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The Horse Genome Derby
The Horse Genome Derby
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
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
EST
FISH
FPC V8.5.3
FP-miner
HAS
IHRFP
IL
ISCNH
MHC
MMP-13
MSY
PAB
PAR
RH
RT-PCR
110
SCH
SNP
SSH
STS
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.
111
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
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
113
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.
114
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).
115
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-
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
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
118
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
121
Table 1. Equine genetic disorders/traits with known causative genes and available genetic tests
Trait/condition
Locus
Chromosome
Reference
ASIP
MATP [SLC45A2]
MC1R
GBE1
STX17?
ECA22q
ECA21q
ECA3p
ECA26q
ECA25q
PPIB
LAMC2
SCN4A
EDNRB
ECA1
ECA5p
ECA11p
ECA17q
GYS1
ECA10
KIT
PRKDC
PMEL17
ECA3q
ECA9p
ECA6q23
Chromosomal inversion
ECA3q
Locus
Chromosome
Reference
Appaloosa spotting
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
ECA4/ECA12?
Sex reversal
ECAY
ECA13
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.
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
123
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