Download The Horse Gene Map

The Horse Gene Map
Ernest Bailey and Matthew M. Binns
INTRODUCTION
TABLE 1
The first contribution to the horse gene map was identification of linkage between 6-phosphogluconate dehydrogenase
and the K blood group system (Sandberg 1974). During the
next 20 years, additional linkage groups were identified and
the map was periodically reviewed (Sandberg and Andersson
1993). Gene mapping discoveries were incidental to studies
of new genetic systems for parentage analyses in horses. The
concept of creating a comprehensive gene map for the horse
appeared to be too expensive, requiring more resources than
were available for research on horses. This changed in the
early 1990s with advances in biotechnology and as the successes associated with the human genome project became
publicized.
During the early 1990s, inexpensive techniques became
widely available for identifying, sequencing, and mapping
large numbers of genes. This area of research became known
as "genomics." Cattle, pigs, chickens, and sheep were among
the first species for which scientists developed comprehensive gene maps. These maps were developed through efforts by individual laboratories as well as through collaborative efforts between laboratories. Following the successes of
those programs and inspired by potential applications of gene
maps for horses, scientists conducted a workshop in October
1995 to collaborate on constructing a gene map for the horse.
This workshop marked the beginning of genomics research
on horses.
REASONS FOR MAPPING THIS SPECIES
The domestic horse belongs to the genus Equus, which is
composed of 9 extant species including horses, donkeys,
hemiones, and zebras (Table 1). The horse evolved in North
America approximately 3.5 to 5 million yr ago and migrated
to the Asian/European continent across the Bering Strait
before becoming extinct in the Americas between 20,000
and 10,000 yr ago (Simpson 1951). The horses and donkeys
populating North America today are descendants of those
reintroduced from Europe, Africa, and Asia over the last 500
years.
Ernest Bailey, Ph.D., is with the M. H. Gluck Equine Research Center,
Department of Veterinary Science, University of Kentucky, Lexington,
Kentucky. Matthew M Binns, B.Sc, Ph.D., is with the Centre for Preventive Medicine, Animal Health Trust, Suffolk, United Kingdom.
Volume 39, Numbers 2 and 3
1998
Extant species of Equus?
Genus/species
Equus przewalskii
Equus caballus
Equus asinus
Equus hemionus
onager
Equus hemionus
kulan
Equus kiang
Equus grevyi
Equus burchelli
Equus zebra
hartmannae
Common
name
Chromosome
no. (2N)
Mongolian wild horse
Domestic horse
Domestic ass/donkey
66
64
62
Persian wild ass
56
Kulan
Kiang, Asian wild ass
Grevy's zebra
Burchelli's zebra,
common zebra
Hartmann's mountain
zebra
54/55
51/52
46
44
32
^Adapted from Lear 1997.
The evolution of Equus is an example of evolution associated with rapid karyotypic change. Member species are
clearly delineated by differences in chromosome numbers,
ranging from 32 in the Hartmann's zebra (Equus zebra hartmannae) to 66 for Przewalski's horses (Equus przewalskii)
(Table 1). Equid species can be induced to hybridize under
artificial conditions; however, most of the hybrids are sterile,
probably due to chromosome instability during meiosis. The
most common hybrid is the domestic mule, produced by
crossing a male donkey (jack) with a female horse (mare).
Mules have 63 chromosomes, compared with 64 for horses
and 62 for donkeys.
The horse was domesticated approximately 6000 yr ago
and was a primary source of power and transportation until
the advent of the combustion engine. Diverse breeds of
horses have been developed worldwide for diverse applications. Horses range in size from the heavy European draft
horses such as the Percheron, Clydesdale, and Belgian horse
to the diminutive pony breeds such as the ancient Exmoor
pony, the well-known Shetland pony, and the modern pony
breed known as the American Miniature Horse.
Genetic diversity is great among horses despite a long
history of selection. Although founder stallions have had a
profound influence on some breeds, horse breeders have used
crossbreeding extensively until modern times. Furthermore,
genetic diversity has been maintained because horse popula171
tions have been large, and great numbers of mares have been
used in founding most breeds. The extent of variation among
horses is reflected by the power of the early blood typing
programs to resolve questions of parentage using biochemical and blood group markers. These horse blood typing tests
were able to exclude 95 to 98% of incorrect paternities in
most breeds when using between 12 and 15 genetic systems
(Bowling and Clark 1985). By comparison, comparable exclusion power was not attained for human or canine paternity cases until the introduction of DNA-based tests.
Horses remain economically important and have been
used increasingly for sports and recreation during the last 80
years. More than 70% of the approximately 6.9 million horses
in the United States are involved in showing or recreational
uses. The estimate of 7.1 million Americans who participate
in the horse industry includes those who are employed in
connection with horses, those who own or use horses as
recreation, and those who provide related services. Even
more people participate as spectators at horse racing meets
and horse shows. The horse has a similar economic impact
in Europe, Australia, and parts of Asia and Africa (Barents
Group 1996).
CURRENT MAP STATUS
The development of the horse gene map has involved an
international gene mapping workshop, database development, international agreement on a standard karyotype, and
comparative mapping. The techniques used and the accomplishments resulting from use of those techniques (such as
linkage mapping and physical mapping studies—fluorescence in situ hybridization [FISH1] and synteny mapping)
are described below.
International Equine Gene Mapping
Workshop
As noted in the Introduction, the International Equine Gene
Mapping Workshop had a large impact on gene mapping
research for the horse. Construction of a comprehensive
gene map requires more resources than are available to any
of the laboratories conducting genomics research on horses.
To address this problem, the first workshop meeting was
held by the Dorothy Russell Havemeyer Foundation in October 1995. At the conclusion of the meeting, the 70 participating scientists from 23 countries agreed to collaborate over
a 5-yr period to share resources and construct a gene map for
the horse. Some of the results of these collaborations are
described immediately below and in Approaches Used to
Develop the Map.
'Abbreviations used in this paper: FISH, fluorescence in situ hybridization;
SCID, severe equine combined immunodeficiency disease.
172
Database
The gene map of the horse is developing so rapidly that any
published list of markers will soon be out of date. The status
of the gene map for the horse is best determined by consulting the databases available through the World Wide Web.
As information is published, the data are entered onto the
databases. Addresses of the 2 databases in current development through the auspices of the International Equine Gene
Mapping Workshop are as follows:
Roslin,
Scotland—http://www.ri.bbsrc.ac.uk/cgibin/arkdb/browsers/browser.sh?species=horse
Jouy-en-Josas, France—http://locus.jouy.inra.fr/cgibin/horsemap/Horsemap/main.pl
Standard Karyotype
Chromosomes are identified in most species based on chromosome banding patterns produced after chemical treatments. During 1996, the Dorothy Russell Havemeyer Foundation hosted a workshop meeting to establish a new
international standard. That standard was published in 1997
(ISCNH 1997) and has been important for accurate physical
mapping of genes to chromosomes.
Comparative Mapping
The genome organization among mammals is similar, and the
human gene map is best characterized. Knowing the regions
of the horse genome that correspond to the different regions of
the human genome makes it possible to use data from the
human genome studies to predict the genomic organization of
the horse without actually sequencing the horse genome. This
area of research is called comparative gene mapping. This
approach offers significant opportunities to draw on the research from other species and to more quickly apply the map
to identify economically important genes. The first comprehensive comparative gene mapping study for the horse is described in the ZOO-FISH section below.
APPROACHES USED TO
DEVELOP THE MAP
The genome organization of the horse is similar to that of
other mammals. The approaches used in genome studies
have included development of genetic tests for biochemical
markers, blood groups, lymphocyte alloantigens, and DNA
markers. The markers have also been used for investigations
involving linkage mapping, cytogenetic studies, and synteny
mapping. Studies are under way in several laboratories using chromosome flow sorting, chromosome microdissection,
and bacterial artificial chromosome libraries. These techniques are being used together to provide valuable, indepen-
ILAR Journal
dent confirmation of map positions and to extend the borders
and resolution of the horse gene map.
Linkage Maps
A linkage map allows us to identify DNA markers that are
closely linked to genes for inherited diseases, performance
traits, or other inherited characteristics for the horse. A first
male linkage map was published based on investigations of 140
markers in 8 half sibling families with a total of 263 offspring
(Lindgren and others 1998). Based on segregation of markers
from the stallions, 100 markers were found in 25 linkage groups,
22 of which could be mapped to 18 autosomes.
At the time of this writing, 2 additional linkage maps are
being developed concurrently and were presented in poster
format at the 26th International Conference on Animal Genetics (Auckland, New Zealand, August 1998). Swinburne
and others (1998) tested 180 markers on a family composed
of 5 grandparents, 5 parents, and 41 progeny. This family
structure is unusual for a horse and was constructed with the
use of 2 pairs of identical twin mares covered by a single
stallion and embryo recovery at 30 days to increase the number of available offspring. DNA-based genetic marker testing was used. This study identified 27 linkage groups of
which 20 could be assigned to 19 chromosomes, including
the X chromosome.
A third linkage map is being constructed at the time of
this writing on the basis of an international collaboration.
The International Equine Gene Mapping Workshop includes
20 laboratories that have tested 162 markers on 448 offspring distributed among 12 families (Guerin and others
1998). Of these markers, 124 were found in 29 linkage
groups and appear to be distributed among 25 of the 31 autosomes of the horse. The main tool of the workshop is the
International Equine Gene Mapping Reference Families,
which will be a resource for continued development of the
linkage map by diverse laboratories.
The maps constructed by Lindgren and others (1998) and
Guerin and others (1998) take advantage of the large number
of offspring produced by individual stallions. Most genetic
markers will be informative when multiple families are used.
However, it is not possible to map genes to the sex chromosomes. The advantage of the family used by Swinburne and
others (1998) is the reduced cost of testing fewer individuals
and the ability to map markers on the X chromosome and
place them on the Y. All 3 maps make extensive use of
microsatellite DNA markers, and there is considerable overlap in the markers used, facilitating comparison of maps and
eventual development of consensus on the linear relationship
of genetic markers.
FISHing Horse Genes
Before 1995, only 5 genes had been mapped to horse chromosome, including HBA, MHC, GPI, CRC, and PGD (Table 2).
Volume 39, Numbers 2 and 3
1998
TABLE 2 DNA markers mapped to horse chromsomes
Chromosome
Markers
Reference
1q2.1
1q12->q13
1q13
1q16->q17
1q14
Iq14
1p16->p15
1p1.2
1q1.l
2p
2p1.3->p1.4
2p14->p15
2p17->p18
3p15
3q21->q22.1
3p13->p14
3q12,
3q22
4p12->p13
4q21
4q27->cen15
5
6q21
7pter
7p15
7p1.1->p1.2
7p2.1
8
9p12
9q16->q18
9?
9q15->ql6
9p13->p14
9p15
9p1.2
1 Opter
10pter
ECA2
ASB12
ASB13
ASB8
SGCV02
SGCV25
HP27.1
ECA6
ECA13
PGD
ECA3
ASB17
ASB11
GOT2
KIT
SGCV18
SGCV33
ASB23
ASB3
ASB22
SGCV23
None
ASB14
C3
PR
ECA5
ECA12
None
DNApk
ASB4
ASB5
SGCV17
SGCV20
SGCV32
ECA14
GPI
CRC
Sakagami and others 1995
Breen and others 1997
Breen and others 1997
Breen and others 1997
Godard and others 1997
Godard and others 1997
Lear and others 1998b
Hirotaand others 1997
Hirotaand others 1997
Gu and others 1992
Tozaki and others 1995
Breen and others 1997
Breen and others 1997
Lear and others 1997
Lear and others 1997
Godard and others 1997
Godard and others 1997
Lear and others 1998b
Breen and others 1997
Breen and others 1997
Godard and others 1997
10p13
10q21->q23
11q12
11pl4
11p12
11 pi .1
12q13
12p13
1 3qter
13q13->q15
13q12
13q11->q12
13p1.2
14
15q21
15q21.3->q23
15q21.3->q23
15q24
15q23
16q14->q16
ASB6
ASB9
SGCV13
SGCV22
SGCV24
ECA10
IGF2
SGCV10
HBA
ASB16
SGCV03
ASB37
#2->33
None
ASB15
ASB19
ASB2
SGCV06
SGCV21
ASB7
Breen and others 1997
Millon and others 1993
Lear and others 1997
Hirota and others 1997
Hirota and others 1997
Bailey and others 1997
Breen and others 1997
Breen and others 1997
Godard and others 1997
Godard and others 1997
Godard and others 1997
Hirota and others 1997
Harbitz and others 1990
Chowdhary and others
1992
Breen and others 1997
Breen and others 1997
Godard and others 1997
Godard and others 1997
Godard and others 1997
Hirotaand others 1997
Raudsepp and others 1997
Godard and others 1997
Oakenfull and others 1993
Breen and others 1997
Godard and others 1997
Lear and others 1998b
Hirota and others 1997
Breen and others 1997
Breen and others 1997
Breen and others 1997
Godard and others 1997
Godard and others 1997
Breen and others 1997
173
TABLE 2 {Continued)
Chromosome
Markers
Reference
16q24->q25
17
18q21
18q2.3->q2.4
19q21
19
19q22->q23
19q2.6
19q2.7->q2.8
2Oq14->q22
HP7.2
None
SGCV07
ECA7
SGCV01
SGCV08
ASB25
ECA4
ECA9
MHC
Learetal. 1998b
20q2.2
21q13
21q13
22q19
23q19
24q15
25
26q17->q18
26q17->q18
27
28
ECA8
SGCV14
SGCV16
SGCV19
SGCV04
HP13.
None
MX
ETS
None
None
None
None
ER
29
30
31q
Xq2.8
#4->6
Godard and others 1997
Hirota and others 1997
Godard and others 1997
Godard and others 1997
Lear and others 1998b
Hirota and others 1997
Hirota and others 1997
Ansari and others 1988;
Makinen and others 1989
Hirota and others 1997
Godard and others 1997
Godard and others 1997
Godard and others 1997
Godard and others 1997
Lear and others 1998b
Lear and others 1998a
Lear and others 1998a
Lear and others 1997
Hirota and others 1997
With the advent of FISH and cloning of horse genes, a total of
73 genes have been mapped to chromosomes as indicated in
Table 2. Many of these mapped markers were microsatellite
DNA sequences cloned into cosmid or lambda vectors. These
markers are useful because they can be used to integrate the
physical and linkage maps (Breen and others 1997; Godard
and others 1997). Mapping genes encoding proteins is useful
to compare the organization of the horse map with the maps
for other species (O'Brien and others 1993).
ZOO-FISH
The first comprehensive genome map for the horse was a
"comparative map" reported in 1996 (Raudsepp and others
1996). These scientists used the technique of ZOO-FISH
(also known as chromosome painting) to identify regions of
homology between the human and horse genome. The results are summarized in Table 3. Based on their study, the
number of chromosome rearrangements that occurred since
divergence of the common ancestor of people and horses
was relatively limited, especially when compared with the
large number of rearrangements found between the mouse
and human genomes. For example, chromosome 9 of the
horse appears to correspond entirely to the genome for hu174
TABLE 3 Conserved chromosomal segments
detected on equine metaphase chromosomes after
zoological fluorescence in situ hybridization (ZOOFISH) with individual human chromosome-specific
libraries (CSLs). None of the human chromosome
paints hybridized to ECA6p, ECA12, ECA13p, ECA27,
ECA31,orECA-Ya
Human CLS for
chromosome no.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
X
Conserved horse chromosome
segments revealed by ZOO-FISH
2p, 5, 30
l q , 15, 18
16, 19
2q, 3q
14, 21
10q, 20
4
9
23,25
1p, 29
7p, q
1q, 6q, 8p, 26
17
1qter, 24
iq
3p, 13q
11
8q
10p, 7qcent
22
28
1 pter, 8pter, 26ter
X
a
Adapted from Raudsepp and others 1996.
man chromosome 8. However, the resolution of this technique does not detect inversions within chromosome regions
or translocations of small chromosome segments. Although
most of the ZOO-FISH assignments are being confirmed by
subsequent physical mapping studies in other laboratories, a
few discrepancies have been found and will be the subject of
future reports. Regardless of future clarification and refinements to this map, this work was a major stimulus for research and a major landmark for gene mapping.
Synteny Mapping
Somatic cell hybrid panels can be a powerful tool for gene
mapping research. This tool is based on hybridization of
horse lymphocytes with a mouse cell line, subsequent random and partial loss of horse chromosomes during culture to
produce sets of unique cell lines, each with a different subset
of horse chromosomes. The distribution of 2 genes compared across a large number (20 to 80) of these lines will
indicate whether the genes occur on the same or different
ILAR Journal
chromosomes. If 2 genes are present on the same chromosome, they will tend to have the same distribution among the
cell lines; if they are on different chromosomes, then their
distribution will appear unrelated.
Two reports have described the development of synteny
mapping panels for the horse, identifying several new
synteny groups including biochemical markers (Williams and
others 1993) and microsatellite markers (Bailey and others
1995). Recently, a third synteny panel has been developed
and used to develop a comprehensive synteny map for the
horse composed of microsatellite markers, randomly amplified polymorphic DNA markers, and DNA-based markers
for genes encoding proteins (Shiue and others 1998). This
report identified synteny groups associated with 21 of the
horse chromosomes and evidence that 12 other synteny
groups were associated with the remaining 12 chromosomes.
Synteny mapping provided a rapid and inexpensive method
to map markers to chromosomes and confirm or predict other
physical or linkage map assignments.
SCIENTIFIC CONTRIBUTIONS OF THE MAP
Use of the newly invented horse gene map has been limited
to date. Bailey and coworkers (1997) used markers developed for the gene map in a genome screening study to investigate linkage with the gene causing severe equine combined
immunodeficiency disease (SCID1) in horses. That study
identified microsatellite marker HTG-8 as being closely
linked to the SCID gene. Synteny mapping demonstrated
that a candidate gene identified by Wiler and coworkers
(1995), DNA-PK, was syntenic to HTG-8; a phage clone
containing part of the DNA-PK gene was mapped to equine
chromosome 9 using FISH (Bailey and others 1997). Subsequently, Shin and coworkers (1997) identified a 5-base deletion in the DNA-PK gene that was responsible for SCID in
horses.
ANTICIPATED FUTURE CONTRIBUTIONS
OF THE MAP
Genetics is important to horse breeders who continue to select characteristics of the horse related to gait, behavior, size,
color, and performance. Horses have changed over the last
50 years. Modern horses run faster than those of previous
generations, although some controversy exists in this area.
Gaffney and Cunningham (1988) noted that record-breaking
performances at classic thoroughbred races have become increasingly less common. At the same time, they found that
horses, on average, continued to exhibit genetic gain for racing performance. However, although breeders have effectively selected for performance, many horses do not perform
because of health problems (Jeffcott and others 1982). For
example, chondrodysplasias (developmental bone diseases)
are thought to have a significant hereditary component and
to affect 10 to 25% of horses across a wide range of breeds
Volume 39, Numbers 2 and 3
1998
(Jeffcott 1996). Limited and usually indirect selection is
applied to hereditary aspects of developmental bone diseases,
allergic diseases, infectious diseases, and behavior in horses.
As noted above, health problems are important to horse performance, but horse breeders do not select for health at the
expense of selecting for performance. Therefore, genetic
studies on diseases of the horse will likely be the primary
focus of genomics research in horses.
USES OF THE MAP AND ACCESSIBILITY
The order Perissodactyla includes species of rhinoceros and
tapirs as well as the members of the genus Equus. The
evolution of the Equidae has been 1 of the standard models
used for education in biology. The horse gene map will
provide tools for investigations of phylogeny within
Perissodactyla, providing valuable information about the process of evolution. Furthermore, the addition of the horse
gene map to the developing comparative map information
for diverse species is important because this species is the
best characterized member of Perissodactyla to date.
CONCLUSION
The horse industry is very important to the economies of
many countries of the world through the use of horses for
recreational riding, showing, and racing. Genetics is important to horsemanship, and a gene map for the horse will be
useful not only for investigating performance characteristics
but also, more importantly, for understanding hereditary aspects of health in horses. Although limited funds delayed the
start of gene mapping research for the horse, current work on
the gene map of the horse at the time of this writing is based
on collaborative activities of more than 25 laboratories associated with the International Equine Gene Mapping Workshop and through independent research at those laboratories.
Linkage, physical, and comparative maps are under construction using diverse techniques and resources, including reference families, synteny mapping, FISH, and ZOO-FISH.
More specific information about the map is available through
2 World Wide Web databases.
ACKNOWLEDGMENTS
The International Workshop was supported by the Dorothy
Russell Havemeyer Foundation, Inc. Work at the Animal
Health Trust was supported by the Horse Racing Levy
Board and the Childwick Trust. Work at the Gluck Equine
Research Center was supported by Fares Farms, Inc., The
Grayson-Jockey Club Research Foundation, Inc., the Morris Animal Foundation, Inc., and Invitrogen Corporation.
This report (98-14-37) was prepared in connection with a
project of the University of Kentucky Agricultural Experiment Station.
175
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