome

Abstract

The genome sequence (1.9-fold coverage) of an inbred Abyssinian domestic cat was assembled, mapped, and annotated with a comparative approach that involved cross-reference to annotated genome assemblies of six mammals (human, chimpanzee, mouse, rat, dog, and cow). The results resolved chromosomal positions for 663,480 contigs, 20,285 putative feline gene orthologs, and 133,499 conserved sequence blocks (CSBs). Additional annotated features include repetitive elements, endogenous retroviral sequences, nuclear mitochondrial (numt) sequences, micro-RNAs, and evolutionary breakpoints that suggest historic balancing of translocation and inversion incidences in distinct mammalian lineages. Large numbers of single nucleotide polymorphisms (SNPs), deletion insertion polymorphisms (DIPs), and short tandem repeats (STRs), suitable for linkage or association studies were characterized in the context of long stretches of chromosome homozygosity. In spite of the light coverage capturing ~65% of euchromatin sequence from the cat genome, these comparative insights shed new light on the tempo and mode of gene/genome evolution in mammals, promise several research applications for the cat, and also illustrate that a comparative approach using more deeply covered mammals provides an informative, preliminary annotation of a light (1.9-fold) coverage mammal genome sequence.

During 2005, the National Human Genome Research Institute (NHGRI) endorsed a “light” coverage (2×) whole-genome sequencing strategy for 26 mammals, including Felis catus, the domestic cat (Supplemental Fig. S1). The domestic cat was included in this mammalian genome set mainly to stimulate genome research on a species that provides a large number of important human medical models (Supplemental Table S1). Cats, like dogs, enjoy an extensive veterinary medical surveillance that has described ~200 genetic diseases analogous to human disorders (Griffin and Baker 2000; O’Brien et al. 2002; O’Brien 2004). Feline infectious agents offer powerful natural models of deadly human diseases including feline immunodeficiency virus (FIV)-AIDS, feline coronavirus (FeCoV)-SARS and avian influenza, canine distemper virus (CDV)-neurotropic viruses, and feline leukemia and sarcoma virus (FeLV, FeSV)-leukemia and sarcoma (O’Brien et al. 2002; Kuiken et al. 2004; O’Brien 2004). Cats are a domesticated representative of a family, Felidae, that includes some of the most successful, but now the most threatened, predator species to walk the earth (Nowell and Jackson 1996; O’Brien and Johnson 2005). The rich literature of feline disease pathogenesis, human fascination for cats in art and history, plus the demonstration of a highly conserved ancestral genome organization make the cat genome annotation a highly informative advance that complements other research endeavors (O'Brien et al. 1999; Lyons et al. 2004; Fyfe et al. 2006; Johnson et al. 2006).

Although 2× genome coverage would provide limited (<80%) sequence representation of a species, it supports the primary goal of cost-effective identification of highly conserved sequence elements revealing patterns of conservation and divergence across the mammalian radiation. Moreover, the availability of annotation of six mammal genomes sequenced at high coverage (Wheeler et al. 2005; http://www.ncbi.nlm.nih.gov), a radiation hybrid (RH) physical map of cat including some 1680 markers (Murphy et al. 2007), plus new algorithms and bioinformatics tools described here have facilitated a depth of genome annotation not possible for earlier light-coverage genomes (Kirkness et al. 2003; O’Brien and Murphy 2003).

Recognition of expressed genes in a genome entails deciding which regions correspond to potential transcripts. Common strategies to this end include aligning the genome to cDNA sequences, such as the Riken mouse cDNA library (The FANTOM Consortium and the RIKEN Exploration Research Group Phase I and II 2002); the detection of similarity between imputed translations of genomic DNA and sequences of known proteins; and the use of de novo predictions of genes based on open reading frames using such programs as GENSCAN (Burge and Karlin 1997). The availability of six deep-coverage (3.6- to 7-fold) mammalian genomes enables the annotation of additional mammalian genome sequences by a combination of sequence alignments, map locations, and gene identification described here for the cat genome. The comparative strategy has the added advantage of sequence homology alignments between annotated genes, introns, and intergenic regions, as well as gene order synteny as a criterion for gene homology.

Here we describe an annotation of the cat genome based on 1.9× genome sequence. In spite of light sequence coverage, the analysis revealed numerous genome sequence features; a view of the rearrangements that have occurred since the primate, rodent, and carnivore orders diverged; and interesting aspects that stand out for cats among mammals. Our key findings include:

  1. Definition, assembly, and chromosome mapping of >1 million reciprocal best match alignments (RBMs) between cat and six other mammalian genomes, revealing a set of 133,499 conserved sequence blocks (CSBs) present in all seven genomes (Supplemental Tables S2 and S3).
  2. Assigning the chromosomal position of CSBs in six mammals enabling the construction of a set of homologous synteny blocks (HSBs) and use of these blocks to discern chromosomal exchanges between cat and other mammalian genomes. Deduced patterns of chromosomal exchanges that punctuate mammalian genome evolution (Figs. 1, ,2;2; Supplemental Table S4), revealing a balance between inter- and intrachromosomal rearrangements in primate, rodent, and carnivore lineages.
    Figure 1.
    Homologous synteny blocks (HSBs) of the cat genome as compared to corresponding syntenic blocks in five mammalian species: (Cfa) Canis familiaris, (Hsa) Homo sapiens, (Ptr) Pan troglodytes, (Mmu) Mus musculus, and (Rno) Rattus norvegicus. The empty line ...
    Figure 2.
    Counts and rates of chromosome rearrangements detected among human, chimpanzee, cat, dog, mouse, and rat genomes, based on HSBs of at least 500 kb. Branches are labeled on the top with the estimated minimum number of intrachromosomal rearrangements (inversions) ...
  3. Discovery and mapping of some 20,285 regions orthologous to genes annotated in other mammalian genomes (Table 1).
    Table 1.
    Features of the cat genome annotation and of other mammalian genomes
  4. Details of interspersed repeat families relative to the human and dog genomes (Table 2).
    Table 2.
    Interspersed repeat elements of cat and other mammals
  5. Detection of previously undiscovered lineages of nuclear mitochondrial (numt) gene sequences distributed across all cat chromosomes (Fig. 3; Supplemental Fig. S2).
    Figure 3.
    Phylogenetic analyses of felid mitochondrial (cymt) and homologous domestic cat numt sequences. Divergence dates of numt lineages-defining nodes were estimated following Lopez et al. (1994). Divergence dates (in gray boxes) assumed for the Felidae radiation ...
  6. Description of previously undiscovered retroviral elements that are 10 times more abundant in the cat genome than FeLV or RD114 sequences (Fig. 4; Supplemental Fig. S3; Table 3).
    Table 3.
    Genomic coverage of feline retroelements
    Figure 4.
    Phylogenetic relationship among endogenous retroviruses. (A) Endogenous FeLV present in the genome of the domestic cat. Analysis is based on a 274-bp alignment of 13 previously published proviral LTRs (GenBank accessions) and 47 cat genomic sequences ...
  7. Identification of 327,000 new SNPs, 208,177 new STR loci, and a mosaic genome pattern of homozygosity useful for linkage disequilibrium mapping of complex traits in the cat (Fig. 5).
    Figure 5.
    Homozygosity across Cinnamon’s chromosomes represented in non-overlapping windows of 100 kb. (Red) Regions with more than two SNPs per 100 kb; (green) homozygous regions (<2 SNPs/100 kb); (white gaps) gaps in the chromosome assembly.
  8. A dynamic online genome browser of Genome Annotation Resource Field (GARFIELD) (Pontius and O’Brien 2007) for the display and download of the assembly annotations, with hyperlinks to and related bioinformatics resources (http://lgd.abcc.ncifcrf.gov; Fig. 6).
    Figure 6.
    Gene Annotation Region Field (GARFIELD genome browser; http://lgd.abcc.ncifcrf.gov) showing the region of the cat genome corresponding to the taste receptor gene TAS1R2 on chromosome C1 at two levels of resolution. (A) Chromosome view showing homologous ...

The feline genome sequence, assembly, and map

We sequenced the genome of a female Abyssinian cat (Cinnamon, who resides at the University of Missouri, Columbia, MO) at Agencourt Bioscience Corp. (Beverly, MA), using a whole-genome shotgun (WGS) approach (Supplemental Table S5). Sequence data were assembled using both the PHUSION (Mullikin and Ning 2003) and Arachne (Batzoglou et al. 2002; Jaffe et al. 2003) programs, with the latter incorporating a novel assisted assembly algorithm (Supplemental Methods). This algorithm uses the read placement on two reference genomes (human and dog) to confirm the linking information from their independent assembly. A total of 8,027,672 sequence reads (84% from plasmids and 16% from fosmid paired ends) were assembled to 817,956 contigs, covering 1.642 Gb of sequence with an N50 contig length (i.e., half of the sequenced base pairs reside in contigs >N50) of 2378 bp (Supplemental Table S6). Contigs were then assembled into scaffolds (N = 217,790, N50 length of 117 kb) assisted by a close evolutionary relationship of cat and dog, both members of the mammalian order Carnivora. The cat genome size estimate of 2.7 Gb (2.5 Gb euchromatin) was imputed by extrapolating the average length of the cat sequence within fosmids as compared to the homologous sequence stretches in the dog and human genomes, presuming a genome size of 2.8 Gb for human and 2.4 Gb for dog. The cat genome coverage (~1.9×) is lower than the finished or “deep” coverage mammalian genome sequence recently annotated (finished human, mouse and rat 7×, dog 7.5×, and cow 7.1×), but between the chimpanzee (6×) and the earlier dog (1.5×) (International Human Genome Sequencing Consortium 2001; Venter et al. 2001; Mouse Genome Sequencing Consortium 2002; Kirkness et al. 2003; Rat Genome Sequencing Project Consortium 2004; Chimpanzee Sequencing and Analysis Consortium 2005; Lindblad-Toh et al. 2005; http://www.hgsc.bcm.tmc.edu/projects/bovine/). The relatively low coverage is reflected in more contigs, lower contig N50, and lower overall euchromatin genome coverage (60% of the 2.7-Gb genome, or 65% of the 2.5-Gb euchromatin genome) than for the higher coverage genomes.

To order and orient the assembly onto the feline chromosomes, we constructed a sequence map using comparative data available from high-coverage dog and human genomes. The map was built by first aligning the feline sequence to the CanFam2 version of the domestic dog genome (Lindblad-Toh et al. 2005) using BLASTZ (see Supplemental Methods). Initially, scaffolds were placed in the same order and orientation as their homologs in dog. When scaffolds defined by the Arachne assembly mapped to more than a single dog chromosome (425 scaffolds represented by at least two included contigs), the scaffolds were broken and placed on separate dog chromosomes. A total of 1680 ordered markers from the radiation hybrid map (Murphy et al. 2007) were then used to place scaffolds on cat chromosomes. The mapped feline contigs include 1.36 Gb from 663,480 contigs, or 54% of the 2.5-Gb euchromatin genome. The cat whole-genome sequence (WGS) contigs are available at the Broad Institute, the National Center for Biotechnology Information (NCBI), Ensembl, UCSC (http://www.broad.mit.edu; http://www.ncbi.nlm.nih.gov; http://www.ensembl.org; www.genome.ucsc.edu), and the assembly ordered on the cat chromosomes can be found at the NCI-GARFIELD browser (http://lgd.abcc.ncifcrf.gov).

To evaluate the assembly and mapping achieved for the cat genome sequence, we compared it to two “finished” cat genome subset regions, each derived from BAC-based (bacterial artificial chromosome library) sequence assemblies. First, we evaluated 18 Mb of the 30 Mb of the ENCODE project sequenced for cat by the NIH Intramural Sequencing Center (ENCODE Project: ENCyclopedia Of DNA Elements; The ENCODE Project Consortium 2004; Guigó et al. 2006). All but four of 30 ENCODE regions (Table 4) map to cat chromosomes, and two of these are split into segments that are not assigned to cat chromosomes. To gauge the level of orientation problems, the alignment of each ENCODE region was divided into 1-kb segments, and these segments as mapped onto the cat assembly were evaluated for correct orientation. The most challenging region was the beta-globin region, ENm009, with the fraction of correctly oriented 1-kb segments at 85%. This region is also difficult for the NISC BAC assembly as there were three BAC clone gaps for this region. Supplemental Figure S4 shows the coverage and average contig size for each of the regions calculated by aligning the multi-BAC assemblies for each region to the WGS assembly and then taking all ordered and oriented contigs within that segment of the WGS assembly and realigning the two versions of each ENCODE region to each other using Cross_match software (P. Green, unpubl.). From this, we derived coverage and average contig size for each region. We also mapped the position of each contig in the assembly to its corresponding region in the ENCODE multi-BAC assembly, producing the plots shown in Supplemental Figure S5 for six example regions. The long-range order and orientation (length of chromosomes) were confirmed in these analyses across the sampled ENCODE regions.

Table 4.
Comparison of ENCODE regions in the multi-BAC cat assemblies to same regions in the cat genome assembly

The second region was the 3.3-Mb feline major histocompatibility complex FLA, which has been sequenced and ordered from a BAC library (O’Brien et al. 1999; Yuhki et al. 2003; Beck et al. 2005) (Fig. 7). FLA is broken into two distinct regions of the cat’s genome, the first containing class II, class III, and 12 class I-like genes (2,975,515 bp) adjacent to the chromosome B2q centromere, and the other (361,545 bp) on the B2p telomere containing six genes of the distal class I region. The high density of genes, the existence of multiple gene paralogs, plus the rapid evolution of class I and class II genes render this region among the most challenging for gene annotation. In Figure 7, we present a map comparing the sequence coverage of the feline whole-genome sequence aligned to the FLA BAC, to the dog major histocompatibility complex, DLA, represented in the dog WGS assembly, and to the human major histocompatibility complex, HLA. From this comparison, the feline WGS includes a detectable sequence from 191 of 202 FLA gene sequences (95%) present in the FLA BACS (58 class II, 40 class III, and 93 class I region genes). Of these, 104 (54% of FLA genes) included >50% of the gene exons seen in DLA (CanFam 2). The large representation of MHC genes in cat WGS (95% of cat MHC genes), the recapitulation of gene syntenic orthology, the recovery of 54% of BAC-based FLA genes with >50% exonic sequences, plus the designation of 11,000 SNPs within FLA (see below) constitute an extensive annotation considering the light sequence coverage and the refractory nature of this region.

Figure 7.
FLA annotation from finished BAC sequence (RPCI 86 BAC library constructed from the DNA of a domestic cat, Gus) and 1.9× WGS contigs alignment with three MHC models (Yuhki et al. 2003; Beck et al. 2005). Two segments of cat MHC (FLA) sequences—2.976-Mb ...

Over the course of the sequencing of the cat genome and assembly of the sequence traces, the data were used in the mapping and characterization of several cat genes (footnote a in Table 5). For two phenotypes, spinal muscular atrophy SMA-LIX1 (Fyfe et al. 2006) and dilute MLPH (Ishida et al. 2006), linkage mapping was performed in pedigrees using additional STRs, tightly linked to candidate genes. The order of the STRs in these genomic regions, which cover tens of centimorgans, was exactly concordant with the orders of the markers imputed in the WGS assembly (Supplemental Table S7). In the case of both MLPH and SMA-LIX1 regions, the cat marker order includes a rearrangement in the cat genome with respect to human and dog. Agreement between marker orders for SMA-LIX1 and MLPH by linkage analyses versus the cat WGS assembly of the same regions plus the finished ENCODE and FLA regions’ order agreement with the cat WGS assembly provide independent validation of cat WGS assembly for all these regions.

Table 5.
Feline genetic diseases/phenotypes characterized at the molecular level

Genome landscape

Gene annotation

The cat genome contigs were aligned to NCBI annotated genome sequence of six index mammalian genomes (human, chimpanzee, mouse, rat, dog, and cow) (Wheeler et al. 2005; http://www.ncbi.nlm.nih.gov) using MegaBLAST (Zhang et al. 2000). These alignments include between 267,764 (cat vs. rat) and 1,235,641 (cat vs. dog) reciprocal best matches (RBMs) of average length ranging from 927 to 1000 nt (Supplemental Table S2). The mean percent identity of the alignments was highest for dog (79%), followed by cow (73.4%), primate (73.0%), and rodent (69%). Slight length discrepancies between the species imply that the primate-aligned regions are on average 0.5% longer than their cat counterpart, while those of rodent are 2.0% shorter, and cow and dog span regions of similar lengths.

Each RBM between cat and an NCBI-annotated mammal genome sequence was screened for matches with annotated genes and gene features (exons, introns, UTRs, upstream and downstream regions of protein coding genes) within that mammal. The average percent nucleotide of the NCBI annotated mammalian gene features that aligned to the cat sequence is summarized in Table 6. To support gene identification, syntenic orthology of a putative cat gene was assessed by determining whether its adjacent feline genes (one upstream and one downstream of a particular cat gene candidate) were homologous to adjacent genes of the gene ortholog in the index mammal genome. Cat genes with homologous neighbors on both sides in an index species were considered to be part of an exact syntenic gene triplet. For dog, 92% of the cat orthologs are exact syntenic triplets. Inexact triplet gene matches (when at least one of two upstream neighbors and one of two downstream neighbor genes matched) reach a high of 94% in dog–cat and 90% in human–cat comparisons (Table 1).

Table 6.
Annotated features from mammalian genomes and their representation in the Felis catus assembly

A summary of gene annotation statistics is presented in Table 1 and is available in our feline genome Web browser GARFIELD (Fig. 6). Feline gene orthologs from different mammalian species comparisons were then merged to define a set of nonredundant genes on the cat genome. The merging process involved 11 steps (detailed in Supplemental Methods) that are based on those RBM alignments that span the annotated mammalian genes, with priority given to those alignments that span exons. A list of 20,285 putative genes discovered includes homologs for 80% of annotated dog genes, 90% of human genes, and slightly fewer in the other mammals’ gene lists (Table 1). The average percent coverage of these gene coding sequences ranged from 64% to 81% of the length of the gene in the NCBI annotated mammals (Table 1). Although there exist observed and anticipated weaknesses in the comparative approach (e.g., inconsistencies between different mammals, evolutionary distance, gene birth and death, gene annotation quality for different mammals, and absence of cDNA transcript sequences), the identification of >20,000 gene candidates represents a preliminary glimpse of the disposition of the cat’s gene complement.

Comparative genome organization

A CSB is a sequence that is represented by an RBM in two or more genomes (Bejerano et al. 2004; Siepel et al. 2005). An invaluable application of a new mammalian genome assembly is comparative genomic inference derived from inspecting the linear position of conserved sequence (Bourque et al. 2004; Murphy et al. 2004; Everts-van der Wind et al. 2005). By applying the principles of rearrangement parsimony, one can reconstruct the extent and pattern of chromosome segment exchanges that occurred during lineage evolution among different mammalian orders. Such comparative genomic analyses enjoy much higher precision with the availability of whole-genome sequences of additional mammals.

To build comparative maps between cat and each of the other genomes, we used GRIMM-Synteny (Pevzner and Tesler 2003; Bourque et al. 2004) to construct 339 HSBs of size ≥500 kb (Fig. 1). These were based on the 98,313 six-way CSBs (i.e., shared between cat-dog-human-chimpanzee-mouse-rat) that were placed on chromosomes (unplaced contigs, as well as the entire cow genome, which includes large numbers of unplaced contigs, were not included in this analysis; see Supplemental Methods). For each species comparison, the imputed coordinates of the chromosome breakpoints were assembled and tabulated. These blocks represent large-scale orthologous regions that may include small-scale internal shuffling but reflect ancestral chromosomal rearrangements that occurred in different ordinal lineages.

We used the MGR and GRIMM algorithms to construct a rearrangement-based evolutionary scenario minimizing inversions, translocations, fusions, and fissions (Bourque and Pevzner 2002; Tesler 2002a, b). We estimated the number of rearrangement events among these species’ genomes as well as between modern species and imputed genome arrangement of four putative ancestors: a cat/dog carnivore ancestor (CDA; 55 million years ago [Mya]), a mouse/rat ancestor (MRA; 16 Mya), a chimpanzee/human (Pan/Homo) ancestor (PHA; 5.5 Mya), and a Euarchontoglires ancestor (EA; 87 Mya) (Kumar and Hedges 1998; Springer et al. 2003).

In Figure 2, we present a phylogenetic tree of the six mammals with the number of imputed intrachromosomal and interchromosomal arrangements listed on each lineage. Three to four times more intrachromosomal rearrangements versus interchromosomal rearrangements were observed for cat and primate lineages. On the path from the Carnivore ancestor (CDA) to cat, we estimate at least 37 inversions and 10 interchromosomal rearrangements (seven translocations and three fusions), while from CDA to dog we estimate five inversions and 48 interchromosomal rearrangements (31 translocations and 17 fissions). For the primates, we estimate 42 inversions, eight translocations, and one fission on the path from the Euarchontoglires ancestor (EA) to the chimpanzee/human ancestor (PHA). For rodents, intrachromosomal and interchromosomal rearrangements are roughly balanced (Fig. 2; Supplemental Table S4).

These results reflect the well-known interchromosomal reshuffling of murid and canine genome organization relative to the more conserved disposition in the human (primate) or cat (Felidae) genomic history (O’Brien et al. 1999; Bourque et al. 2004; Murphy et al. 2004, 2005). The apparent dichotomy of the interchromosomal exchange rate (i.e., slow in most lineages, but accelerated in others) was apparent from early comparative gene mapping and chromosome painting studies, which were insensitive to intrachromosomal inversions. However, the number of intrachromosomal rearrangements for cat and primates is higher than the number of interchromosomal, while interchromosomal are predominant over intrachromosomal rearrangements in the dog and rodent lineages. Thus, in the carnivore lineage, the total rate of chromosomal exchanges (i.e., inter- and intrachromosomal) for cat (0.85/Myr) is roughly equivalent to that of dog (0.96/Myr), and these rates are similar to the rates of rearrangements in the primate lineage for human (1.09/Myr) and chimpanzee (1.27/Myr), while being approximately half the rate in the rodent lineages, specifically, of mouse (2.25/Myr) and rat (2.38/Myr).

Together, the observations suggest a re-thinking of the previous paradigm of dichotomous modes of chromosome exchange, that is, rapid in genome-shuffled lineages such as dog, bears, murids, gibbons, and New World monkeys and a slower default mode in conserved lineages such as felids, cetaceans, most primates, and other mammals (O’Brien et al. 1999; Murphy et al. 2004). The heretofore conserved species’ genomes (the slow default mode group) display a slow translocation rate that suggested a close homology with the imputed ancestral genome organization for placental mammals, estimated to have lived some 105 Mya (Murphy et al. 2001; Springer et al. 2003). However, these differing ratios of translocations to inversions, which were also suggested by the recent dog genome and cat RH map analyses (Lindblad-Toh et al. 2005; Murphy et al. 2007), show that both human and cat lineages display an apparent speed-up of intrachromosomal inversions relative to the rapid-translocation species, suggesting an overall range of breakpoint occurrence rates among the mammals studied that is narrower than previously supposed.

Repetitive elements

Mammalian genome sequences carry a sizable proportion of interspersed repeat sequences (Table 2), including vestigial mobile elements that invaded the ancestral genomes of modern species. Nearly half (46.5%) of the human genome is flagged by RepeatMasker (A.F.A. Smit, R. Hubley, and P. Green, 1996–2004. RepeatMasker Open-3.0; http://www.repeatmasker.org) as being repetitive, with slightly lower representation (39.1%) in the mouse. The cat sequence also shows a relatively low prevalence of interspersed repeats (32.12% of contigs). Low levels of repeats were also detected in the “finished” FLA region (3.8 Mb from cat BAC sequence and assembly) (Yuhki et al. 2003; Beck et al. 2005) and also in the cat’s 18-Mb ENCODE region (The ENCODE Project Consortium 2004; Guigó et al. 2006), suggesting that the reduction is not an artifact of low (1.9×) coverage. The observed level does raise the possibility that the cat genome includes repetitive elements that are not included in or detected by the RepeatMasker libraries.

A more detailed analysis was done of specific repeat classes, including LINES, SINES, and Satellite DNA (Table 2; Supplemental Fig. S6; see Supplemental Materials). A feline-specific Satellite DNA (FA-SAT) reported as representing 1%–2% of the cat genome (Fanning 1987) comprised 2.1% of the 1.9× cat contigs. In spite of assigning a high percent of the LINE sequences to cat chromosomes, no full-length LINE elements were assembled. Sequence analyses of SINE elements revealed that the majority likely originated from tRNALys as observed in previous felid studies (Pecon-Slattery et al. 2000, 2004). Additional phylogenetic analyses (Supplemental Fig. S7) affirmed that the majority are members of the FC1 and FC2 SINE group that is exclusively found in cats (Fanning et al. 1988; Smit 1996). The remainder were SINEs that were related to canid and carnivore SINES (Fanning et al. 1988; Smit 1996; Vassetzky and Kramerov 2002) and appeared more ancestral.

Short tandem repeats (STRs)

An extremely useful category of polymorphic short tandem repeats (also termed microsatellites or simple sequence length polymorphism, SSLPs) is abundant across all cat chromosomes in the cat. These hypervariable STR loci have been applied in linkage mapping (Lyons et al. 2004; Fyfe et al. 2006), in forensic individualization (Menotti-Raymond et al. 1997a, b, 2005), and in assessment of historic demographic events that have molded domestic cats and wild felid species (O’Brien and Johnson 2005). We annotated 208,177 STR loci, fewer than were described for the human (542,183), dog (955,555), or mouse (1,346,134) genomes (Table 1). These STR loci have been placed on the feline map, annotated with specific position and suggested primer pairs in GARFIELD (Fig. 6).

Micro-RNAS (miRNAs)

Micro-RNAs (miRNAs) are a family of highly conserved short RNA transcripts that regulate translation of gene products (Lee et al. 2002; Lagos-Quintana et al. 2003; Lecellier et al. 2005; Hertel et al. 2006). The regulatory effects of these molecules are mediated by an interaction between a short processed section of the miRNA and the 3′-UTR of the target mRNA. Based on homology with sequences from the Micro-RNA Registry (Griffith-Jones 2004) and potential stem–loop secondary structure, we identified 179 potential miRNA feline sequences (Table 7; Supplemental Methods). These include 177 sequences that are found across most mammals and two that are annotated as being specific to rodents, and several that have duplicated copies. A total of 201 feline homologs of human miRNAs are distributed across the assembly; 93 loci correspond to a single miRNA locus, while the others belong to 37 clusters (<10 kb apart) of multiple miRNA sequences. Seventeen of the 37 locus clusters have the same number of sequences as their human counterpart and are located in the homologous syntenic region, annotated in GARFIELD. Twenty locus clusters have a different number of included miRNA copies from that found in the human homologous locus. Table 7 summarizes 10 locus clusters that have three or more miRNAs in the human and cat genome, along with the disposition of the homologous locus cluster in the cat.

Table 7.
MiRNA clusters with three or more members shared by human and cat

Nuclear mitochondrial (numt) sequences in cat

Eukaryotic genomes retain relict sequences of mitochondrial genes that were transposed to nuclear chromosomes in their ancestry (Richly and Leister 2004). The cat family has two well-characterized numt loci: (1) Lopez-numt in domestic cats, which comprises a 7.9-kb segment spanning the <CR-12S-16S-ND1-ND2-CO1-CO2> gene segments of mtDNA repeated in 38–76 tandem copies on chromosome D2 distinguished by a 10-bp deletion (Lopez et al. 1994, 1996); and (2) a recent 12.5-kb mtDNA transposition (~3.5 Mya) to chromosome F2 in the common ancestors of the great cats, genus Panthera (Kim et al. 2006).

A BLAST search comparing cat genome sequence to full-length cytoplasmic mtDNA (cymt) sequences (Lopez et al. 1996) yielded 489 sequence matches of 334 kb total, of which 36 kb (10.8%) was identical to cymt, leaving 298 kb of potential numt (covering 99% of the cymt sequence span). One-third of the cat’s numt sequences (96 kb) corresponded to Lopez-numt. One large 78-kb scaffold (scaffold ID 112,167) showed 12 Lopez-numts and likely represents the chromosome D2 numt tandem repeat. Twelve percent of the mtDNA sequence matches that were neither cymt nor Lopez-numt had nuclear DNA flanking regions (5′ or 3′) that allowed them to be mapped to specific chromosomes (Supplemental Fig. S2 shows the chromosome distribution of numts). Phylogenetic analyses of homologous numts suggest multiple numt historic insertions over time in the cat genome (Fig. 3). When numt segments that included the ND1 gene (~570 bp) present in Lopez-numt were examined, a minimum of four distinct numt lineages were apparent, three of which predated the species divergence of the genus Felis (Fig. 3A). In addition, novel numt sequences that included mitochondrial genes not present in Lopez-numt (e.g., CytB; Fig. 3B) suggested three additional numt insertions that originated since the onset of the Felidae family radiations (Johnson et al. 2006).

Based on differences in mutational rates and differences in the genetic code between the mitochondrial and nuclear genomes, it would seem that the transpositions of numt sequence across the cat genome (and in other species) are likely vestigial and with no function. However, the origins of mitochondrial–nuclear complementation in energy metabolism (mitochondria contain 37 and nuclear chromosomes contain >1500 mitochondrial bound genes) clearly involved an early numt transposition, which by evolutionary processes would build the energetics pathway now operative in every eukaryotic species (Margulis 1970; Wallace 2005). The chromosomal disposition of feline numt and the multiple phylogenetic lineages reflect a more recent record of dynamic mitochondrial DNA transposition to disparate chromosomal positions in the ancestors of modern cats, providing yet another informative character for genomic inferences.

Feline endogenous retrovirus-like sequences (FERVs)

Domestic cats carry endogenous retroviral genomic sequences descended from ancestral infections and integrations into the germline. RD114 is an endogenous retrovirus related to baboon endogenous retrovirus with ~20 copies in cats (Benveniste et al. 1974; Reeves and O’Brien 1984; Coffin et al. 1997). Full-length RD114 virus is inducible with halogenated pyrimidines. Because RD114 is relatively innocuous but replicates well in human tissues, RD114-based vector constructs have been used extensively in human gene therapy applications (Relander et al. 2005; Ting-De Ravin et al. 2006).

Endogenous feline leukemia viruses (enFeLVs) are a second group with nine to 16 copies per cat genome, many of them truncated and insertionally polymorphic, with sequences related to exogenous feline leukemia virus (exFeLV) (Roca et al. 2005). By themselves, enFeLVs do not cause disease, but they recombine with exogenous viruses to create new virus subtypes that can augment the pathogenicity of exogenous FeLV (Roy-Burman 1995). In some cases, translation of partial enFeLV envelope protein may also protect against infection by some exFeLVs (McDougall et al. 1994). A phylogenetic analysis of endogenous FeLV LTR sequences from the cat genome sequence defined two distinct lineages, suggesting that at least two different germline FeLV infections occurred in the history of cats (Fig. 4A). Numerous RD114-related traces were also evident, consistent with the presence of both functional and truncated endogenous RD114 sequences (Supplemental Fig. S3b).

Approximately 4% of feline genome sequences are retrovirus-like sequences (Table 2). A homology search using 703 known retroviral sequences uncovered five new FERV lineages distinct from and more abundant than enFeLV and RD114 (Table 3). One major new group of retroviruses, FERV-1, included one locus embedded in the FLA BAC sequence, is related to porcine ERV (Fig. 4B), and is the most abundant of the novel retroviral elements. The other less abundant FERV sequences were related to human ERV lineages and to other mammalian retroviruses including mouse mammary tumor viruses. As with mouse and human, the cat genome is littered with relict FERV sequences descended from ancestral infections of virulent retroviruses (annotated in GARFIELD).

Single nucleotide polymorphisms (SNPs)

The contig sequence reads were examined to discover sites of nucleotide variation in cats or, more precisely, sites of heterozygous SNPs in Cinnamon. A total of 327,000 SNP variants were detected, submitted to dbSNP, and are annotated in GARFIELD. To verify SNP recognition, a random sampling of 200 SNPs were selected for re-sequencing. Ninety percent (180 SNPs) sequenced well, and of these 91% were validated SNP heterozygotes. The genome of Cinnamon was separated into segments covering 43% of the genome that contains multiple heterozygous SNP loci, while the remaining 57% contains long homozygous segments (Fig. 5). Within the heterozygous segments, the SNP loci incidence was 1/600 (0.00167), while the size of homozygous segments in Cinnamon varied from <10 kb to >4.0 Mb with a median length of 170 kb (N50 ≥ 60 kb). The long stretches of alternating homozygous and heterozygous segments are likely a consequence of the domestication process, close inbreeding during Abyssinian breed development, and disease pedigree establishment. Homozygous segments also occur in dogs, possibly for the same reasons (Lindblad-Toh et al. 2005). The FLA region sequence (Fig. 7) derived from Cinnamon was largely homozygous for SNP variants. However, comparison of the Cinnamon sequence to the FLA BACs from a different cat revealed 11,654 SNPs (873 coding) (Yuhki et al. 2003; Beck et al. 2005). The SNP loci incidence of this region (f = 0.00391, or 1/256) is comparable to that of HLA (f = 0.00349, or 1/286).

To explore the breed-specific patterns of common segment homozygosity, as well as to estimate the size of linkage disequilibrium stretches in cat breeds, a group of 350 SNPs were genotyped in multiple individuals from each of 24 certified cat breeds. Briefly, 35 SNPs were selected across 10 ~600-kb highly heterozygous segments (in Cinnamon) from different cat autosomes. For each region, eight SNPs fell within 15 kb of each other, while an additional 27 SNPs were added at 20-kb intervals to fill out the 600 kb. The average homozygosity for SNP loci across the 10 10-kb regions was ~53%. Conditional on homozygosity within the first 10-kb window, the extent of homozygosity was recorded, and the fraction of loci that remained homozygous at different distances was plotted (Supplemental Fig. S8). The fraction of homozygous loci decays as a function of physical distance roughly threefold faster in cats than in dogs (Lindblad-Toh et al. 2005). This may reflect more recent inbreeding and/or restricted gene flow between dog breeds than for cat breeds resulting in shorter haplotypes and linkage disequilibrium in cats. A rough estimate (based on genotyping two to three individuals per breed) would suggest approximately three to five haplotypes per breed within 10-kb and 100-kb windows, very similar to that seen for dog breeds. The extent of homozygosity together with haplotype diversity can be used to infer the number of equally spaced SNPs required for genomewide association mapping within a specific breed. Since ~15,000 SNPs are required for mapping in dogs, we estimate that ~45,000 equivalently spaced SNPs (three times the number for dogs) would be appropriate in cat breeds.

Conclusions and applications of the feline genome sequence

The feline genome sequence, here annotated, has immediate value in many aspects of biology, particularly in the discovery of the genetic basis of hereditary and infectious diseases (Table 5; Supplemental Table S1). Other areas to benefit include comparative genomics for which mammalian CSBs, representing both long genes and short conserved elements, provide the means of reconstructing chromosome exchanges that punctuate mammal evolution. Feline models of hereditary disease/phenotypes are already being uncovered using the genome sequence annotated here. Forensic evidence from cats, already established in legal precedent (Menotti-Raymond et al. 1997a, b, 2005), can now be further characterized in terms of the additional SNP and STR variants made available here. Cat models of emerging infectious agents can now be approached in the context of host genetic variation in immune response, such as the cat FLA complex studied here. Finally, the genome sequence and variation shared with other felid species can increase natural history studies of free-ranging cat species for conservation and management purposes (O’Brien and Johnson 2005).

In spite of the benefits derived from the comparative genomics-based genome annotation presented here, there are some notable weaknesses due to a light coverage. Among them are the following: (1) The assembled cat genome retains only 65% of the euchromatin genome sequence, leaving some 660,000 gaps between the contigs; (2) fewer than 58% of the genes have >50% of their gene feature sequence captured (based on cat–dog gene homologs); and (3) estimating the number, extent, and location of segmental duplications (which comprise 5% of the human genome) is difficult with low coverage since segmental duplication discovery depends on highly redundant genome coverage for accuracy (International Human Genome Sequencing Consortium 2001; Mouse Genome Sequencing Consortium 2002).

These limitations notwithstanding, our analysis of the cat genome sequence in a comparative context has allowed an examination of genome structure and features, genome evolution, and useful applications for comparative genomics and cat biology. The cat genome annotation has increased the depth of evolutionary perspective required for comparative inference. We anticipate that genome annotation of additional species will reveal the cryptic process of species differentiation, development and adaptation. The approach used here could hopefully be applied to the other mammalian species scheduled for 2× sequence coverage (Supplemental Fig. S1); however, the availability of the 1680-marker cat RH map, the BAC and fosmid libraries, breed populations, linkage map, and gene discovery analyses has aptly complemented the cat genome annotation exercise.

Acknowledgments

This project has been 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. This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. This research was supported in part by the Intramural Research Program of the National Institutes of Health, NCI, NHGRI, and NLM. G.T. was funded by a Sloan Research Fellowship in Molecular Biology. G.B. was supported by the Agency for Science Technology and Research (A*STAR), Singapore. W.J.M. was funded by the Winn Feline Foundation. U.G. was funded by NIH Grant NIH RR 02512.

Footnotes

[Supplemental material is available online at www.genome.org.]

Article is online at http://www.genome.org/cgi/doi/10.1101/gr.6380007

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