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Chromosome Research (2008) 16:109Y127

DOI: 10.1007/s10577-008-1204-z

# Springer 2008

The Horse Genome Derby: racing from map to whole genome sequence
Bhanu P. Chowdhary* & Terje Raudsepp
Department of Veterinary Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences,
Texas A&M University, College Station TX 77843-4458, USA; E-mail: bchowdhary@cvm.tamu.edu
* Correspondence

Key words: Equus, gene maps, genome analysis, horse

Abstract
The map of the horse genome has undergone unprecedented expansion during the past six years. Beginning from
a modest collection of 300 mapped markers scattered on the 31 pairs of autosomes and the X chromosome in
2001, today the horse genome is among the best-mapped in domestic animals. Presently, high-resolution linearly
ordered gene maps are available for all autosomes as well as the X and the Y chromosome. The approximately
4350 mapped markers distributed over the 2.68 Gbp long equine genome provide on average 1 marker every
620 kb. Among the most remarkable developments in equine genome analysis is the availability of the
assembled sequence (EquCab2) of the female horse genome and the generation 1.5 million single nucleotide
polymorphisms (SNPs) from diverse breeds. This has triggered the creation of new tools and resources like the
60K SNP-chip and whole genome expression microarrays that hold promise to study the equine genome and
transcriptome in ways not previously envisaged. As a result of these developments it is anticipated that, during
coming years, the genetics underlying important monogenic traits will be analyzed with improved accuracy and
speed. Of larger interest will be the prospects of dissecting the genetic component of various complex/multigenic
traits that are of vital significance for equine health and welfare. The number of investigations recently initiated
to study a multitude of such traits hold promise for improved diagnostics, prevention and therapeutic approaches
for horses.
Abbreviations
AHT
BAC
BALF
BLAST
BLAT
CHORI-241
COMPASS
CR
ECA
ELA
ENSEMBL

Animal Health Trust


bacterial artificial chromosome
bronchoalveolar lavage fluid
Basic Local Alignment and Search Tool
Blast Like Alignment Tool
Children_s Hospital Oakland Research Institute Y
241 horse BAC library
Comparative Mapping by Annotation and
Sequence Similarity
centromere repositioning
Equus caballus
equine major histocompatibility complex
containing region
genome browser, http://www.ebi.ac.uk/ensembl/

EST
FISH
FPC V8.5.3
FP-miner
HAS
IHRFP
IL
ISCNH
MHC
MMP-13
MSY
PAB
PAR
RH
RT-PCR

expressed sequence tag


fluorescence in situ hybridization
http://www.agcol.arizona.edu/software/fpc/
r8.9.html
http://www.bioinforsoft.com/downloads.html
Homo sapiens
International Horse Reference Family Panel
interleukin
International System for Cytogenetic Nomenclature
of the domestic Horse
major histocompatibility complex
matrix metalloproteinase 13
male specific region of the Y chromosome
pseudoautosomal boundary
pseudo autosomal region
radiation hybrid
real time polymerase chain reaction

B. P. Chowdhary & T. Raudsepp

110
SCH
SNP
SSH
STS

somatic cell hybrid


single nucleotide polymorphism
suppression subtractive hybridization
sequence tagged site

Introduction
Within a short span of ten years, information on the
structure and organization of the horse genome has
grown exponentially. Beginning with a just few
markers organized in a handful of syntenic/linkage
groups and assigned with limited confidence to just
2Y3 chromosomes in 1990, the horse gene map has
expanded rapidly in recent years. At present, not only
there are high-resolution gene maps for all equine
chromosomes, but the entire female genome has been
sequenced and annotated. This phenomenal success
can largely be attributed to the exceptional cooperation and collaboration demonstrated by the international equine community to develop high-quality
tools and resources which eventually encouraged
NIH and the Broad Institute at MIT and Harvard to
choose horse as their next species for sequencing.
The availability of whole-genome sequence in turn
has suddenly promoted horse genetics research to a
new level where investigators can conduct studies
that previously seemed impossible due to lack of
advanced tools. Some of these studies include those
aimed at deciphering genetic causes for a range of
complex equine diseases.
Analysis of the equine genome has progressed on
several fronts. Although recent development of highresolution gene maps, identification of mutations for
some of the genetic conditions, and generation of
whole-genome sequence information have captured
the primary attention of researchers and the equine
industry alike, the considerable amount of effort
simultaneously invested in creating tools and resources that facilitated these achievements also needs due
recognition. Prominent among the new tools are the
whole-genome expression microarrays that are critical for functional analysis of the horse genome, and a
dense collection of validated single nucleotide polymorphisms (SNPs) distributed throughout the genome
that are essential for identifying regions harboring
candidate genes governing diseases or other traits
important for equine health and welfare. In essence,
while the early stages of equine genome analysis
were, as expected, devoted to infrastructure and map

development, present efforts are focused on expanding the horizon of horse genetics research beyond
the realm of laboratory experiments such that novel,
effective and more accurate diagnostic, preventive
and therapeutic approaches can be developed for a
healthier horse. However, how quickly the deliverables of this research will be available to horse
owners will largely depend on active participation of
the equine industry.
In the following paragraphs we summarize the
current status of the horse gene map and relate it to
recent advances that will define how equine genome
research will evolve during coming years. First a
brief overview of various types of gene maps is
provided. This is followed by an update regarding the
sequencing and annotation of the horse genome and
how this information is presently being used to
develop new tools and launch advanced-level research.
Next, a synopsis of how the mapping information has
been useful in isolating genes and identifying variations/mutations responsible for various disease and
coat color traits is provided. Lastly, a perspective of
future equine genome research is given wherein
potential challenges are highlighted and expected goals
are outlined. These goals will eventually guide geneticists and clinicians in designing research plans aimed at
improving equine health and welfare.

Mapping the horse genome


The nuclear genome of the horse comprises 64 chromosomes: 31 pairs of autosomes and the sex chromosomes. Of the autosomes, 13 pairs are metacentric
or submetacentric and the remaining are acrocentric.
The X chromosome is the second largest chromosome and is metacentric, while the Y chromosome is
one of the smallest acrocentric ones (ISCNH 1997).
The average size of the horse genome is anticipated
to be close to the average for mammals (3 billion
base pairs). However, following sequencing and
assembly of the female horse genome, a more accurate
estimate of the size is now available (described in the
section on whole genome sequence).
The horse gene map presently contains 5000
markers. This represents a 100-fold increase in the
number of mapped markers compared with the
figures reported a decade ago when the international
equine community, under the aegis of a Dorothy
Russell Havemeyer Foundation-supported workshop,

The Horse Genome Derby


decided to use a concerted approach to create novel
tools and resources, and map the horse genome.
Since then, the biannual international Havemeyer
Workshop has become the primary platform for
equine geneticists worldwide to discuss the progress
made by different laboratories and brainstorm a
work-plan for subsequent years. A summary of
progress made in mapping the horse genome particularly during the past 6Y7 years, a period during
which the mapping data have exploded, is presented
in the next few paragraphs. Progress made before this
period has unarguably been vital in setting the stage
for the present progress, but has been described in
detail elsewhere (Bailey 1998, Bailey & Binns 1998,
Marti & Binns 1998, Chowdhary & Raudsepp 2000,
2005, 2006, Chowdhary & Bailey 2003). Noteworthy
among this is the mapping of 500 markers
predominantly to horse  mouse somatic cell hybrid
(SCH) panels, leading to the development of syntenic
groups that were assigned to almost all autosomes
and the X chromosome (reviewed by (Chowdhary &
Raudsepp 2000, 2005, 2006). However, the use of
the equine SCH panel was discontinued around year
2000 due to decreasing DNA stock of the cells and
the availability of more efficient mapping resources.

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A total of 742 markers (734 microsatellites and
8 gene-based markers) were genotyped on the AHT
reference family, and a single linkage group was
obtained for each of the autosomes and the X
chromosome (Swinburne et al. 2006). The total span
of the map thus generated is 2772 cM and the
markers are spaced on average at 3.7 cM intervals.
Interestingly, the authors used the flanking sequences
of the microsatellite markers to BLAT against the
human database and the information was used as
comparative anchor points to align the horse and the
human genomes. Almost concurrently, a wholegenome map was generated using the IHRFP
(Penedo et al. 2005). Compared to the AHT map,
this map contained 776 markers, of which 626 were
linearly ordered, and the remaining 140 markers
were placed in bins to specific regions of the chromosomes. The total length of the map is 3740 cM
and the markers are distributed on average at 6.3 cM
intervals. Overall, the map was created by merging
different datasets to obtain a collection of markers
that could be used for genome scan experiments
aimed at mapping various traits of significance in
horses. While more than half the markers are
common between the IHRFP and AHT maps, over
200 markers are unique to each map.

Linkage map
Radiation hybrid (RH) map
Three reference families together with a collection of
polymorphic markers generated worldwide have
contributed to the generation of linkage maps in the
horse. The number of polymorphic markers generated to date is 4300. The large majority of these
markers (2400) have been generated and tested for
polymorphism by Japanese researchers (Tozaki et al.
2007), while the remaining 1900 have been contributed by various researchers worldwide. The three
reference families that have contributed significantly
to the development of linkage maps include: the
Uppsala half-sib family (Lindgren et al. 1998), the
International Horse Reference Family Panel (IHRFP)V
also composed of half-sib families (Guerin et al.
1999)Vand the Animal Health Trust (AHT) family
panel comprised of 3-generation full-sibs (Swinburne
et al. 2000). Of the three family resources, the latter
two have been used more extensively, and each has
provided two iterations of linkage maps. A summary of
the latest iterations of these maps is provided here to
give an overview of the current status of the horse
linkage map.

Following the generation of a 5000 rad horse  hamster RH panel in 2001 and its use to generate a physical and comparative map of ECA11 (Chowdhary
et al. 2002), the panel has become the sole resource
for researchers worldwide to rapidly assign loci to
specific chromosomes or order them in relation to
mapped markers. The resource has been instrumental
in developing the first-generation medium-density
RH and comparative map of the horse genome
(Chowdhary et al. 2003) that incorporated 258 type
I and 472 type II markers and integrated synteny,
cytogenetic and meiotic maps into a comprehensive
consensus map for all autosomes and the X chromosome. Since then, the 5000 rad RH panel has
been used to obtain high-resolution maps (on average
1 marker/Mb) for some of the horse chromosomes,
viz., ECA17 (Lee et al. 2004), ECAX (Raudsepp
et al. 2004a), ECAY (Raudsepp et al. 2004b),
ECA22 (Gustafson-Seabury et al. 2005) ECA15 and
18 (Wagner et al. 2006), parts of ECA7, 10 and 21
(Brinkmeyer-Langford et al. 2005), a short segment

B. P. Chowdhary & T. Raudsepp

112
of ECA4q (Dierks et al. 2006), and ECA14 and 21
(Goh et al. 2007). Concurrently, a medium-density
map of the horse genome was also reported by
adding 165 gene-specific markers to the existing
maps (Perrocheau et al. 2006). Additionally, several
research groups worldwide have used the RH panel
to independently map a number of gene-specific and
microsatellite markers during the period 2004Y2007
(e.g., Brenig et al. 2004, Mickelson et al. 2004,
Takahashi et al. 2004, Wagner et al. 2004a,b,c, Beck
et al. 2005, Boneker et al. 2005, 2006, Bricker et al.
2005, Leeb et al. 2005, Momozawa et al. 2005, 2006,
2007, Muller et al. 2005a,b,c, Wittwer et al. 2005,
Dranchak et al. 2006a, Klukowska-Rotzler et al.
2006a,b).
More recently, the 5000 rad panel was used to
create a second-generation whole-genome RH and
comparative map for the horse genome (Figure 1).
This high-resolution map comprises of 4101 markers
distributed over all autosomes and the X chromosome. The overall resolution of the map is one
marker every 720 kilobases, which represents a
6-fold improvement over the first-generation map.
The map integrates available genetic linkage (907
markers shared with the AHT and IHRFP linkage
maps) and RH mapping data into a physically
ordered map for all equine chromosomes except the
Y chromosome. The assignment and orientation of
various linkage groups is strongly supported by
1100 FISH-mapped markers. The integration of
the RH and the two most recent meiotic maps is
particularly useful in getting a comparative overview
of the three maps, particularly because the linkage
maps were obtained using different reference family
resources and in some instance show disagreements
(Figure 2).
The comparative part of the map is generated by
finely aligning 1902 equine loci with sequence
information available for eight diverse vertebrate
species (human, chimp, cow, dog, mouse, rat,
opossum, and chicken, see Figure 1). This highresolution map is a valuable tool for the identification
of genes and/or markers associated with economically important traits such as disease resistance/
susceptibility, growth, reproduction, and performance. The RH panel has been used to map
candidate genes for equine conditions such as
recurrent airway obstruction (Klukowska-Rotzler
et al. 2006a), glycogen storage disease IV (Ward
et al. 2003), and even for traits such as temperament

and anxiety (Momozawa et al. 2006, 2007). Bearing


in mind that six years ago only 350 markers were
mapped in the horse, the high-resolution maps
presently available for all chromosomes represent a
major improvement in understanding the organization of the equine genome.
Cytogenetic map
Horse is indisputably one of the species with the
highest number of cytogenetically mapped markers
among the domestic animals. Since mid-1990s
(Oakenfull et al. 1993, Breen et al. 1997, Godard
et al. 1997, 1998, Raudsepp et al. 1999), FISH has
been the primary approach used to map gene-specific
and microsatellite markers in the horse (Godard et al.
2000, Lear et al. 2001, Lindgren et al. 2001, Mariat
et al. 2001, Raudsepp et al. 2001, 2002a, 2004a,b,
Chowdhary et al. 2002, 2003, Milenkovic et al.
2002, Brinkmeyer-Langford et al. 2005, GustafsonSeabury et al. 2005, Perrocheau et al. 2005, Goh
et al. 2007). The availability of the CHORI-241 BAC
library and the isolation of BAC clones for a large
assortment of loci have been instrumental in facilitating their chromosomal localizations. Presently,
1100 loci have been mapped by FISH to equine
chromosomes, providing an average of one cytogenetically mapped marker every 2.5 Mb of the
genome. This degree of coverage of the genome has
been extremely useful in accurate physical alignment
and orientation for various types of maps (synteny,
genetic linkage, RH, etc.) to specific chromosomes or
chromosomal regions in the horse.
Incidentally, horse is also the domestic species in
which multicolor-FISH on metaphase/prometaphase
chromosomes, interphase chromatin and mechanically stretched DNA fibers has been carried out
extensively (see Figure 3a,b,c,d; Chowdhary et al.
2003, Raudsepp et al. 2004b, Goh et al. 2007). These
experiments have been pivotal in orienting and
ordering closely located markers, particularly
markers tightly linked or having identical vectors in
the RH and meiotic maps. Moreover, interphase- and
fiber-FISH have also contributed significantly to the
development of the horse Y chromosome map where
BAC contigs have been established over the pseudoautosomal region (PAR; Raudsepp & Chowdhary
in preparation) and the male specific region of the Y
(MSY; Raudsepp et al. 2007b), which are briefly
discussed in the section on Y chromosome map.

The Horse Genome Derby


Lately, cytogenetic mapping has also been used to
localize candidate genes for some equine conditions
such as recurrent airway obstruction (KlukowskaRotzler et al. 2006a, Jost et al. 2007) and genes
involved in circadian clock (Murphy et al. 2007) and

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the development of skeletal and nervous systems
(Zabek et al. 2007). In 2006Y2007, altogether around
a dozen publications have reported FISH mapping of
30 new loci in the horse. The approach has also been
used to anchor and orient 18 unassigned supercontigs

Figure 1. Composite high-resolution map of ECA25 is shown with the cytogenetic map showing FISH alignments on the left and
comparisons with sequence maps of six eutherian mammals, opossum and chicken on the right. Comparative map shows syntenic segments
(green bars) with megabase positions at the ends of the bars and the chromosome number in the middle.

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B. P. Chowdhary & T. Raudsepp

Figure 2. An integrated map for ECA25 shows the second-generation RH map (middle), aligned with dotted lines to the markers shared with
the IHRFP linkage map (left, Penedo et al. 2005) and the AHT full-sib family linkage map (right, Swinburne et al. 2006).

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Figure 3. Two-color FISH on (a) metaphase chromosomes with signal for GRB14 (green) on ECA18q23 and DDX1 (red) on ECA18q15; (b)
interphase chromatin: probes representing ELA class I (red), class II (red) and class III (green) genes showing that class III region is located
between classes I and II; (c, d) mechanically stretched DNA fibers showing partial overlap (c) and a distinct gap (d) between two different
pairs of closely located BAC clones mapped in the ECAY contig. Bar = 10 mm.

from the whole-genome sequence, thus assisting assembly of the horse genome (Lear et al. 2007). Last, FISH
has also been used as a supplementary tool in cytogenetic analysis of complex autosomal rearrangements
(Durkin et al. 2005, 2008), for identification of chromosomes involved in autosomal trisomies (Durkin et al.
unpublished) and for defining sex chromosome rearrangements (Bugno & Slota 2007, Bugno et al. 2007a,b).
Comparative map
The horse genome has been compared with a variety
of mammalian/vertebrate genomes using a range of
approaches. While linkage, synteny and cytogenetic
mapping gave preliminary indications of segmental homologies between horse and human genomes
(Chowdhary & Gustavsson 1992), Zoo-FISH or com-

parative chromosome painting helped to identify 43


homologous chromosomal segments between the two
species, thus providing the first glimpse of similarities between their karyotypes (Raudsepp et al.
1996, Chowdhary et al. 1998). This landmark
comparison between horse and human chromosomes
unambiguously laid the foundation for mapping the
equine genome using comparative approaches. The
map was later verified and partially redefined by
horseYhuman reciprocal painting (Yang et al. 2004).
While comparative chromosome painting indicated
segmental homology between the horse and the
human chromosomes, a much more detailed comparison than this was obtained by a combination of
synteny, FISH and RH mapping data (e.g., Caetano
et al. 1999, Chowdhary et al. 2002, 2003, Milenkovic
et al. 2002, Brinkmeyer-Langford et al. 2005,

B. P. Chowdhary & T. Raudsepp

116
Perrocheau et al. 2005). This is evident from the firstgeneration RH map of the equine genome, where a
total of 447 genes (256 linearly ordered RH-mapped
and additional 191 FISH-mapped) helped to align
the horse genome with the genomes of human and
mouse. The comparisons were further refined through
improved resolution maps that had one mapped
marker per 2 Mb for a number of equine chromosomes (Lee et al. 2004, Raudsepp et al. 2004a,b,
Brinkmeyer-Langford et al. 2005, Gustafson-Seabury
et al. 2005, Wagner et al. 2006, Goh et al. 2007).
More recently, the second-generation RH map used
a total of 2000 gene-specific loci to finely align
the horse genome with the sequenced genomes of a
range of mammals (Gustafson-Seabury et al. 2007,
Raudsepp et al. 2007a).
During recent years, flanking sequences of equine
microsatellite markers have been analyzed for possible use as comparative anchor points with genomes
of other species (Farber & Medrano 2004). Tozaki
et al. (2007) further expanded this work by analyzing
flanking sequences of 2346 microsatellite markers
and discovering that 15% of the sequences could
be used as comparative markers. Additionally Leeb
et al. (2006) compared a total of 9473 BAC end
sequences by BLASTn against the human genome
sequence and identified that 33% of the ends could
serve as comparative anchor points. The findings
were validated by mapping the BAC end STSs on the
5000 rad RH panel and aligning the HSA6 sequence
map with corresponding regions on ECA 10, ECA20
and ECA31. A Comparative Mapping by Annotation
and Sequence Similarity (COMPASS) strategy was
used to computationally predict the location of 9322
equine expressed sequence tags (ESTs) from a
cartilage library in the horse genome, based on the
available horseYhuman comparative map and the
first-generation RH map. The findings were validated
by typing the RH panel with markers anticipated to
be on ECA17 and ECAX. The strategy was proposed
to be useful for in silico mapping of large sets of
ESTs in unsequenced genomes.
While the equine genome has been primarily
compared with human and other evolutionarily
diverged mammalian/vertebrate genomes, attempts
have also been made to compare it with the genomes
of others equids. Of great interest is the comparison
of horse and donkey karyotypes that, despite differing only by a single pair of chromosome (horse
2n = 64 and donkey 2n = 62), have undergone a

number of fusions and rearrangements in relation to


each other while evolving from a common ancestor
(Raudsepp et al. 1999, 2001, 2002b, Myka et al.
2003b, Yang et al. 2004). Comparisons have also
been made between the genomes of domestic horse
and Przewalskii_s horse (Myka et al. 2003a, Yang
et al. 2003), horses and zebras (Yang et al. 2003),
and even zebras and rhinos (Trifonov et al. 2003) to
understand karyotype evolution in equids. More
recently, chromosome arm-specific painting probes
were generated for all horse and a few Hartmann_s
zebra chromosomes and used to study karyotypic
relationships among zebras and the horse (Musilova
et al. 2007). Also, centromere repositioning (CR) has
been studied in horses and other equids as part of
genome comparisons. It appears that CR is a
common evolutionary event in karyotype/chromosome evolution in the genus (Carbone et al. 2006), as
is evident from at least eight centromere repositioning events identified between all equids, of which
five took place in the donkey lineage alone.
BAC contig maps
The availability of BAC libraries at the beginning of
year 2000 allowed equine researchers to initially
develop BAC contigs over shorter regions of interest
of the horse genome and lately to develop a complete
physical BAC contig map of the entire genome.
Among the former category, the development of a
contig map over the equine major histocompatibility
complex-containing region (ELA) represents the first
organized effort focused on an important region of
the genome (Gustafson et al. 2003). For this, 238
BAC clones isolated from the CHORI-241 library
were assembled into two contigs spanning the region.
The first contig containing the MHC class II region
was reduced to a minimum tiling path of nine BAC
clones that spanned approximately 800 kb and
contained at least 20 genes; the second contig
included the class III/I region and contained 14 BAC
clones in its minimum tiling path. The latter had 34
identified genes and spanned approximately 1.6 Mb.
FISH using representative clones from each of the
three regions of the equine MHC localized the contigs
to ECA20q21 and oriented them in relation to each
other and the centromere. Dual-colored FISH revealed
that the class I region is proximal to the centromere,
the class II region is distal, and the class III region is
located between the two regions (Figure 3b). These

The Horse Genome Derby


data indicate that the equine MHC is a single genedense region similar in structure and organization to
the human MHC and is not disrupted as in ruminants
and pigs. Later Tallmadge et al. (2005) identified 15
MHC class I genes in BAC subclones and obtained
their full sequence. The expression of seven of the loci
was verified by reverse transcriptaseYpolymerase
chain reaction in adult, fetal, and placental tissues,
while the remaining eight genes were designated as
pseudogenes.
Additionally, a BAC contig map comprising 207
clones and containing 42 genes, 5 microsatellites,
and 106 STSs was recently developed over the
proximal one-quarter of horse chromosome 21
(ECA21; Brinkmeyer-Langford et al. 2007). This
region corresponds to parts of human chromosome
19 (HSA19; 15Y20 Mb region on the sequence
map) and HSA5 (67Y69 Mb region). STS content
mapping of these markers by PCR on the BACs
resulted in ordering and orienting the BACs into two
contigs with 4Y5 coverage of the region. Twentysix of these BACs are included in a minimum tiling
path across the region. Dual-color FISH using BACs
at the boundaries of the one remaining gap between
the two contigs suggests that the gap size is not more
than 40 kb. Attempts are under way to study the
sequence constitution of the evolutionary breakage/
fusion point on ECA21 that connects segments
corresponding to HSA19 and HSA5. BAC contig
maps have also been developed over the euchromatic
region of the horse Y chromosome (Raudsepp et al.
2004b, Raudsepp & Chowdhary in preparation). A
summary of these contig maps is presented in the
section describing the horse Y chromosome map.
Among the most recent BAC contig maps are the
efforts by Ottmar Distl, Tosso Leeb and colleagues
(Woehlke et al. 2008) to develop a physical map
of the horse genome based on a combination of
fluorescent fingerprinting and end sequencing of
180 000 BAC clones from the 11 coverage
CHORI-241 equine BAC library. The generation and
analysis of 314 972 BAC end sequences has been
completed (http://www.tiho-hannover.de/einricht/
zucht/hgp/index.htm), and fluorescent fingerprints
are currently being obtained. The raw data thus
collected are being used to assemble the fingerprint
contigs employing the FPMiner 2.0 and FPC V8.5.3
software. Additionally, the BAC end sequences are
being used in conjunction with the horse genome
draft sequences to anchor the fingerprint contigs,

117
close the gaps, and determine the minimal tiling path
BACs for adequate coverage of the horse genome.
Map of the horse Y (ECAY) chromosome
ECAY is indisputably the most extensively studied Y
chromosome among domestic animals and presently
has a comprehensive map spanning the entire
euchromatic region which includes the pseudoautosomal region (PAR; a region of shared homology
with the X chromosome) and the male specific region
on the Y (MSY). A detailed physical map of the
horse Y chromosome was reported by Raudsepp
et al. (2004b). This first generation map showed that
the euchromatic region of the chromosome comprises approximately 15 Mb of the total 45Y50 Mb
size and lies in the distal one-quarter of the long arm,
where the PAR is located terminally. The rest of the
chromosome is predominantly heterochromatic.
Analysis of the 5000 rad RH panel provided a
baseline map spanning 88 centirays with 8 genes
and 15 sequence-tagged site (STS) markers. Further,
isolation of BAC clones for markers mapped by RH,
end sequencing of the BACs, STS development from
the end sequences, and bidirectional chromosome
walking yielded 109 markers (100 STS and 9 genes)
contained in 73 BACs. STS content mapping
grouped the BACs into seven physically ordered
contigs that were verified by metaphase-, interphase-,
and fiber-FISH and also BAC fingerprinting. The
BAC contigs provided 20Y25% coverage of the
euchromatic region of the chromosome.
The foundation laid through the first-generation
map of the Y chromosome was recently used to
characterize the estimated 1.8 Mb equine PAR by
(i) isolating and arranging 71 BACs containing 129
markers (110 STSs and 19 genes) into two contigs
spanning the region;, (ii) precisely localizing the
pseudoautosomal boundary (PAB); and (iii) describing part of the contiguous X- and Y-specific regions
(Raudsepp & Chowdhary in preparation). Following
human/chimp and mouse, horse is the only species
for which PAR is described in such detail and the
PAB is defined. Interestingly, a 200 kb region was
discovered in the middle of the PAR that is also
present in the male specific region of the Y (MSY).
Duplication like this is a novel observation in
mammals. Further, comparison of the equine PAR
with the human counterpart showed that despite
containing orthologues from an additional 1 Mb

B. P. Chowdhary & T. Raudsepp

118

Figure 4. Schematic overview of the BAC contig map of horse Y chromosome.

region beyond the human PAR1, the size of the


equine PAR is 0.9 Mb smaller than in humans.
Based on the comparisons made between PARs in
different species, it was hypothesized that the region
varies in size and gene content across evolutionarily
closely as well as distantly related mammals.
In addition to PAR, extensive work has also been
done to develop a detailed map of the equine MSY
(BP Chowdhary & T Raudsepp, unpublished data).
The current map comprises 400 BAC clones that
are arranged into five contigs containing 300 STSs
and 32 gene-specific markers (Figure 4). The existing
four gaps do not exceed a total of 1 Mb as revealed
by interphase FISH analysis (Raudsepp et al. 2007b).
The map is currently being completed by making
final attempts to find BAC clones for gaps between
existing contigs. Experiments are also underway to
isolate novel equine-specific genes or transcripts
from the region. Jointly, the high-resolution map of
horse PAR and MSY with the BAC contigs developed over the region form an important foundation
for complete sequencing of the euchromatic region of
the Y chromosome. Currently efforts are being made
to obtain expression profiles for all known and novel
equine-specific ECAY genes and to evaluate their
role in regulating stallion fertility (Paria et al. 2007).

New tools and resources


The equine whole-genome sequence
The horse genome was sequenced by the Broad
Institute at MIT and Harvard in conjunction with the
Equine Genome Sequencing Consortium. Using the
whole-genome shotgun (WGS) approach, a 6.8

coverage assembly of the genome was recently prepared (http://www.broad.mit.edu/mammals/horse/).


A female Thoroughbred (Twilight) was selected for
sequencing because of her low heterozygosity rate of
1/1380 bp. Paired end reads were generated from 4
and 10 kb plasmid and 40 kb fosmid libraries. The
version 2 draft assembly (http://www.broad.mit.edu/
ftp/pub/assemblies/mammals/horse/Equus2/) contains on average N50 contig size 112 kb and N50
supercontig size of 46 Mb for the estimated 2.68 Gb
genome of the Thoroughbred mare. Further, a polymorphism rate of 1/1500 bp and a highly repetitive
content of 10% have been found in the genome.
Roughly 92% of the sequence has been ordered and
oriented on the chromosomes using available genetic
linkage maps, the second-generation RH map and
FISH mapping data. The genome sequence is currently being annotated by ENSEMBL.
Discovery of single nucleotide polymorphisms
(SNPs) and development of a SNP-chip
During the past six or seven years several researchers
around the world have analyzed a large assortment of
genes to identify SNPs that could potentially be
associated with traits of interest in the horse such as
diseases, performance, coat color, reproduction and
fertility, behavior and temperament, and disease
resistance. Among the disease-related genes, SNPs
have been identified in: SLC26A2 (a candidate gene
for chondrodysplasia; Hansen et al. 2007); cyclophilin B (PPIB; known to carry a missense mutation
in HERDA individuals; Tryon et al. 2007); FOXC2
(a candidate gene for chronic progressive lymphedema; Young et al. 2007); and LAMC2 (an insertion
mutation that causes Herlitz junctional epidermolysis

The Horse Genome Derby


in two French draft horse breeds; Milenkovic et al.
2003). In addition, a number of SNPs have been
identified in immune system genes. These genes
include IL4R (Solberg et al. 2004), TNFa (Brown
et al. 2006) and OAS1 (Rios et al. 2007), which were
studied for susceptibility/resistance to various infectious diseases. Among the performance-related
genes, SNPs have been identified and analyzed in
potassium and amino acid transporters SLC12A4 and
SLC7A10 (Hanzawa et al. 2002), lactate transport
genes MCT1 and CD147 (Reeben et al. 2006), and
18 candidate genes considered as candidates for
performance (McGivney et al. 2007). SNPs have
been instrumental in mapping some of the coat color
genes (e.g., gray; Rosengren Pielberg et al. 2007) and
identifying causative mutations in, for example,
MC1R causing chestnut coat color (Marklund et al.
1996) and in PMEL17 causing silver coat color
(Brunberg et al. 2006, Reissmann et al. 2007).
Recently, Hamann et al. (2007) reported a SNP in
CRISP3 that was considered to have a significant
affect on stallion fertility. Interestingly, attempts are
also being made to find association between SNPs in
nine candidate genes and behavior and temperament
in horses (Momozawa et al. 2005, 2006). Last, as
expected, SNPs are being considered as the next
generation of markers with which to conduct parentage testing and breed diversity analysis during
coming years. The feasibility of using them for these
purposes is currently being examined.
One of the emerging technologies for mapping
disease traits in various mammalian species is the use
of genome-wide SNP markers. The availability of
such a tool in the form of an SNP-chip facilitates
rapid mapping of diseases to specific chromosomal
region(s) and allows identification and analysis of
responsible candidate genes. The Broad Institute at
MIT and Harvard in collaboration with the Equine
Genome Sequencing Consortium is developing a
SNP map by discovering SNPs within the genome
assembly of the sequenced female horse Twilight and
by comparing 100 000 WGS reads from each of
seven horse breeds including: Akhal Teke, Icelandic,
Arabian, Andalusian, Quarterhorse, Thoroughbred,
and Standardbred (Wade et al. 2007). These breeds
were chosen to represent a mixture of ancient and
recent populations. The work should result in a map
with 1.5 million SNPs. Further, to characterize the
haplotype structure of the equine genome, 24
individual representatives from diverse horse breeds

119
have been re-sequenced over a targeted 100 kb
region (20 locations each of 5 kb) to evaluate the
total diversity within the horse population as a whole.
In addition, 10 regions have been genotyped over
2 Mb in groups of 24 representatives from each of
10 horse breeds (Thoroughbred, Arabian, Quarterhorse, Icelandic, Hokkaido, Hanoverian, Andalusian,
Belgian Draft, Norwegian Fjord, and French
Trotters). The extent of linkage disequilibrium and
haplotype diversity both within and across breeds is
now known and an Equine Illumina 60K SNP array
is being designed and constructed.
Functional analysis of equine genome
Rapid developments in EST generation, gene mapping and whole-genome sequencing have opened a
new front of research in horses, viz., functional
genomics. This requires development of a whole
genome expression microarray that can simultaneously analyze the expression patterns of thousands
of genes. Importantly, the need for this resource is
emphasized not only by equine geneticists but also
by equine clinicians and researchers working in a
wide variety of areas including infectious diseases,
inflammatory and degenerative conditions of bone/
cartilage and muscle, respiratory diseases, allergy
related syndromes, reproduction and fertility, embryonic and postnatal growth and development, exercise
physiology, etc.
Although the majority of the initial functional
studies in horses have used cross-species expression
microarrays, some newer reports show the use of
horse-specific cDNA or oligonucleotide-based arrays.
One of the initial equine studies used a 9132-element
human cDNA microarray (Ing et al. 2004) to elucidate
molecular mechanisms during the early stages of
spermatogenesis in dark and light testicular tissues to
identify new therapies for enhancing male fertility.
Differential expression was noted in 93 genes for two
of the three microarray analyses. Next, development
of two independent sets of equine-specific expression
microarrays was reported. The first arrayVreferred to
as the Affymetrix Equine Gene ChipVincludes 3098
expressed equine sequences derived from 19 000
traces submitted to public databases by various
sources, and was created by using 25-oligomer probes
representing the genes on an Affymetrix platform
(Gu & Bertone 2004). The utility of this array
was evaluated via lipopolysaccharide exposure of

120
synoviocytes. The chip was also used recently to identify patterns and correlations of gross, histological, and
gene expression characteristics of articular cartilage
from horses with osteoarthritis (Smith et al. 2006).
Metacarpal condyles of horses with naturally occurring osteoarthritis had an identifiable and regional
gene expression signature that was associated with
specific morphological features. The second microarray spotted 1000 cDNAs representing equine genes
to examine the in vitro effects of bacterial cell wall
toxins on leukocyte gene expression (http://fungen.
botany.uga.edu/Projects/Horse/Equine%20EST%
20Libraries.htm).
An interesting comparison of gene expression
patterns between normal intact skin (IS) and 7-dayold wound margin (WM) equine biopsies was carried
out using suppression subtractive hybridization
(SSH) of cDNAs obtained from two time points
(Lefebvre-Lavoie et al. 2005). The experiment led to
the identification of 226 nonredundant cDNAs. A
RT-PCR assay confirmed an increase in the expression of specific genes as evidenced through an
increase in the population of cDNAs. Among these
genes, COL1A2 and MMP1 were earlier documented
to be associated with wound repair in horses, while
other highly expressed genes such as spermidine/
spermine-N-acetyltransferase, serine proteinase inhibitor B10, and sorting nexin 9 were identified as
potential candidates in regulating the proliferative
response to wounds.
Some of the recent equine studies have used human
and mouse expression arrays to identify candidate
genes associated with traits important to the equine
industry. Nomura et al. (2007) used a human cDNA
GEarray (SuperArray Bioscience, USA) and found
that the expression level of matrix metalloproteinase
13 (MMP-13) is vastly upregulated in digital flexor
tendinitis as compared to normal tendon. It was
inferred that MMP-13, but not other collagenases or
gelatinases, may play an important role in tendon
injuries in racehorses. Next, Ramery et al. (2007)
used a human microarray to study gene expression in
nucleated cells from peripheral blood and bronchoalveolar lavage fluid (BALF) in heaves-affected horses
to study gene expression patterns in relation to
unaffected controls. The authors identified a total of
46 candidates that were differentially regulated
between heaves-affected horses and controls. It is
noteworthy that the human microarray failed to
detect the upregulation of interleukin (IL)-1b and

B. P. Chowdhary & T. Raudsepp


IL-8 expression in the nucleated cells from BALF
that was earlier reported from real-time RT-QPCR.
Interestingly, a mouse cDNA microarray including
15 264 unique genes has also been used to study gene
expression patterns in the horse. Mucher et al. (2006)
used the array to analyze gene expression patterns in
equine muscle tissue to understand metabolic adaptations in response to exercise and metabolic disorders.
The authors concluded that following application of
proper filters, up- and downregulation of genes could
be quantified using the mouse cDNA array. The array
was also used to study gene expression in leukocytes to
obtain signatures of physiological adaptations and
metabolic disorders in endurance horses (Barrey et al.
2006). It was noted that long exercise induced many
significant gene modulations in leukocytes compared to
rest, and compared to horses with metabolic disorders.
Additionally, some genes were expressed distinctly in
relationship with the clinical phenotype observed in
horses with rhabdomyolysis and hemolysis.
The past couple of years have seen the emergence
of equine cDNA microarrays. One of these containing
9322 elements from a cartilage cDNA library printed
in duplicate has been used to study the transcriptional
profiling of equine articular cartilage (MacLeod
2007). Another array containing 8000 unique elements originating from four different tissues is being
used to study the expression profile during early
embryogenesis in the horse (Chowdhary, unpublished). The equine cDNA array is also employed to
document transcriptomic response of skeletal muscle
to exercise in Thoroughbred horses (McGivney et al.
2007). A new development in the microarray arena
in horses is the generation and characterization of a
12 000-element equine oligonucleotide expression
array (Nixon et al. 2008). The array is being used
to obtain a preliminary molecular signature, from
normal articular cartilage of skeletally immature
horses, for use as a valuable reference for future
analysis of cartilage diseases and chondrogenesis in
stem cell cultures.
The recently available 7 coverage assembled
and annotated sequence of the equine genome is
currently being used by researchers at Texas A&M
University to develop a 22 000 element 70-mer
oligoarray that would represent the majority of the
expressed equine sequences (Chowdhary, personal
communication). This array will be available by
early 2008 and will serve as a powerful resource for
the international equine community to study the

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121

Table 1. Equine genetic disorders/traits with known causative genes and available genetic tests
Trait/condition

Locus

Chromosome

Reference

Agouti color (bay)


Cremello color
Extension (red/black color)
Glycogen storage disease IV, GBED
Gray color

ASIP
MATP [SLC45A2]
MC1R
GBE1
STX17?

ECA22q
ECA21q
ECA3p
ECA26q
ECA25q

Hereditary equine regional dermal asthenia, HERDA


Herlitz junctional epidermolysis bullosa, H-JEB
Hyperkalemic periodic paralysis, HYPP
Overo lethal white foal syndrome, OLWFS

PPIB
LAMC2
SCN4A
EDNRB

ECA1
ECA5p
ECA11p
ECA17q

Polysaccharide storage myopathy, PSSM

GYS1

ECA10

Sabino white spotting


Severe combined immunodeficiency, SCID
Silver color

KIT
PRKDC
PMEL17

ECA3q
ECA9p
ECA6q23

Tobiano white spotting

Chromosomal inversion

ECA3q

Rieder et al. (2001)


Locke et al. (2001), Mariat et al. (2003)
Marklund et al. (1996)
Ward et al. (2003)
Locke et al. (2002), Swinburne
et al. (2002), Pielberg et al. (2005),
Rosengren Pielberg et al. (2007)
Tryon et al. (2007)
Spirito et al. (2002)
Rudolph et al. (1992)
Metallinos et al. (1998), Santschi
et al. (1998), Yang et al. (1998)
Dranchak et al. (2007), McCue
et al. (2007)
Brooks and Bailey (2005)
Shin et al. (1997)
Brunberg et al. (2006),
Reissmann et al. (2007)
Brooks et al. (2002, 2007)

entire equine transcriptome in pursuit of genes and


genetic mechanisms governing normal and perturbed
physiological and developmental conditions.
Application of genomic tools and resources
Coat color and a range of genetic diseases (predominantly monogenic) are the focus of investigation for
equine researchers worldwide. Understandably, the
tools and resources available in recent years have

been suited to the study of these traits. While in


some cases available gene maps and comparative
approaches have helped to chromosomally localize
the traits and narrow them down to a specific region/
band through tightly linked markers, in others they
have led to the identification of the responsible gene
and the causal mutation (see Tables 1 and 2).
The majority of the genomic tools and resources
presently available in the horse are useful for studying monogenic traits. However, a large proportion

Table 2. Equine genetic disorders/traits with known linked markers


Trait/condition

Locus

Chromosome

Reference

Appaloosa spotting

TRPM1?, ASB8, 1CA43

ECA1q

Cerebellar abiotrophy
Degenerative suspensory ligament desmitis, DSLD
Dominant white
Endurance performance
Epitheliogenesis imperfecta
Fertility (spermYegg fusion)
Insect bite hypersensitivity, IBH
Osteochondrosis
Recurrent airway obstruction

DMAP1, PRNPIP
microsatellite
KIT ?
ACE
LAMA3
CRISP1
HMS01
8 candidate genes
microsatellite

ECA2p
ECA14qter
3q?
ECA11
ECA8
ECA20q
ECA15

Recurrent exertional rhabdomyolysis, RER

microsatellite, gene exclusion

ECA4/ECA12?

Sex reversal

Y deletion including SRY

ECAY

Terry et al. (2004),


Bellone et al. (2005)
Brault et al. (2007)
Cothran et al. (2005)
Mau (2003), Haase et al. (2007)
Ellis et al. (2005)
Lieto and Cothran (2003)
Giese et al. (2002)
Marti et al. (2005)
Johannessen et al. (2005)
Jost et al. (2007),
Swinburne et al. (2007)
(Hasegawa et al. (2005),
Dranchak et al. (2006b)
Raudsepp and Chowdhary,
unpublished

ECA13

B. P. Chowdhary & T. Raudsepp

122
of the traits important to the equine industry are
polygenic and also have an environmental component. The availability of new tools and resources
such as the whole-genome sequence, SNP-chip,
cDNA arrays and oligoarrays hold promise for a
new level of analyses that was previously unthinkable. It is not surprising that, supported with new
tools that permit one-step whole-genome probing,
equine researchers are focusing their efforts on
investigating a wide range of equine conditions,
viz., chronic obstructive pulmonary disease, sweetitch, osteochondrosis dessicans, laminitis, exerciseinduced pulmonary hemorrhage, susceptibility and
resistance to infectious diseases, inflammation, stress,
performance or athletic ability, endurance, exercise
intolerance, conformation, behavior, fertility, etc.
While identifying and analyzing the genetic components of these complex traits will undoubtedly be
challenging, the very fact that now possibilities exist
to carry out such research testifies that the discovery
of improved ways for prevention and treatment of
these and other similar equine conditions is possible.

diseases/conditions and selection of animals that


stringently meet the criteria established. Also, there
will be an acute need to obtain/bank tissues from
sufficient numbers of animals meeting the criteria in
order to conduct meaningful experiments in the future.
There is no doubt that the initial momentum of
equine research using the new tools and resources
will be directed toward dissecting disease traits.
However, with the passage of time the need to
understand the normal biology of the horse and the
functioning of the transcriptome will become paramount because analysis of complex traits/diseases
will require a multilateral approach that includes
extensive knowledge of expression patterns of genes
as well as their interactions in the tissues concerned.
In summary, the new developments in equine
genome analysis have been rapid. This has, in some
ways, put the genomics cart ahead of the horse.
However, once the equine research community
redefines its goals and judiciously identifies priority
areas, the horse will once again be at the forefront.
Acknowledgments

Concluding remarks
Horse genomics is currently in a transitional phase.
While the mapping era is close to conclusion in the
horse, the era of applying genomic knowledge to
study traits of interest is experiencing a fresh
beginning. At this juncture the international equine
research community will be hard-pressed to complete
some tasks and organize itself to make the best use
of the newly acquired knowledge base. Among
the prominent and most pressing tasks confronting
the equine geneticists will be to make sense of the
whole-genome sequence data and have the annotation completed. Next, the imminent availability of
novel tools like the 60K SNP-chip and expression
microarray by early 2008 will require appropriate
validation experiments to confirm their utility. Concurrently, rigorous brainstorming will be needed
within the community, particularly together with
equine clinicians, to carefully identify areas/conditions where these tools could be most efficiently
applied. Appropriate design of experiments and establishing infrastructure to analyze huge amounts of data
following the use of these tools will also require
substantial attention. A key challenge confronting the
researchers will be appropriate definition of various

This work was supported by USDA-NRI grant


2006Y04801, Link Endowment, the Morris Animal
Foundation, the Havemeyer Foundation and the
Grayson Jockey Club.
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B. P. Chowdhary & T. Raudsepp


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The Horse Genome Derby


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125
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126
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B. P. Chowdhary & T. Raudsepp


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The Horse Genome Derby


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127
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