Report to the BMDCA on the 3rd International Symposium, Increasing the life
expectancy in Bernese Mountain Dogs. Burgdorf, Switzerland. August 10, 2007.
On August 10, 2007 the 3rd International Symposium devoted to Berner Sennenhunde
health was held in Burgdorf, Switzerland. The 2007 Symposium theme was: Increasing
the Life Expectancy in Bernese Mountain Dogs. Held at the Auditorium der Hochschule
für Technik und Informatik, complete with translators and translation facilities, over two
hundred people (36 from USA) representing twenty three nations attended. This years
symposium was sponsored by the Schweizerischer Klub fur Berner Sennenhunde held in
conjunction with their founding and 100 Jahre Anneversary. This year’s symposium was
largely funded by the Alberto Vittone estate.
Schweizer!scher Klub fur Berner Sennenhunde
Club Suisse du Bouvier Bernois
Club Svizzero del Bovaro del Bernese
Swiss Club for Bernese Mountain Dogs
Ladies and Gentlemen
Dear Friends of the Bernese Mountain Dog
It is with great pleasure that I welcome you to Burgdorf, the location in which the
Bernese Mountain Dog Club (BMOC) of Switzerland was founded one hundred years
ago. I am happy to see that close to two hundred fanciers and breeders of Bernese
Mountain Dogs from twenty-three different nations across the world celebrate this
important anniversary with the BMOC of Switzerland by attending this symposium.
The main topic of this symposium is: "Increasing the life expectancy in Bernese
Mountain Dogs". It supports the objective which the International Working Group (IWG)
set for itself at the 2005 symposium, organized in Salzburg by the Schweizer Sennenhund
Verein Osterreich (VSSO), namely: To further world-wide cooperation in matters of
health and longevity to achieve an average life expectancy of ten years (Objective 10) for
our beloved breed. The 2006 symposium, organized in Como by Societa Italiana del
Bovaro del Bernese (SIBB), concentrated on scientific research carried out world-wide
on the illnesses which most drastically shorten the life-span of our dogs, i.e. tumors and
especially malignant histiocytosis. The present symposium will provide updates on the
status of that world-wide scientific research initially presented in Italy by Catherine
Andre, PhD, France, Matthew Breen, PhD, USA and Gerard R. Rutteman PhD, Holland.
In addition it will provide an insight into how genetics influence life-expectancy by
Gaudenz Dolf, PhD, Switzerland and into how the environment/behavioral health
influences longevity by Urs Andrew Luscher, PhD, USA. Mrs. Christel Fechler will
inform us about practical steps and measures taken in the breeding program of the
Schweizer Sennenhund Verein (SSV) Germany to increase longevity. My sincere thanks
go to these speakers who are willing to share their specialist knowledge with us.
My thanks go to the VSSQ, Austria and SIBB, Italy who have organized the previous two
symposia. We were able to build our program as a logical continuation to the topics that
were discussed during the conferences they had organized.
The present symposium could not take place in its actual form, were it not for a very
generous donation received from the heritage of Alberto Vittone. We remember Alberto
in gratitude as one of the best friends the Bernese Mountain Dog ever had. Also, the
Alberto Vittone Award, an annual financial award to support one or more projects to
better the health and longevity of the Bernese Mountain Dog, will be distributed for the
first time at this symposium.
Finally I would like to sincerely thank all the people who helped organize this
symposium, especially Christine Irrgang Vogt and Silvia Brugger who carried the main
responsibility for its organization.
I hope that this symposium will bring us another step closer to a better cooperation
among all Bernese Mountain Dog breed clubs world-wide and to a better cooperation
with the scientific community world- wide. Our beloved breed deserves nothing but the
best. This may be a passionate statement, but nothing great has ever been achieved or
created without passion.
Martha Cehrs
President
Bernese Mountain Dog Club of Switzerland
============================
The focus of Dr. Dolf’s presentation was to impress upon the community that it is
possible to breed for longevity. Dr. Dolf’s specialty lies in cattle genetics. Having the
proper data at hand from which to make educated predictions is imperative. Cattle
industry genetics and data gathering is at an advantage as it is almost completely
governed by market economics. Only the very best cattle are breedable and ultimately
sold. Very strong incentives exist across the spectrum insuring extensive data gathering
on this population. The canine population is at a disadvantage as there is a very large
ratio of pet owners to breeders. It is very hard gathering strong and detailed information
in such situations. This leaves our dataset, necessary to making educated decisions
regarding selections for life expectancy and/or any trait of polygenic nature, very
challenging and insufficient. To develop a master plan for breeding for longevity will
necessitate analysis of data collected on hereditary diseases, environmental
deteriorations and other potential modifiers of life expectancy coupled with innovative
strategies to analyze and keep good phenotypes for longevity in breeding programs.
============================
Life Expectancy and Genetics
Is it possible to breed for longevity?
Gaudenz Dolt, PhD
Institute of Genetics, Vetsuisse Faculty, University of Berne, Berne, Switzerland
Life expectancy is the period of time an individual can be expected to live. The term can
be used interchangeably with average lifespan and average longevity. Typically an
individual takes some time to reach sexual maturity, then lives through a reproductive
phase, and finally enters the complex process of aging. In humans aging is composed of
several features:
* An exponential increase in mortality with age, that is the probability of dying at age 30
is much smaller than dying at age 70.
* Physiological changes that typically lead to a functional decline with age. Aging often
is accompanied by unpleasant features such as loss of hearing or loss of eye sight.
* An increased susceptibility to certain disease with age. Such diseases causing death are
heart diseases, cancer or neurological disorders, to name the most frequent ones.
The process of aging can not only be observed at the individual level but all the way
down to the single cell. Factors influencing aging cannot easily be separated from those
influencing longevity as in most organism aging is an integral part of longevity. In the
following we do not pretend to be able to dissect this complex of longevity and aging but
rather focus on the question whether there is enough genetics behind longevity in the
Bernese Mountain Dog to breed for longevity. For this purpose we first should look at
what is known in other organisms about longevity and aging.
There can be no doubt that environmental factors do have an impact on longevity as
accidents or diseases can terminate a life. But there must be a strong genetic component
as well. Otherwise it would be difficult to explain why a mouse should live no longer
than 4 years but a bat of similar body mass should live up to 34 years. The life span of the
calico rockfish is about 12 years whereas its close relative, the rougheye rockfish lives
over 200 years with no signs of aging. All salmons die shortly after reproduction but for
the steel head trout this holds not true. Although most of them die after reproduction
some are able to return to the sea and reproduce another year. The female of the plaice, a
flounder-like fish, continually grows and shows no sign of aging while the male ages and
dies. These examples suggest that a genetic background must be rather complex. Despite
these obvious differences in aging, the process of aging, at least in mammals, appears as a
consistent process albeit proceeding at different rates.
Independently of the environmental conditions a mouse will age 25 to 30 times faster
than a human being. Nutrition and exercise can make you live longer and attenuate
certain age-related diseases, but you will not be able to live as along as a rougheye
rockfish because humans age according to their genetic plan. This does not imply that
aging evolved with a purpose that we easily could recognize. Also cancer has a strong
genetic basis but it did not evolve with an apparent purpose. The greatest evidence in
favor of seeing aging as a genetic plan is that many genes that modulate aging have been
identified in model organisms such as yeast, a worm called Caenorhabditis elegans, fruit
fly, and mice. In the GenAge database 61 genes are listed for yeast, 255 for
Caenorhabditis elegans, 44 for the fruit fly and 47 for the mouse. All these genes seem to
have an impact on aging and therefore on longevity. In the following table some of the
genes investigated in these organisms are listed. The column "Life span" refers to the
difference in the mean life span of mutants in comparison to wild-type individuals.
In humans the Cockayne syndrome type I seemingly leads to premature aging due to a
recessive mutation in the ERCC8 (excision repair cross-complementing rodent repair
deficiency, complementation group 8) gene. The Hutchinson-Gilford's progeroid
syndrome is characterized by features resembling accelerated aging and caused by a
dominant mutation in the LMNA (Iamin A/C) gene. In Werner syndrome, caused by
mutations in the WNR gene, the age-related changes of patients are remarkably similar to
normal aging, only they occur at earlier ages. Further, apolipoprotein E has been
implicated in human aging. The variant e2 seems to be associated with longevity,
whereas the variant e4 is associated with early onset Altzheimer's disease. Besides the
genes already mentioned, there are 15 other genes, among them interferon gamma,
insulin receptor and tyrosin hydroxylase, which are significantly associated with aging in
humans.
With the availability of the dog genome sequence it is now possible to directly identify
all the genes, that have been implicated in the aging process in model organisms or
humans, in the dog as well. For instance, ERCC8 is located on canine chromosome 2
covering the region 50'368'759 bp to 50'423'886 bp, LMNA on canine chromosome 7
covering the region 44'673'637 bp to 44'691'143 bp, and WNR possibly on canine
chromosome 16 covering the region 36'120'426 bp to 36'257'633 bp. In the future this
knowledge could be useful to elucidate the genetic background of longevity in the
Bernese Mountain Dog. But would the knowledge of a single mutation in a gene
modifying longevity allow us to better the present situation by breeding?
The fact that wild-derived mouse strains take longer to reach sexual maturity and live
significantly longer than common laboratory strains suggests that longevity indeed can be
altered by breeding. It is conceivable that in the Bernese Mountain Dog we unknowingly
selected for gene constellations unfavorable for longevity. But if we can push longevity
in one direction by breeding we should be able to reverse the process.
In order to increase the longevity we first have to know about the factors modifying life
expectancy in the Bernese Mountain Dog. As in different species several hundred genes
have been implicated in aging and, by extension in longevity, we have to assume that
longevity in the Bernese Mountain dog is a rather complex trait too. Complex traits have
in common that they include a genetic and an environmental component. The genetic part
can be purely polygenic, but often one or more major genes can be identified. A major
gene explains a large part of a phenotype but not the whole phenotype. In order to
determine the nature of a complex trait a series of analyses is necessary. Variance
component analyses will show whether environmental factors playa major role in the
longevity problem. When including the relationships between the animals in the analyses,
heritabilities, maternal effects and genetic correlations can be estimated. Further,
segregation analyses will reveal the nature of the genetic component if present. If a major
gene can explain a substantial part of the variation in longevity we can go back to our list
of genes involved in aging and try to narrow down that list in order to investigate one or a
few such candidate genes. If a polygenic inheritance is most likely then the best way to
tackle the problem would be to estimate breeding values for longevity.
Up to here we have discussed possible factors influencing longevity and analyses able to
reveal such factors. Once we know the factors we can develop strategies to improve
longevity in the Bernese Mountain Dog. But before we enter this discussion we first have
to think about the data needed to perform the analyses. Do we have the data necessary at
hand or could the data be generated in a reasonable way? This is not a straightforward
task as causes and effects of aging are not easily separated. For instance, the occurrence
of hereditary diseases can interfere with longevity. Does, for example, malignant
histiocytosis playa major role in decreasing the average longevity or would the dogs die
anyway because of an altered genetic plan for aging? The problem boils down to the
question of what information should enter the analyses to ensure meaningful results. The
following list does not claim to be complete but it shows the basic information needed.
*
*
*
*
*
*
*
*
Identity of Individuals
Date of birth
Sex
Litter size
Date of death
Cause of death
Kennel
Pedigree
For dogs registered with a kennel club information on identity, sex, date of birth and
kennel is readily available. Also pedigree information poses no problem as the ancestry
generally is well documented, often reaching back to the beginning of the breed. These
data can be easily retrieved if stored in a computer database.
The litter size usually reported is the number of live registered puppies. But the true litter
size often is larger as reported in the studbook, because there are puppies either stillborn
or destroyed right after birth that do not appear in the studbook. This missing information
usually can be obtained from the Kennel Club but often is incomplete. Consider a trait
that is either present or absent at birth and the following pedigree:
Looking at this pedigree you immediately would suspect an X-chromosomal mode of
inheritance of the trait as only the two male offspring are affected. Any decent computer
program would come to the same conclusion. But now you learn that there were another
three stillborn puppies in this litter. The stillborn female was affected but the two
stillborn males were not affected.
Now you certainly would dismiss an X-chromosomal mode of inheritance in favor of an
autosomal recessive mode of inheritance. Even if the phenotypes of the three stillborn
puppies were not known they would allow for an autosomal recessive model. In a
segregation analysis not only monogenic models but also more complex models
including a polygenic component are tested. Therefore it is important to have the true
litter size whenever possible in order to come up with the correct model.
The date of death is not available for most dogs, but a prerequisite if we want to find out
about longevity. The same holds true for the causes of death. In most instances they
simply are not available. But if we want to find out about the genetic background of
longevity we need to have both, the date of death and the cause of death. These data are
not easy to generate in the field as the majority of dogs of a breed belong to the nonbreeding part of a given population. These dogs usually are kept as family or working
dogs and their owners most often take not part in the activities of the kennel club.
Therefore these owners cannot easily be enrolled in collecting data on a genetic disease
even if it benefits their breed. With respect to longevity the real problem is that an owner
should remember to report the date and cause of death at a time of mourning for a dear
companion.
The cause of death rarely is established and only in context with accidents or a disease.
The cause of death most often is based on the owner's opinion or a clinical diagnosis.
Diagnoses based on necropsy findings virtually are not available as they cost additional
money and often owners do not want to submit their dogs for a necropsy, especially in
the case where the obvious reason for death was old age. But it is essential to know about
the causes of death in order to find out whether we have a longevity problem or not. It is
conceivable that by removing some of the causes of death the normal longevity could be
restored. But it is also possible that some causes of death merely coincide with the natural
time of death meaning that the genetic plan of dying indeed has been altered.
As we believe longevity to have a genetic basis, environmental factors should not playa
crucial role. But as we do not know this for a fact it is worthwhile to evaluate possible
environmental factors. For instance longevity could differ among different geographic
regions which can be defined by the location of the different kennels. Or maybe dogs die
more often in winter than in summer, which would be a seasonal effect defined by the
dates of death.
Based on the prior knowledge on longevity it is safe to assume that we deal with a strong
polygenic component which includes environmental factors and possibly one or more
major genes. Getting a handle on such major genes even today with the availability of
DNA microarray technology is a challenge anc;J involves considerable time and money.
Should the hypothesis of a strong polygenic component hold true the estimation of
breeding values as basis for selection promises a faster and more cost-efficient way to
deal with the longevity problem. It could be argued that by selecting for longevity we
indirectly select against diseases which are leading to premature death. So all we would
need would be the date of birth and the date of death to address the problem. But we have
to keep in mind that the trait longevity could be correlated with other traits important in
Bernese Mountain dogs. Therefore we cannot simply look at longevity but we have to
monitor all the other traits as well in order to avoid improving longevity at other
important traits' expense.
In conclusion, based on the knowledge on longevity in other species, it should be possible
to increase longevity in dogs by breeding, provided the data necessary for the analyses is
available or can be generated.
The statements on longevity in model organisms and humans are based on
http://www.senescence.info; Partridge L and Gems D, 2002, Nature Reviews Genetics 3,
165-175; Finkel T and Holbrook NJ, 2000, Nature 408, 239-247.
PD Dr.Gaudenz Dolf
Institute of Genetics
Vetsuisse Faculty Berne
University of Berne
Bremgartenstrasse 109a
P.O. Box 8466,
3001 Berne, Switzerland
Phone +41 31 6312320
Fax +41 31 6312640
E-mail dolf.gaudenz@itz.unibe.ch
Studied Agronomy at the Swiss Federal Institute of Technology (ETH) in Zurich,
majoring in Animal Production and specializing in Animal Genetics, graduated as
Dipl.lng.-Agr. ETH (1976-1980). Thereafter Assistant at the Institute of Animal Sciences
at the ETH in Zurich (1980-1986) obtaining the Doctorate in 1984. Further studies at the
University of Texas System Cancer Center, MD Anderson Hospital and Tumor Institute,
Department of Molecular Genetics, Houston, Texas, USA (1986-1988). Since 1988
working at the Institute of Genetics at the University of Berne, and since 1999 Lecturer in
Animal Genetics.
Research activities originally concentrated on Genome Analysis of farm and companion
animals using molecular genetic methods. In the last 10 years there has been a strong
emphasis on statistical genetics with the main focus on coupling und segregation analysis
and genetic epidemiology. His research resulted in over 90 publications in peer reviewed
scientific journals.
Member of the Scientific Advisory Committee of the Swiss Kennel Club, member of the
Vetsuisse Research Commission of the University of Berne, member of the Advisory
Board of Swissgenetics, Member of the Board of the Swiss Association of Animal
Production, member of the Scientific Advisory Council of FUGATO (Functional
Genome Analysis in Animal Organisms) of the Federal Ministry for Education and
Research in Germany.
Also advisory functions for various breed clubs in Switzerland and Germany particularly
focusing or breeding strategies with respect to specific problems.
========================================
Life Expectancy and Genetics
Is it possible to breed for longevity?
Gaudenz Dolf
Institute of Genetics
Vetsuisse Faculty
University of Berne
Is it possible to breed for longevity?
What is life expectancy?
life expectancy = average lifespan = average longevity
masterplan
birth
death
juvenile phase
30/08/2007
reproductive phase
aging
2
Is it possible to breed for longevity?
Is it possible to breed for longevity?
death
birth
why?
change in the masterplan?
hereditary disease?
deteriorating environment?
30/08/2007
3
Is it possible to breed for longevity?
Is it possible to breed for longevity?
Based on literature on longevity in model organisms and man:
hereditary
diseases
accidents,
nutrition,
excercise
longevity
several hundreds
of genes
30/08/2007
acquired
diseases
4
Is it possible to breed for longevity?
Is it possible to breed for longevity?
Based on literature on longevity in model organisms and man:
there is a genetic masterplan for longevity
genetic factors influencing longevity cannot easily be isolated
longevity – aging – disease – complex
environment modifies longevity
wild-type mice live longer than mice of laboratory strains
Yes, it is possible to breed for longevity
but it might proof to be difficult.
30/08/2007
5
Is it possible to breed for longevity?
Genetics behind a phenotype
quantitative trait
categorical trait
environment
threshold trait
30/08/2007
6
Is it possible to breed for longevity?
What is the genetics behind longevity?
Goal
breeding strategy for longevity
Prerequisite
mode of inheritance must be known
Method
segregation analysis
Prerequisite
complete, meaningful data
selection based on breeding values
Results
let you decide
selection based on phenotype
30/08/2007
7
Is it possible to breed for longevity?
Segregationanalysis
threshold
frequency
dominance
d=1-
Aa
μAa - μAA
μaa - μAA
affected
AA
aa
unaffected
penetrance
liability
displacement
30/08/2007
t=
μaa - μAA
σ
8
Is it possible to breed for longevity?
Segregationanalysis
find out the mode of inheritance
Pedigree Analysis Package (Hasstedt, 1994)
comparison of different models
general model
environmental model
mixed inheritance model
estimation of effects
major gene model
polygenic model
30/08/2007
9
Is it possible to breed for longevity?
Segregationanalysis: Example
dilated cardiomyopathy in cattle
affected, no
diagnosis
affected, diagnosis
carrier
unaffected
unknown
Angus
male
female
30/08/2007
10
Is it possible to breed for longevity?
Segregationanalysis: Example
Results for dilated cardiomyopathy in cattle
113 animals in the analysis
model
frequency
dominance
displacement
heritability
-2 ln likelihood
general
This
0.321
10.655 for longevity
0.000
107.119
kind 0.688
of analysis
can be done
in the
Bernese
Mountain
Dog,
provided
we
have
the
data,
as
environment
0.725
0.000
0.675
--191.698
complete as possible, necessary for correct results.
mixed
0.684
0.137
10.906
0.000
119.693
major gene
0.684
0.000
10.906
---
119.694
polygenic
---
---
---
1.000
130.499
30/08/2007
11
Is it possible to breed for longevity?
What kind of data is needed?
segregation analysis using PAP
pedigree information and a phenotype for longevity
besides the major gene everything else
goes into the polygenic component
hypothesis
there may be a major gene but we expect a polygenic component
therefore we must be prepared to disect the polygenic component
therefore we may need other phenotypes and environmental factors
30/08/2007
12
Is it possible to breed for longevity?
What kind of data is needed?
main target trait
actual lifespan of an individual
genes
environmental factors
longevity
ageing
hereditary diseases
others
acquired diseases
accidents
culling
nutrition
kennel
others
30/08/2007
13
Is it possible to breed for longevity?
What kind of data is needed?
What is feasible?
readily available
pedigree information
date of birth
kennel
not readily available
date of death
cause of death
hereditary diseases
disease history
nutrition
excercise
others
30/08/2007
14
Is it possible to breed for longevity?
We need consistent records
example: cause of death is disease XY
all pedigree members are dead
the reds ones died of XY
all pedigree members are dead
the reds ones died of XY, but ...
the pink ones could have died of XY ...
the brown ones died of XY, but
30/08/2007
15
Is it possible to breed for longevity?
We need consistent, complete records
the major problem is a practical one .....
population
breeding population
non-breeding population
extremly difficult to get
information on phenotypes
in dog analyses are primarely based on the breeding population
30/08/2007
16
Is it possible to breed for longevity?
After the segregation analyses
assumption
sufficient data of sufficient quality
major gene
results
polygenic
for longevity?
for aging?
for a hereditary disease?
for ???
covariates?
fixed effects?
random effects?
maternal effects?
we may guess based on
the data
variance components
analyses
more analyses are needed but at this point we can turn to breeding strategies
30/08/2007
17
Is it possible to breed for longevity?
Breeding strategies: major gene
if a major gene can explain most of the phenotypic variation
we know the penetrances and allele frequencies
selection based on the phenotype in this case is a bit difficult as
the animal is dead at the time you get the phenotype
selection based on the phenotype of relatives is not easy
you may have to develop a marker or a gene test, in which case
you need DNA samples
other factors need to be considered when developping a breeding
strategy
30/08/2007
18
Is it possible to breed for longevity?
Breeding strategies: major gene
even if the major gene is autosomal recessive and fully penetrant
number of dogs
number of dogs
aa
aa
Aa Aa
AA
AA
age
age
we cannot be certain whether a dog is a carrier or not because
we have to wait until the offspring are dead
if the major gene is not fully penetrant we have no way to select in
a meaningful way
30/08/2007
19
Is it possible to breed for longevity?
Breeding strategies: major gene
although there is a close relationship between phenotype and
genotype, the selection based on the phenotype is not possible
as it is not available at the critical time
it is not possible to establish reliable genotypes based on the
phenotypes of relatives
developement of a marker or gene test should be possible using
groups of extremes
the use of a marker or gene test will only have a noticeable
impact on longevity if the gene concerned explains a large part
of longevity
disadvantage  time
30/08/2007
20
Is it possible to breed for longevity?
Breeding strategies: major gene
assumption:
you have a gene test for longevity
longevity is monogenic
exclude all aa and Aa from breeding?
other points to be considered
animal wellfare
other traits
effective population size - inbreeding
costs
breed standard
30/08/2007
21
Is it possible to breed for longevity?
Breeding strategies: general aspects
How stringent can you select?
increase of inbreeding per generation ΔF %
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breeding
population
number of
sires
number of
dams
effective
population size
ΔF % per
generation
100
50
50
100
0.50
100
40
60
96
0.52
100
30
70
84
0.60
100
20
80
64
0.78
100
10
90
36
1.39
100
5
95
19
2.63
100
1
99
4
12.63
22
Is it possible to breed for longevity?
Breeding strategies: general aspects
How stringent can you select?
increase of inbreeding per year ΔF %
breed 1
breed 2
breed 3
breed 4
new sires / year
3
14
53
53
new dams / year
15
92
263
263
0.20
0.15
0.20
0.20
generation interval
5
5
5
9
ΔF sires / year in %
0.1667
0.0357
0.0094
0.0029
ΔF dams / year in %
0.0333
0.0054
0.0019
0.0006
total ΔF / year in %
0.2000
0.0411
0.0113
0.0035
sires / dams
30/08/2007
23
Is it possible to breed for longevity?
Breeding strategies: major gene
Can we do without this sire or dam?
Aa
AA
Aa
AA
Aa
aa
Aa
Aa
Aa
criteria
genetic merit
genetic uniqueness
other
AA
Aa
AA
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AA
Aa
Aa
perfect dog
except
longevity
Aa
Aa
AA
AA
consequences
Aa
mating recommendations
mating instructions
other
24
Is it possible to breed for longevity?
Breeding strategies: polygenic
if the polygenic model explains our data best
we can estimate the heritability
we can estimate breeding values for the trait
the reliability of the breeding values depends on the number and
quality of the informations available
selection based on breeding values will be successful only if a
breeding strategy is properly designed and consequently
adhered to
other factors need to be considered when developping a breeding
strategy
30/08/2007
25
Is it possible to breed for longevity?
Breeding strategies: polygenic
phenotype of
ancestors
own
phenotype
individual
breeding value
phenotype
of sibs
phenotype of
offspring
30/08/2007
26
Is it possible to breed for longevity?
Breeding strategies: polygenic
P – AC = (PM + BVI + Ep + Et) – (PM + ΣBV / n + Ep + ΣEt / n)
if the population is large, then ΣBV / n und ΣEt / n  0
P – AC = BVI + Et
we drop Et as we cannot estimate it and we adjust for the
heritability, the degree of relatedness of the individual with all others
and the degree of relatedness of all others among themselves
BVI = b (P – AC)
30/08/2007
27
Is it possible to breed for longevity?
Breeding strategies: polygenic
How reliable are breeding values?
correlation coefficient between the estimated BV and the true BV
Information
reliability r2 in %
h2 = 0.2
30/08/2007
h2 = 0.5
individual
20
50
sire and dam
10
25
individual & sire and dam
26
58
4 fullsibs
15
29
10 halfsibs
9
15
20 offspring
52
74
100 offspring
85
94
28
Is it possible to breed for longevity?
Breeding strategies: polygenic
Individual
rather cautious,
BV around 103,
variation in
offspring smaller
rather risky, BV
around ?,
variation in
offspring larger
breeding value
reliability %
sire 1
114
32
sire 2
105
83
dam 1
118
28
dam 2
101
69
dam 3
104
52
mating
breeding value
reliability %
sire 2 x dam 2
103
38
sire 1 x dam 1
116
15
sire 1 x dam 3
109
21
30/08/2007
29
Is it possible to breed for longevity?
Breeding strategies
How are dogs bred?
dogs are selected for breeding according to the breed standard
tests for behaviour, work, racing, ....
cryptorchidism, anomalies, gene tests, marker tests, ....
trait 1
trait 2
30/08/2007
30
Is it possible to breed for longevity?
Breeding strategies
you have the knowledge, you have the data,
but you do not use it to its full extent
population
breeding population
non-breeding population
genetically valuable dogs never make the breeding population
30/08/2007
31
Is it possible to breed for longevity?
Breeding strategies
selection today
killer criteria
independant selection thresholds
index = phen1 + phen2 + phen3 + BV + .....
genetic gain where you have high heritabilities
genetic gain where you have genotypes
little or no genetic gain where you have low
heritabilities or antagonistic correlations
How can this situation be improved?
30/08/2007
32
Is it possible to breed for longevity?
Breeding strategies
selection tomorrow
set priorities
estimate breeding values
index of combined breeding values
conformation judgement
tests: behaviour, work, ...
linear description instead of grades
breeding values for each trait
combine breeding values  partial breeding values (PBVs)
overall breeding value = b1PBV1 + b2 PBV2 + b3 PBV3 + ...
30/08/2007
33
Is it possible to breed for longevity?
Breeding strategies
all dogs have breeding values
breeding population
population
evaluate as many dogs as possible
non-breeding population
you will breed with these dogs
30/08/2007
34
Is it possible to breed for longevity?
Breeding strategies
assumption:
breeding values for conformation
breeding values for behaviour
breeding values for hereditary diseases
breeding values are standardized
greater breeding values are better
all breeding values are available for all breeders
30/08/2007
35
Is it possible to breed for longevity?
Breeding strategies
Dog XY
gene test Aa
BVoverall 105
Rel% 63
ld
30/08/2007
BVconformation 107
conf 1
7
conf 2
5
conf 3
8
conf 4
4
conf 5
9
conf 6
8
behav 1
5
behav 2
2
1
Rel% 67
2 3 4 5 6
7
Rel% 51
8 9
x
BV
100
x
112
x
102
x
82
x
x
x
x
BVbehaviour 100
109
91
111
88
36
Is it possible to breed for longevity?
consequences
current selection processes have to be changed
traits have to be ranked according to their priority
some of your favorite traits may not rank top
linear description has to be introduced
conformation judgement and tests for non-breeders
genetic gain in traits other than longevity may become minimal or zero
mating directives may be necessary
30/08/2007
37
Is it possible to breed for longevity?
Summary
longevity probably is a complex trait with a genetic background
polygenic inheritance seems more likely than monogenic inheritance
it should be possible to breed for longevity
minimal data required: date of birth, date of death, cause of death
most promising: estimation of breeding values for longevity
consequences: restructuring of the selection process
outlook: genetic gain for longevity depends on the implementation of a
consequent breeding strategy
increase of the average lifespan per year will be small
30/08/2007
38
==============================
Dr. Luescher lectured on the importance of stress and it’s implications on welfare and
longevity in dogs. Reducing and managing stress in dogs can be a beneficial component
of lifespan expectancies. Dr. Luescher first discussed some of the common causes of
stress and anxiety by detailing predisposing factors in dogs. Global fear (fear of
everything) developed during lifecycle fear periods, specific fears (e.g. fear of loud
noise), shyness, blindness and sensitivities to inconsistencies, unpredictabilities and
uncontrollable environmental factors are all considered disposing factors, and
potentially learned, to damaging stress.
It becomes important that factors potentially responsible for eliciting stress be carefully
introduced and managed for maturing puppies and dogs. One recent study found that
puppies exposed to traffic noise are less likely to be fearful later in life when exposed to
noise spectrums that reach crescendos and then taper off. Traffic noise provides that
spectrum. Neonatal mild stress may have beneficial effects in the individual’s
development.
The importance of knowing the heritage and developmental utilizations of the breed are
important to understanding and mitigating potential stressors. Highly trainable breeds
tend to be more sensitive to their perceived inabilities to predict or control what is
happening to them.
Misinformed or instilled insecure leadership values can set up a lifelong cycle of stress in
dogs by creating mindsets of learned helplessness. Changing rules and giving
inconsistent directions, applied inconsistent punishments and rewards given for noncontingent behaviors can all play together to develop damaging stress capable of
affecting life expectancy.
Treatments of anxiety/stress developed disorders can be difficult and challenging.
Consistency in environment, absolute rules for punishments, exercise, outlets for normal
canine behaviors and environmental stimulations all need to be provided. Additionally, it
may be necessary to incorporate pharmacological treatments. Novel approaches can
include Dog Appeasement Pheromones (found in lactating bitches and induce relaxing
behaviors) as vapor infused collars.
Given difficulties of dealing with and treating a lifetime of learned stress necessitates
strong actions rooted in prevention and recognizing breed predilections that set up unnatural stress. In closing Dr Luescher gave five requirements aiming toward
achievement of increasing life expectancy. Breeding with offspring of long lived
ancestors, creating stock with high genetic diversity, feeding naturally, providing
maximum physical health care, and improving mental health by husbandry appropriate
to the species should provide high vitality values leading to increased life expectancy.
============================
Life Expectancy and Environmental Factors: Maintaining Behavioral
Health
Andrew Urs Luescher Dr. med vet PhD DACVB ECVBM
Introduction
I have not found any publications that studied the relationship between stress and
longevity in dogs. However, the documented detrimental effects of stress on
physiological and behavioral well being allow the conclusion that appropriate
management of distress will contribute to welfare and longevity of our dogs.
Signs of Stress
Stress in dogs can be recognized by various physiological signs (Lindsay, 2000), such as:
* Pupillary dilatation
* Dilatation of blood vessels in the retina of the eye (change of eye color)
* Decreased pain sensitivity
* Decreased appetite and thirst
* Panting
* Increased perspiration on pads of the feet
* Increased heart rate
* Increased sympathetic arousal
* Frequent defecation, diarrhea
* Frequent urination
* Stronger startle and withdrawal reflexes
Behavioral signs include:
* Body language (ears back, tail tucked, body lowered)
* Conflict behavior (yawning, scratching, shifting eyes, scanning, pacing, etc.);
compulsive disorder
* Escape behavior, scurrying, hiding
* Hyperactivity, hyper-reactivity
* Destructiveness, chewing licking
* Self-directed behaviors
* "Sexual" mounting
* Vocalization (high-pitched screaming, repetitive barking)
* Survival behaviors such as aggression (initially defensive, but may become offensive
through conditioning with negative reinforcement)
* Inability to learn, focus
* Not accepting treats
Consequences of Stress
Stress, especially if frequent or chronic (non-avoidable) and anxiety have detrimental
consequences:
* Atrophy of lymphatic glands and immunosuppression
* Changes in red-cell and white-cell blood values
* Gastric ulcers
* Degenerative effects on the brain that reduce ability to cope (less inhibition by higher
brain centers)
* Increase in cortisol secretion
* More frequent and irregular urination, loss of house training
* Decreased appetite
Causes of Stress:
Stress can be caused as a result of genetic predisposition and the way we raise a puppy.
Stress may also be caused by environmental conditions, including by how we manage the
dogs, and by the nature of our interactions with dogs.
* Genetic predisposition: Some dogs are genetically predisposed to develop generalized
fear or anxiety, sometimes very early in life. Others have a predisposition for developing
specific fears, such as fear of loud noises (frequently late onset). Dogs that have been
selected to be highly trainable are particularly prone to suffering from an inconsistent,
unpredictable and uncontrollable environment.
* Early experience: A restricted early environment inhibits learning ability probably
because of increased emotionality. Early removal from the litter has been shown in other
species such as rats and cats to increase emotionality and anxiety (increased stress
hormone turnover, decreased serotonin production). Severe disease in the first 16 weeks
of a dog's life can also adversely affect emotionality (as evidenced by increased incidence
of owner-directed aggression). Puppies that are not exposed to normal every-day stimuli
between 3-14 weeks of age will be fearful and anxious as adults. If they are left in a
restricted environment until 12-14 weeks of age, the chances of establishing normal
responses are virtually non-existent. Psychological trauma in a fear period may result in
generalized anxiety or specific fear.
* Traumatic experience: An adverse experience in a particular situation will cause
anxiety and fear in that situation or to the aversive stimulus in the future (classical
conditioning). Dogs can also suffer from post-traumatic stress syndrome.
* Environment: Unpredictable environment and social interactions, lack of consistent
rules, loss of control over environment and over pleasant and aversive stimuli can result
in learned helplessness.
* Motivational conflict: Strong opposing motivations resulting in conflict and conflict
behavior. Frequently caused through inconsistent interactions and, especially,
inappropriate use of punishment.
* Frustration: resulting form thwarted motivation, e.g., caused by social isolation, lack of
exercise or lack of opportunity to investigate ("cabin fever”).
Treatment of Stress and Anxiety:
Treatment needs to be specific to the cause, or to the specific anxiety-related behavior
problem (e.g., compulsive disorder or separation anxiety). However, there are some
general measures that can help alleviate stress:
* Consistent environment: Absolute rules and predictable and consistent interactions
empower dogs by giving them the ability to control appetitive and aversive stimuli.
Obedience training and command-response-reward type interactions contribute much to
stress reduction.
* No punishment: Punishment is a very complex technique and difficult to use correctly.
In addition, punishment is only appropriate for a very limited number of problem
behaviors. Alternatives to punishment include, e.g., avoiding triggers, removing the
reward, giving acceptable alternatives, and teaching an alternate behavior (response
substitution).
* Exercise: Physical exercise has a modulatory effect on stress hormones, increases brain
serotonin, boosts the immune system and reduces impulsive behaviors. Exercise off the
property also allows for investigation of novel stimuli. Regular (twice-daily) walks off
the property greatly reduce anxiety and alleviate behavior disorders that involve anxiety.
* Outlet for normal behavior: Investigation, chasing (predatory behavior), chewing, play,
social interactions, etc, are normal dog behaviors that need an appropriate outlet.
* Environmental stimulation: All sensory systems, in particular the vomeronasal organ,
give input into the limbic system that controls emotions. A very monotonous
environment will increase anxiety (this may be why meal feeding is better than freechoice feeding in dogs), a more complex (albeit consistent and predictable) environment
will decrease it. Commercially available pheromones (DAP) can be used to reduce
anxiety
* Pharmacological treatment: Because of the limitations of and requirements for behavior
modification techniques, temporary pharmacological intervention is often necessary to
reduce the anxiety to a level where the animal can learn and behavior modification
techniques can be effective.
* Specific treatment of behavior disorders: There are specific treatment protocols for
anxiety- related behavior disorders such as separation anxiety, many forms of aggression,
compulsive disorder, etc.
Prevention of Stress and Anxiety
Sound genetic makeup, optimal raising conditions, sufficient socialization and exposure,
canine- appropriate management, feeding and exercise, a complex and consistent
environment, predictable social interactions, competent training methods and restraint on
discipline, the avoidance of traumatic experiences and good health status, all contribute to
an emotionally balanced dog.
Genetic basis for emotionality: Researchers identified four personality traits in dogs, i.e.,
aggressiveness, playfulness, curiosity/fearlessness and chase-proneness, the latter three
traits forming the super-trait shyness/boldness. Heritabilities of chase-proneness and
aggressiveness have been shown to be moderate, but those for playfulness and
curiosity/fearlessness are high. Therefore, selection of breeding animals for temperament
should be successful given reliable and valid tests to measure it.
Complexity of Early Environment: An animal's central nervous system only retains its
genetically predetermined functions if exposed to environmental stimulation, especially
early in life. A restricted early environment will result in an animal with abnormal
sensory perception that is emotionally unstable. In addition to emotionality, the
complexity of the early environment also greatly influences learning ability. A restricted
early environment may result in reduced trainability. It is therefore important to provide
an interesting, stimulating early environment. In addition it is also important that the
early environment be predictable and consistent. If not, the animal will learn that its
behavior has no impact on what is happening around it, and it will be in a state of learned
helplessness. Such animals are exceedingly hard to train later on.
Effect of Neonatal Stress: Some degree of stress (e.g. handling, cold temperature) in the
neonatal period of dogs may accelerate growth, reduce emotionality, and increase
resistance to some diseases. Handling sessions from the first days of a puppy's life are
therefore recommended (about 3 minutes/day are sufficient). In addition, puppies may be
removed from the nest (best while someone else walks the mother) and placed on a cool
vinyl floor for a brief time (30 seconds) before being put back into the warm nest. If done
in the first few days after birth, this is expected to result in reduced behavioral and
physiological reaction to chronic stress, an increased physiological reaction to acute
stress, and reduced emotionality of the adult dog. Chronic stress is caused by unavoidable
and long-lasting aversive conditions. Since they are unavoidable, the stress reaction does
not result in coping, and just drains the animal's resources. Such chronic stress causes
stomach ulcers and other impairment of health. A strong reaction to acute stress,
however, is desirable. If a grand piano falls from the sky directly towards you, it may
save your life to mobilize all your resources to get away from there. So both a reduced
reaction to chronic stress and an increased reaction to acute stress are beneficial.
Socialization and exposure: The socialization period of dogs begins at about 3 weeks and
extends to about 12 or 14 weeks of age. Socialization to dogs and to people has to occur
during this time (it needs to be continued thereafter). If this opportunity is missed, the
puppy will most likely always be fearful of dogs and/or humans. During the socialization
period, the puppy should also be exposed to all situations that it is likely to encounter
during its life. The best prevention of behavior problems is to take the puppy to puppy
classes during that time. During the socialization period, the puppy can already learn
some commands. It should learn a biting inhibition, and should start to learn to fit into a
social group.
Managing for Success: Problem prevention includes managing the puppy for success, i.e.,
arranging the environment so that the puppy cannot do the wrong thing, and
automatically chooses to do the right thing (e.g., house training, chewing). If appropriate
behaviors are successful from the puppy's point of view from the beginning, it will repeat
these and not try other behaviors (and if we have set up the environment correctly, if it
ever tries other behaviors, these are not successful). This includes puppy proofing the
house and appropriate confinement and supervision.
Exercise: Exercise off the property will satisfy the dog's innate motivation to explore new
things, help with exposure and desensitization to stimuli, and facilitate socialization.
Exercise off the property also decreases arousal and reactivity, reduces anxiety and
reduces the risk of owner-directed aggression. Vigorous exercise also reduces anxiety
through its effect on stress hormones and serotonin.
Environmental enrichment: Interactive toys and games, food dispensing toys, rotating the
toys so they maintain novelty, and appropriate play serve to enrich the environment and
provide mental stimulation.
Obedience training: Obedience training has an enriching effect as well. Furthermore,
humane obedience training (lure training, clicker training) provides for predictable,
consistent and stress-free interaction, and an opportunity for the dog to act upon the
environment with predictable outcome. If we are consistent in training, the dog has a lot
of control over the situation (i.e., over the rewards). In clicker training, they literally can
make us click. Furthermore, command-control over the dog can help diffuse critical
situations by telling the dog what to do, i.e., providing the dog with an appropriate way to
cope with a stressful situation.
In addition to usual commands, a puppy should learn a bite inhibition, food bowl safety,
the "off' (or leave-it and drop-it) command, to walk on a leash, to be alone for some time,
and to accept a crate. A puppy should also learn appropriate play.
Consistent Rules: I don't believe we have to dominate our dogs (I don't think our
relationship with dogs is one of dominance and submissiveness, but that is open to
debate). However, we have to control the contingencies on the dog's behavior. That
means, we have to control consistently, which behaviors pay off for the dog (are
rewarded) and which do not. The establishment and strict enforcement of rules are
extremely important. If rules are not consistent, the dog can never figure them out, and
cannot function within them to achieve success. This situation would be similar to you
visiting with friends who playa card game that you don't know. They ask you to
participate and explain you the rules. You go along with it and after some time think you
have the winning hand, put your cards down and claim that you have won. Now of
course, your friends add another rule, etc. After two or three times of this, you will
become frustrated, angry (as a conflict behavior!) and distressed. This is how our dogs
must feel if we have no rules or constantly change them. They may either compensate for
this by developing survival behaviors that yield short-term predictable consequences
(such as aggression, escape or inhibition), or develop learned helplessness (i.e., they learn
that their behavior has no effect on what happens around them). Enforcing strict rules
therefore has nothing to do with dominance, but a lot with giving the dog a chance to
operate successfully in its environment and achieve predictable outcomes. Particularly a
highly trainable dog, i.e., a dog that is keen on operating on his environment, is in a state
of compromised welfare if a consistent rule structure is not maintained.
Managing the older dog
All the above also applies especially to older dogs that may suffer from declining
cognitive function. Environmental enrichment, mental stimulation and teaching new
behaviors (appropriate for the dog's age, health and physical ability) such as scent
discrimination or searching for a hidden treat or toy, may help prevent cognitive decline.
There are now classes offered for senior dogs. It is important to maintain older dogs'
interest in participating in daily activities, social interactions, play and suitable exercise.
Andrew U. Luescher DVM PhD DACVB ECVBM-CA
Certified Applied Animal Behaviorist (ABS)
Director, Animal Behavior Clinic
Department of Veterinary Clinical Sciences
Purdue University
VCS, LYNN
625 Harrison Street
West Lafayette, IN 47904-2026, USA
E-mail: luescher@perdue.edu
Qualifications:
1975 Med. Vet. Prakt., Zurich, Switzerland
1979 Dr.med. vet., Zurich, Switzerland
1984 PhD (Animal Behavior) Guelph, Canada
1993 Certified Applied Animal Behaviorist (Animal Behavior Society)
1995 Diplomate, American College of Veterinary Behaviorists (ACVB)
2006 Diplomate, European College for Veterinary Behavior Medicine - Companion
Animals
Professional Experience:
1982-1984 Research Associate, Federal Veterinary Office, Bern, Switzerland
1985-1997 Assistant Professor for Ethology, University of Guelph, Guelph, Ontario,
Canada
1995-1997 Adjunct Faculty, animal behavior, Atlantic Veterinary College.
1997- Associate Professor with tenure for Animal Behavior and Director of Animal
Behavior Clinic, Purdue University, W. Lafayette, Indiana.
Research Interests:
Conflict behavior and compulsive disorder in various species
Canine aggression to household members
Psittacine behavior
Learning in dogs and training methods
Behavior Development
=========================
Christel’s presentation was in German, necessitating a translator. In the face of declining
health and lifespans, in the BMD in 2004 the Schweizer Sennenhund-Verein fur
Deutschland (SSV) developed more stringent rules and enforcement measures as part of
the clubs breeding policy. The new policy measures were introduced for use in 2005.
Christel detailed the salient portions of the new policy that are benefiting the breed in
Germany as well as the drawbacks being encountered. The new policy attempts to
structure rewards for transparency (e.g. tendency to be more generous toward breeder
requests for those breeders participating with transparency) in reporting data.
Awareness seminars are presented to the 13 groups of the SSV. Utilization of foreign
dogs for breeding has increased by 30% in Germany. Foreign dogs must be approved as
breed stock by SSV. It proves problematic for SSV to obtain 10 generation data for their
database on foreign dogs. The SSV has built cooperative breed agreements with the
Austrian Club in which information is freely exchanged. Agreements are in place for
breed stock with the Swiss Club.
The SSV has received scrutiny, both positive and negative, regarding the implementation
of their new program. Some feel the restrictiveness and enforcement of the current policy
do not go far enough and others feel it is overly restrictive, so much so, some SSV
members left the club to join the other BMD club in Germany. Christel explained how it’s
been a very fine line to walk. However, in spite of the drawbacks encountered the SSV is
now accumulating much needed data and improvements in breeding programs is being
seen.
==========================
Practical Breeding Rules Adopted by the SSV to Improve Life Expectancy
Christel Fechler
Responsible for all breeding matters in the Swiss Mountain Dog Club (SSV) of Germany
Similar to many other breeding clubs, the SSV (Schweizer Sennenhund-Verein for
Deutschland) began in the early '90s to become very concerned about the very short
average life expectancy of our Berners. Only occasionally we received information about
Berners which had died. Generally such information was conveyed only by hearsay. We
hardly ever received any written confirmation about the death of a Berner. In the past it
was just accepted - although with great sadness - that a lot of dogs were dying at a much
too young age. But now we ask for more details: What was the cause of death? Did the
dogs undergo autopsy and was a pathological examination performed? We developed a
questionnaire which was sent to all dog owners of whom we learned having lost their
companions. The corresponding information was recorded, but at that time, we still had
no effective program in place which would make this information available to the
breeders and owners of Bernese Mountain Dogs. First steps were taken into the right
direction.
We were also very concerned about how often certain stud dogs were being used. At that
time all the appeals of our breeding warden were ignored, asking our breeders to take
more responsibility and to make more use of stud dogs which had either no or very few
offspring, as well as asking the owners of stud dogs to use them not so extensively but
more selectively in making them available for mating. It was reality that individual stud
dogs had up to 740 direct offspring alone in the SSV. Additionally, there might have been
even more matings with the same stud dog in foreign countries.
After considerable discussion within the SSV as well as with the scientific advisory board
of the VDH (Verein for das Deutsche Hundewesen, the German Kennel Club), new
breeding guidelines were proposed and, in autumn 2004, approved and enacted by the
SSV Committee.
Basically these breeding guidelines include the following regulations which we hope will
lead to an increased life expectancy:
•
Optimal use of the available breeding dogs, taking into consideration the age of
their ancestors and siblings
• Comprehensive monitoring of the offspring
• Increasing the responsibility of stud dog and bitch owners
In this context, all breeders and owners of Bernese Mountain Dogs have been requested
to ensure complete and open information with respect to age structure and the
comprehensive monitoring of the offspring.
In more detail the SSV breeding guidelines and rules include:
a) To improve the age structure, Bernese Mountain Dogs which have been approved
according to the Breeding and Selection Rules ("Korung") of the SSV, and which
can therefore be used in the breeding program, can only be considered for matings
in which for at least 10 of the 14 ancestors (i.e. up to the great grandparents'
generation) of each of the partners in the planned mating, either some proof (not
older than 12 months) can be presented that a dog is still alive, or a report of
death. Decisions are made using the data on each dog before the mating. If the
necessary data (life or death reports) are not available and can not be obtained
before the actual mating, an application for permission of the mating can be
forwarded by the breed warden to the Breeding Commission.
b)
After having successfully completed the breeding evaluation test (Korung) and
taking into consideration all the breeding requirements listed above, a stud dog is initially
only allowed to sire a maximum of 21 litters which are to be registered in the SSV
Studbook. Thereby, not more than 7 litters are allowed to be sired within a period of 12
months, counted from the day of the first live born litter. Stud dogs beyond their 8th year
of age (=96 months) are not any longer restricted with regard to the number of matings.
c) For stud dogs younger than 8 years, which have already sired 21 litters registered
in the Studbook of the SSV, an application can be directed to the Breeding
Commission, which may allow further matings, taking into consideration the
relevancy to the situation of the breeding population of the Bernese Mountain
Dogs prevailing at the time the application is made. This application is to be
directed to the breed warden, explaining the reasons for the special application
and also including the life/death reports of the ancestors, the litter siblings, as well
as the offspring of the stud dog and the results of the offspring controls.
"Offspring control "will be explained in detail in paragraph e).
d)
Stud dogs, which were not yet 8 years old but which had already sired 18 or more
litters registered in the studbook of the SSV before the new breeding regulations were
enacted, were allowed to have 3 additional litters. All other breeding approved studs
younger than 8 years were allowed to be used in the breeding program until they had 21
lifters registered in the Stud Book of the SSV, including their SSV registered litters
before the new breeding regulations were enacted. The stipulations in paragraph c) apply
for possible further breeding use.
e) Brood bitches with offspring having reached the age of 18 months, are not allowed
to be used again for breeding until at least 2 (in the case of a litter with only a
single puppy, 1) of these offspring per litter (if possible 1 male and 1 female dog)
have had HD and ED x-ray examinations comprising an official evaluation by the
designated body of the SSV. This is what we mean by "offspring control"
(Nachzuchtkontrolle). The Breeding Committee (represented by the breed warden
responsible for the area) determines together with the breeder during the litter
inspection, which of the puppies should be included in the offspring control. In
case that one of the dogs chosen for the evaluation can not be presented for some
reason (e.g. for health reasons), another puppy must be identified as "substitute
offspring". If the puppies chosen by the breed warden and the breeder at the litter
inspection have not been evaluated at the appropriate age, the necessary offspring
control can alternatively be conducted by an evaluation of 70% of the dogs from
each litter.
The breeders are asked to keep the inbreeding coefficients as low as possible.
For the submission the living/death reports required by the new Breeding Plan, all
members of our Club received special forms together with our Club Newsletter, the "SSV
Kurier". These forms can now also be downloaded from our Club Internet Homepage.
The proof that a dog is still alive must either be certified by a registered veterinarian (e.g.
at the annual vaccination) or by one of the SSV breed wardens. In addition, any
participation of a dog in FCI shows, performance tests, offspring control, breeding
evaluation tests - i.e. at official events - will be automatically recorded. Breeding
notifications and litter reports for the sire and bitch involved, as well as vaccination
certificates which are clearly assigned to a particular dog, are also accepted as proof that
the dog is still alive.
Death reports may also be communicated informally as well as by use of the appropriate
form. In any case either a pathology report should be attached or at least a statement must
be included on whatever a veterinarian presumed to be the cause of death.
So far, the SSV is deliberately not insisting on a mandatory procedure according to which
a pathology report must be submitted for each dog's death, because we feel that in this
way we will get a higher response rate of reports. Some breeders and dog owners are
anyway unwilling to report a death, especially if the dog has died at a young age and of
cancer, because they are afraid of damaging the reputation of their kennel. However, we
certainly hope that in the future, in the interest of the breed, there will be a significant
increase in the willingness of all owners and breeders to submit a pathology report on all
dogs that have died or have been euthanized.
Just recently, in November 2006, to further improve the feedback rate of life/death
reports, the SSV sent 847 questionnaires to the owners of the Bernese Mountain Dogs
which had been born in the years 1997 to 1999. 458 of these forms (only 54%) have been
returned. 305 of the dogs were still living at that time, and 153 were reported to have
died. Unfortunately, most of these dogs had died - as expected - of cancer.
At this point in time we have received a total of about 5,100 death reports. All
information on life or death of the dogs have been entered into a data base named
"Dogbase" and are thus accessible to our breeders and club members. However, the cause
of death has not been made public because only a very small proportion of our breeders
have been honest and open enough to report all dogs from their kennels which have died
at an early age with tumours. We must make sure that dishonesty does not bring any
advantages for the breeders, and that openness and honesty as well as a high return rate of
reports is rewarded. For this reason, the up-to-date results of reports are made public once
a year for dogs coming from individual kennels.
Generally, our experience is positive in dealing with our breeders regarding the new
restrictive breeding regulations. Before we enacted the new regulations, we organized
informational meetings in all of our 13 state groups in order to convince the breeders of
the urgent necessity of our actions. At the same time special attention was given to
elderly dogs at all SSV events and in the media.
I do not wish to hide the fact that there was a lot of resistance which occasionally persists
today from a small percentage of our breeders. Some of these breeders - generally
profit-oriented ones - have left the SSV in the meantime. However the persistent
implementation of the breeding strategies has been accepted by most of the breeders and
is also appreciated by the new puppy owners.
I think we have opened the eyes of many breeders to the problems of the unsatisfactory
life expectancy of our Berners, and specifically to the fact that they have to take more
interest in the age structure of their own dogs, as well as with that of the breeding
partners they choose. Consequently, many of the breeders now accept advice from the
breed wardens of the SSV regarding the breed planning. Unfortunately, I cannot deny the
fact that some of our breeders still select mating combinations with only focusing on the
phenotype conformation , all this in spite of repeated appeals from the SSV to also
strongly consider health and life expectancy in future breeding.
The limited use of stud dogs has now been accepted by most of our stud dog owners. In
fact, this is not a severe restriction, but rather a redistribution. Recently, very few stud
dogs have reached the maximum allowed number of 7 litters a year, or a total of 21.
Studs which have reached the age of 8 years are now being used more often for breeding.
Unfortunately, there are not too many studs of this age which are still capable of siring
litters. It is gratifying to see that the gene pool has already become much wider resulting
from the limited use of individual dogs but using a significantly larger number of
different studs.
The required information about the 10 of 14 ancestors is now available for all dogs
registered or approved for breeding in the SSV. There are many dogs for which the
necessary information is complete for all 14 ancestors and even further back in their
ancestry. The information concerning litter siblings is, in some cases, still incomplete or
not available. Most of the problems we face in data collection are with dogs from other
countries. This is sometimes either very difficult or almost impossible to get. In spite of
this problem, the use of studs from other countries has increased by more than a third. In
the long run, a stronger cooperation between the different clubs and the members of the
International Working Group is the way to move forward. We are so pleased that we have
been able to collaborate and exchange data with several neighbouring clubs and other
befriended clubs. On the positive side, we note that more and more data is being collected
in other countries.
The provisional examination of our data by geneticists has shown that life expectancy is
highly genetically determined. In the near future we hope to be able to define a breeding
coefficient for life expectancy, which needs to be scientifically based. With this we hope
to establish a new tool to reach higher life expectancy of our Berners, a tool to be used by
both, the breeders and stud dog owners.
Because all these rules and measures were introduced only a short time ago, we certainly
hope that they will lead to the success we are driving for in the future.
-------------------------------------------------------------------------------------------------------------------------------------Christel Fechler Curriculum Vitae concerning canine activities
Owner of Bernese Mountain Dogs since 1962, joined the Swiss Mountain Dog Club (SSV) of Germany in the same year.
1974 Breed Warden of the SSV, since 1976 responsible for keeping the Stud Book and in this capacity member of the SSV
committee. 1986 Special Conformation Judge for Swiss Mountain Dogs, 1991 Special Judge for Breeding Evaluation Tests,
since 1999 Head Breed Warden of the SSV Since 2002 Head of the Breeding Commission of the SSV.
In addition, President of the State Club in Nordrhein-Westfalen and Rheinland from 1975-1991,
1993-1998 Puppy and Breeder Referral Officer, since 1976 Breeder of Bernese Mountain Dogs.
=====================================
Working group for analysis of genetic causes on Malignant Histiocytosis (as of 8/07):
In France:
* Benoit Hedan, Laetitia Herbin, Francis Gailbert, Catherine Andre, (CNRS, Rennes
University) Group of 5 to 10 persons on canine genetics.
* Patrick Devauchelle (E.N.V. Alfort): cancer specialist
* Jerome Abadie (E.N.V. Nantes): hsitio-pathologist
4 years: Physiopathological and genetic study
In the USA
* Eduoard Cadieu, Heidi Parker, Elaine Ostrander (NIH Cancer Branch, Bethesda):
canine molecular genetics and cancer.
* Matthew and Tessa Breen (N.C. University, Raleigh): Molecular genetics in canine
cancer: Chromosomes analyses.
* French Club (AFBS) and other European and American Clubs.
10 years of advances on the canine genome: Development of canine Chromosome map
by Guyon et.al., Breen et.al., and Hitte et.al.. Caryotype for Canine familiaris contains
38 pairs of chromosomes plus the X and Y chromosomes.
Canine mapping and sequence in 2005:
1. Map of all chromosomes – 10,000 genes. By collaboration between
Gailbert/Breen/Ostrander (Hitte et.al, 2005 Nature Review Genetics).
2. Sequence of entire canine genome – Lindblad-Toh, Broad Institute, Boston +
Canine genome researchers. (Lindblad-Toh et.al, 2005 Nature).
3. Genomic tools become available for genetic analyses.
Progress flow for Dr Andre’s work:
1. Histiocytic diseases in dogs: What was known?
2. Aim of research: Veterinary Medicine – production of gene tests; Human
Medicine – homologous diseases.
3. Research on Malignant Histiocytosis in the BMD: The work made in Rennes –
physiopathology and epidemology, search of the “genetic basis”, roles of the
Veterinarians, breeders, clubs and researchers. Collaboration with Dr. E
Ostrander, and Dr. M. Breen.
4. Results and future.
P. Moore of UC Davis extensive study of Histocytic diseases in dogs included:
Defined – Histiocytoses: accumulation/proliferation of histiocytes in specific tissues
(tumoral or not).
a. cutaneous histiocytoma
b. reactive histiocytosis (cutaneous and systemic)
* Familial forms in the BMD
* Young adult (4-5 years)
* Cutaneous leasions with extension to lymph nodes, other tissues.
* Non neoplastic lesions: immune system deregulation???
c. Histiocytic sarcoma/malignant histiocytosis (focal or multifocal).
d. Breed specific in BMDs, Rottweillers, Retrievers….Sporadic and very rare in
other breeds.
* In predisposed breeds – Frequent disease, difficult to estimate…approx. 20%
* age of diagnosis – around 6 years
* no treatment
* generally, other cancers in the family (lymphomas, mastocytomas)
* difficult to diagnose (often late), Clinics + Histiopathology
* Physiopathology, epidemiology and genetic causes are still unknown.
e. There is a need for genetic tests to aid in diagnostics and breeder predictions.
2003-2007 Research progress on MH in the BMD at Rennes:
1. In BMDs – incidence >25% and probably under diagnosed.
2. Analysis of a large pedigree – MH is transmitted through generations.
3. From P. Devauchelle – (+/-) 80% Histiocytosis are diagnosed in BMD Rottweiler,
Golden and Flat Coated Retrievers.
4. From French Histology Labs (200 cases) – Age of onset in BMDs, 4-10 years, means
6.5
5. Network (Vet, anapath, breeders, clubs) in France, Europe. Collect blood samples and
data (genealogy, clinics and sibblings).
* 600 blood samples from BMDs (174 HM + 5 HR; 30 unaffected >10 ans
* 50 Tissue Samples from healthy and tumoral tissues to extract RNA.
* Diagnosis – histiopathology and 2nd read (and immunophenotyping), Dr. J. Abadie
(ENVN)
* Questionnaire sent to clinicians of sampled dogs.
* Sample Collection: Belgium – 23, France – 530, Portugal – 23, Italy – 21, Denmark
– 5, Luxembourg – 1, Switzerland – 2.
Based on C. De Britto and J. Abadie publication – Abstract ESVIM Amsterdam, 2006;
Epidemiologic and Pathological characterization of MH, a questionnaire was sent to
each referring veterinarian. It asked for: Signalment of the dog (age, sex, etc.),
Anamnestic data and case history, previous illness or pathologies, clinical presentation
of MH at time of diagnosis, biological evaluations (including hematology, blood
chemistry, etc..), environment, therapeutics and follow up. 60 questionnaires were
analyzed.
1. Epidemoilogy
* High prevalence of MH in the French BMD population.
* Mean age – 6 years (earlier than first report)
* Male/Female ratio - 51%/49%
2. Very homogenous clinical presentation
* Unspecific general signs (anorexia, asthenia, weakness, fever..)
* Presence of internal masse(s): 80% (spleen, lung, liver, lymph nodes)
* Blood analysis: anemia and thrombocytopenia.
3. Etiology?
* No association with other proliferative histiocytic disorders.
* No evidence of association with vaccination, infectious diseases, environmental
factors.
4. Extremely poor prognosis to date.
5. Death on average 41 days after diagnosis even with treatments.
Why are identification of genes in dogs important in the search for genetic causes of
MH?
1. To facilitate the search for the genes responsible for the human form of
Histiocytosis.
2. To better understand the disease and adapt treatments.
3. To develop genetic tests for diagnosis and for assessing predisposition (to help
breeders diminish disease incidence).
Principle and methods behind genetic studies- Transmission Mode in a large pedigree:
Monogenic (1 gene)/Muluitfactorial (several genes and environment), recessive,
dominant, X-Linked. Search a linkage between the disease and markers (analysis of 300
markers distributed on all the chromosomes). Studies:
1. Genetic linkage study in a large family (French), confidential database. DNA are
extracted from blood samples or from paraffin blocs.
* Collection of a family of >500 Bernese Mountain dogs (Vet, anapath, breeders,
AFBS)
* 174 affected dogs (5-10 years) – 82 males and 92 females, histipathological
report assessing MH diagnosis confirmed by a second analysis and
immunohistochemistry.
* 30 unaffected dogs (>10ans)
* Analysis of 300 microstaellites on the 200 DNA samples from the family.
* Comparison of the genome of affected and healthy
* 60,000 PCR reactions – months of work!
* statistical analysis (Linkage and FastLink softwares)
2. Transmission mode – the pedigree is thought to derive from few male ancestors,
diminishes genetic diversity and increases disease incidence , probably polygenic.
3. 3 chromosomes of statistical significance were found.
1. Population study in a population of unrelated healthy and affected dogs
(America).
* The population is composed of more than 350 unrelated dogs
* 55 affected Berners (diagnosed before age 8) – most dogs have a
histopathological diagnosis of MH.
* 125 unaffected dogs (over age 10).
* analysis of 500 microsatellites on DNA from 55 affected and 125 unaffected
dogs
* 100,000 PCR reactions
* Statistical analysis (x2 and Fisher’s extract test)
2. 3 chromosomes with statistical significance were found.
Combination of the French and American studies revealed two chromosomes
identified in common
Where to from this: Fine mapping of the identified regions: more samples, more markers
(130 new samples are being added to the analysis). Search of genes (cancer/immunity):
growth factors, cytokines, and receptors (GM-CSF, G-CSF, M-CSF, MGF/KL, GMCSFR, Fms, Kit..) (Group of Dr. C. London – UC Davis – showed that Kit, FLT3 and
Met receptors were not involved - Zavodovskaya et.al., 2006). Analysis of the 50 tumor
samples – gene expression. Analysis of other chromosomal regions – new technologies
(SNP).
Collection is still ongoing – send samples!
Data will be statistically analyzed with different parameters:
* age (young vs. old diagnosed dogs)
* Malignant vs. Reactive Histiocytosis
* other cancers (all, hematopoietic, only MH, MH+RH…)
* results are shared and compared with M. Breen and E. Ostrander.
* The more samples we have (affected and healthy for sure) better is the location of the
causative genes on the chromosomes.
Protocol for participating in the study:
1. For any BMD >4 years
* Pedigree + blood sample on ETDA tubes – send at room temp.
2. If the dog is affected or supposed to be:
* send histopathological report
* contact us for collecting tumor and healthy tissues (fresh or frozen or formalinfixed or in special RNA solution).
* send data on other members of the family.
3. Contacts in France, Europe:
* Catherine.andre@univ-rennes1.fr
* benoit.hedan@univ-rennes1.fr
* abadie@mail.nih.fr
4. Contacts in USA
* eostrand@mail.nih.gov
* Matthew_Breen@ncsu.edu
============================
Analysis of the genetic causes of Malignant Histiocytosis in Bernese Mountain Dogs
Dr. Catherine Andre
Benoit Hedan(1), Edouard Cadieu(2), Jerome Abadie(3), Patrick Devauchelle(4), Heidi Parker(2), Clothilde de Britto(3),
Elaine Ostrander(2), Francis Galibert(1) and Catherine Andre(1)
1. Laboratoire de Genetique et Developpement, UMR 6061 CNRS, Universite de Rennes1, IFR140, Faculte de Medecine,
35043 Rennes Cedex, France
2. NIH/NHGRI, 50 South Drive, MSC 8000, Building 50, Room 5339, Bethesda, MD 20892 - 8000, USA.
3. Unite d' Anatomie Pathologique, UMR INRA-ENVN 703, Ecole Nationale Veterinaire, BP 40706, 44300 Nantes, France
4. Centre Anticancereux Veterinaire, Ecole Nationale Veterinaire ENVA, 7, Av. General de Gaulle, 94704 Maisons Alfort.
Canine histiocytic proliferative disorders are heterogenous diseases that include reactive
disorders such as cutaneous and systemic histiocytosis, and neoplasia such as cutaneous
histiocytoma and localised and disseminated histiocytic sarcoma (malignant histiocytosis,
MH). Their etiology and pathogenesis are unknown. They share many clinical and
pathological features with histiocytosis in human beings, for which the underlying causes
are still unknown.
Malignant histiocytosis is highly breed specific : its incidence in Bernese Mountain Dogs
(BMD), Rottweillers and Retrievers is high, and MH represents nearly 25 % of the cause
of death in the BMDs, the mean age being 6 years.
We have been working on MH in the BMD for 4 years, to better characterize the clinical
forms, physiopathology, epidemiology by mean of a questionnaire sent to veterinarians
referring MH cases.
Moreover, we undertook the search of the genetic causes of this dramatic disease. We
collected blood samples and clinical data from BMDs in France and recently in other
European countries and constructed a large BMD pedigree of 300 dogs, 100 of which are
affected. All affected have an histopathogical report and are submitted to histological
confirmation and when necessary a characterization through immunohistochemical
analyses. We showed that the transmission mode of the disease is most probably
oligogenic, involving a small number of genes. We also collected tumor and healthy
tissue samples to analyze gene expression at the RNA level. In parallel, a set of 100 cases
and controls from American BMDs have also been collected. Two complementary
genetic approaches have been performed on the 2 sets of dogs (US and European) in
order to localize the genes involved in MH in the BMD.
A total of 191 dogs from the "French pedigree" were analyzed though "genetic linkage
analysis", with 260 microsatellite markers and the very first results, while still under
investigation, point out several regions on 3 chromosomes as containing genes involved
in the disease.
On the other hand, 55 validated MH case and 120 aged control dogs from the US
collection were analyzed through an "association method" with a set of 500 microsatellite
markers, results allowed the identification of several locus.
For both studies, statistical analyses are still running and interpretation of the data are
continuing. Among the several chromosomal regions identified by both groups, at list
four loci are common and under active investigation.
In conclusion, using two complementary genetic methods, and two sets of dogs, US and
European BIVID populations, allowed us to find concordant and very encouraging
results. The identified loci are being examined into details to search for the genes or
genome regions and their mutations involved in the disease. More analyses are needed to
search for other loci. The future aims of this research are to develop genetic tests for
diagnosis and early detection, as well as to transfer knowledge to human medical research
for histiocytic disorders.
The authors warmly thank the numerous breeders and BMD owners and veterinarians for
the collection of samples as well as AFBS (Association Francaise du Bouvier Suisse),
CIAB, SIBB, Belgian Club and other European and American clubs and Margaret
Baertschi and Didier Paineau for generously sharing their knowledge of the breed history.
-----------------------------------------------------------------------------------------------------------------------------------
Dr. Catherine Andre
Laboratoire de Genetique et Developpement
UMR 6061 CNRS
Universite de Rennes1, IFR140
Faculte de Medecine,
35043 Rennes Cedex, France
E-mail : catherine.andre@univ-rennes1.fr
Catherine Andre has graduated as a PhD in Molecular Genetics and Oncology at Paris University in 1992.
She is working since 1995 at CNRS, University of Rennes in France, on canine genomics and genetics. She
manages the "Canine Genetics" group at CNRS which researches the genetic basis of inherited diseases in
canines and humans.
=======================
Dr. Breen was not in attendance and Dr. Andre filled in for him. As of March 31, 2007
the NCSU sample population is as follow:
Total submissions
Confirmed MH/HS
Hemangiosarcoma
Lymphoma
Genuine STS*
Osteosarcoma
Pendeing diagnosis
Unsuitable**
BMD
104
82
6
6
16
2
9
13
Flat Coat Retriever
108 (81)
37
14
5
23
2
7
20
Total
212 (163)
89
20
11
39
4
16
33
* includes fibrosarcoma, hemangiopericytoma
** aeortic tissue, non-tumor tissue, bad packaging.
Confirmed MH is running approx. 63% in the BMD and approx. 46% in FCR. Other STS
is at about 18% in the BMD and 28% in FCR.
Microscopic comparisons of normal chromosome organization to MH chromosomes
shows visible chaotic differences.
Findings since Como, Italy (2006)
1. Cytogenic changes reported in 2006 continue to be evident in subsequent cases.
2. We have identified several areas of the Berner genome that merit more detailed
investigation.
3. These areas will be evaluated using our high resolution cytogenic “toolbox” over the
coming year.
4. In addition to histiocytic malignancies, Dr. Breen is now also investigating lymphoma
and hemangiosarcoma in the Berner.
4. Collaborations with Dr. Ostrander, Andre, Rutteman continue to develop.
Problem: Tissue submissions are not being acknowledged, needs corrected.
=======================
Molecular Cytogenetics of MH in Bernese Mountain Dogs at North Carolina
State University - a brief update
Dr. Matthew Breen
This contribution is presented by Dr. Catherine Andre
At the 2006 meeting in Como, Italy, Dr. Breen described how the main focus of his lab is
to apply sophisticated molecular cytogenetic techniques, developed by his lab over the
past 10 years, to identify regions of the canine genome associated recurrently with a
variety of canine cancers, including histiocytic malignancies in the Berner. The genome
of each cell of a dog is organized in chromosomes, sub-cellular features that Dr Breen
describes as nature's biological filing cabinets When cells become cancerous it is
common for the files (or genes) within these filing cabinets (or chromosome) to become
disorganized. Identifying where these files (genes) move is a key step in learning how
cancer begins and also very important in providing help in understanding how to halt
cancer development
With the availability of a high quality canine genome sequence Dr Breen described how
knowledge of the chromosome changes in cancers now offered a means to pinpoint key
genes involved in the cancers - the first step in the design of improved, targeted
treatments This study uses ownersubmitted tumor biopsy samples recruited from Berners
across the USA and also preserved specimens from tumors from all over the world. Dr.
Breen described how accurate pathology information for each case was critical to making
good progress and emphasized the power and importance of the ongoing
multi-institutional collaboration between Dr. Ostander, Dr Andre and his own lab
Tessa Breen, Laboratory Manager of the NCSU Canine Genomics Laboratory is the
liaison between the owners/vets and the researchers at NCSU. She is also responsible for
receiving ad processing all tumor samples submitted to the lab Tessa described how
Berner samples were recruited and processed to ensure that maximum benefit and
potential information was obtained from each samples
Since last year, Dr. Breen's lab has continued to recruit fresh tumors from Berners and
now has almost 100 samples undergoing analysis This extraordinary level of recruitment
is testimony to the willing participation of the many Berner owners who have had the
courage to submit tumor samples to the study It is also indicative of the astonishing level
of cancer especially those of histiocytic origin that are affecting the Berner breed.
All cases recruited are evaluated by Dr. John Cullen Professor of Pathology at NCSU and
also President of the American College of Veterinary Pathologists Dr Cullen's assessment
is that 69% of cases submitted to Dr. Breen thus far represent cases of malignant
histiocytosis or histiocytic sarcoma, with approx. 10% of cases diagnosed as lymphoma,
10% hemangiosarcoma and the remaining 11% representing mainly a variety of soft
tissue sarcomas.
Initial assessment of the cytogenetic profiles of many of these cases of MH/HS has
revealed several regions in the canine genome that may contain significant genes
involved in malignant histiocytosis in Berners. One of these regions is of particular
importance since it a chromosomal region corresponding to the same region that has been
associated with malignant histiocytosis in Berners by the parallel study of Dr. Ostrander
at NHGRI and Dr. Andre in Rennes Whenever possible, Drs. Breen, Andre and Ostrander
share the samples they recruit so that maximum benefit is obtained from each sample
submitted. Some of the regions identified in Dr. Breen s study are quite large in genomic
terms and so are now being studied in greater detail. This process will refine the data and
so help to generate a shortlist of candidate genes of significance.
With a considerable amount of data generated from fresh case material. Dr Breen is
extending the study to include archival tumor samples - samples that were taken from
Berners several years ago and stored as formalin fixed paraffin blocks - to determine if
the same genetic changes have been present in the breed over a longer time frame.
Thanks to continued support from the Berner community and the AKC Canine Health
Foundation, Dr. Breen's lab will continue to recruit cases for inclusion into this study for
at least a further two years. In addition, with growing sample numbers, attention is also
now being directed toward evaluation of the chromosome changes evident in lymphoma
and hemangiosarcoma samples submitted from Berners.
Matthew Breen, PhD
Associate Professor of Genomics
College of Veterinary Medicine
North Carolina State University
4700 Hillsborough Street
CVM Research Building, Room 348
Raleigh, NC 2706, USA
E-mail: Mafthew.Breen@ncsu.edu
1987
1990
1990-1992
1992-1996
B.Sc. (Hons) Genetics, University of Liverpool, U.K.
PhD Genetics/Cytogenetics, University of Liverpool, U.K.
PostDoc Molecular Cytogenetics, Medical Research Council, U.K.
Senior Research Officer, Head of DNA Group, Australian Equine Blood Typing
Research Laboratory, University of Queensland, Brisbane, Australia
1996 -2000
Cytogeneticist, Animal Health Trust, Newmarket, U.K.
2000- 2002
Head of Molecular Cytogenetics, Animal Health Trust, Newmarket, U.K.
2002 - present Associated Professor of Genomics, Dept of Molecular Biomedical Sciences,
College of Veterinary Medicine, North Carolina State University, Raleigh NC, USA
========================
Dr. G. R. Rutteman
Definitions:
Histiocytes – Cells of the macrophage/monocytes and Langerhans/dendritic cell series.
They function as part of the immune system removing old/abnormal cells and germs and
present molecules to other immune cells.
Histiocytic Proliferative Disorders:
Differentiation:
* Reactive
* neoplastic, benign or malignant.
1. Cell and tissue characteristics lead the pathologist to differentiate histiocytic
disorders.
2. Differentiation from other types of tumor
* Use of markers (enzymes, antibodies, genetic profile)
Expression of Markers:
* All (MHC-II+, CD18+[Cd1a/b/c+, CD11c+, CD45+])
* Histiocytoma/histiocytic sarcoma (CD4-, Thy1- [=CD90])
* Reactive histiocytoses (CD4+, Thy1+)
Reactive diseases:
* Cutaneous histiocytosis
* Systemic histiocytosis
Neoplastic diseases:
* Cutaneous histiocytoma (single/multiple)
* Histiocytic sarcoma (localized/disseminated)
1. Periarticular histiocytic sarcoma
2. Hemophagocytic histiocytic sarcoma < spleen
3. Malignant histiocytosis (disseminated HS from cryptic sites).
Cutaneous histiocytosis:
* young and middle-aged dogs
* single or multiple nodular lesions
* Head, neck, extremities, scrotum (less often trunk/abdomen)
* Progressive disease that clinically waxes and wanes, sometimes spontaneous
regression
Systemic histiocytosis:
* Predominately young male Bernese Mountain Dogs (polygenic mode of inheritance)
* Additional to skin, lesions in other organs (lymph nodes, eyes, nose, lungs, spleen,
liver, and BM).
Histiopathology:
* Identical in CH and SH
* Multinodular infiltrates in deep dermis and panniculus.
* Mainly histiocytes and lymphocytes, some neutrophils around vessels, forming
perivascular cuffs (accumulate around adnexal structures and expand into superficial
dermis).
* In SH more lymphohistiocytic infiltration around vessels and invasion of the vascular
wall.
Reactive histiocytosis:
* CH and SH is reactive histiocytosis (reactive accumulation of dermal interstitial
dendritic APC)
* Could be considered as one entity
* Etiopathogenesis unknown, no proof of infectious agents
* Immunodysregulation?
* Regression with systemic immunosuppressive treatment, including cyclosporine A
Histiocytoma:
* Frequently occurring (3-15% of skin tumors)
* Often young animals (3 months – 2 years)
* Can also occur in old dogs
* Breed predisposition for boxers, tackles, Bobtails, and Great Danes
* Often in head (ears) and legs
* Benign behavior, can regress spontaneously
* Multiple lesions more frequent in Sharpei
Histiocytic Sarcoma Complex:
Histiocytic sarcoma
* histiocytic sarcoma subcutis, periarticular
* hemofagocytic histiocytic sarcoma of spleen
* disseminated histiocytic sarcoma from cryptic primary site (malignant histiocytosis)
Localized Histiocytic Sarcoma:
* locally invasive tumors, often in subcutis
* frequent on extremities (incl. periarticular HS)
* may metastasize to regional lymph node or beyond – Disseminated histiocytic sarcoma
Overlap with Malignant histiocytosis (primary cryptic)
* aggressive multisystem disease
* multiple tumor masses in several organ systems (primary sites lung, spleen and bone
marrow)
Disseminated histiocytic sarcoma/MH:
Breeds:
Bernese Mountain Dog, Flat Coated Retriever, Golden retriever, Rottweiler, Doberman
pinscher and Boxer.
Age:
Rarely <1 year, gradual increase from 3 years, peak at 6-8 years.
Symptoms:
Nonspecific, lethargy, inappetence, weight loss, dyspnea, neural symptoms and anemia
due to erythrophagocytosis.
BMDs presented with suspicion of HS/MH to UUCCA 1996-2006
Clinical/US/RX suspicion of tumor
* Total
249
No histiopathology, wrong tissue
25
Histiopathology, other tumor*
29
Reactive histiocytosis
7**
Inflammation/infection
14
HS/MH
174
No DNA
54
* liver cell carc, mammary carc, lung carc, mult. myeloma, mal. lymphoma,
mastocytoma, melanoma, osteosarcoma
** CH/HS – 2 dogs with hypercalcemia
Conclusion:
* of a total of 249 dogs , verification of HS/MH and availability of DNA: 120 dogs.
* Main obstacle: owner negative about autopsia
* Main bias: BMD with anorexia and a mass – “must be MH” (over estimation).
BMDs that entered the veteran group (>8 years) since 2005
* Total
80
Dead unknown cause
8
Dead, other tumor/imm. dis. 10
(suspicion of MH remains)
Developed HS/MH
12
Investigation of the Genetic Origin of MH/HS
* Open questions:
1. MH/HS common origin?
difference in localization – based upon chance?
2. MH/HS age variation – based upon chance or genetic variation accelerating/
retarding onset of the disease.
3. MH/HS relation with CH/SH?
4. Other tumors – (sometimes) different manifestation of the same cancer syndrome?
Notes on Biases and problems:
1. Post death analysis/ biopsy can now be done via thick needle. Veterinarians are
becoming more experienced at this technique. It leaves little trace of intrusion on
body of deceased dog. Hopefully, this will encourage those owners unwilling to
submit their dogs to be cut up into considering biopsy participation.
2. Vets looking at clinical presentation of BMDs with loss of appetite and anemia as
automatic MH, it’s becoming a problem of assumptions and is problematic for
proper data collection/ utilizations.
======================
Investigation into the genetic background of malignant histiocytic tumors in Bernese
Mountain Dogs
Dr. G. R. Rutteman
Gerard Rutteman(1), Heidi Parker(2), Elaine Ostrander(2), Catherine Andre(3), Matthew Breen(4), Guy Grinwis(5)
1 Utrecht University Clinic of Companion Animals, POX 80. 154, 3508 TD Utrecht, and Veterinary Specialist Centre De Wagenrenk,
6705 BN, Wageningen, The Netherlands
2 NIH/NHGRI, 50 South Drive, MSC 8000, Building 50, Room 5351 Bethesda, MID 20892 - 8000, USA
3 Laboratoire de Genetique et Developpement, UMR 6061 CNIRS Universite de Rennes1, IFR140, Faculte cle Medecine, 35043
Rennes Cedex, France
4 Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, North
Carolina 27606, USA.
5 Department of Pathology, Faculty of Veterinary Medicine, Utrecht University. The Netherlands
In the 1980s it was discovered that Bernese Mountain Dogs were sometimes affected
with a widespread malignant histiocytic cancer, called malignant histiocytosis (MH) and
a familial predisposition was shown. Shortly thereafter, collection of data regarding the
disease began in the Netherlands (NL) and in other countries. Some animals, it was
found, developed a localized form with high metastatic propensity that was often referred
to as histiocytic sarcoma (HS) A few years ago an international consortium was
established to collaborate in the scientific investigation of the genetic background of
MH/HS. Our research involves analysis of the genome of affected animals and healthy
veteran controls, through the use of high density genetic markers. NL is currently
participating in a breed-wide association study, which does not depend upon family
background
Of 250 BMD that were reported to the UUCCA suspected to be affected with MH in the
past 10 years, insufficient data leading to a positive diagnosis or lack of biological
material excluded 100 from entry into the association study. In each of these cases, either
no blood had been collected, or the diagnosis had been based on clinical signs and
radiographic examination without examination of the tumor tissue. Of those dogs where
cytological and/or histological examination was possible. 15 did not have cancer, and 35
dogs with masses in bone or near the joint (HS). or in thorax or abdomen (sometimes
central nervous system) had a variety of other cancers, such as multiple myeloma,
osteosarcoma, bronchial carcinoma, liver or ovarian carcinoma and malignant lymphoma.
not MH Of these tumor types, the latter (malignant lymphoma) is most often
differentiated early on because access is easy and immunohistochemistry can identify the
true histogenetic type. Of the 80 unaffected control dogs that donated blood at > 8 years
of age, subsequent follow-up found that 8 died of unknown causes 10 died of tumor or
immune disease with suspicion of HS/MH, but without verification and 12 developed
either HS/MH (with transport into the MH/HS group) or another malignant tumor that
necessitated exclusion from the control group.
From this experience we found that, for an effective genetic study proper identification of
the tumor type by laboratory analysis, with central revision, and constant follow up
regarding health status is essential
Dr Ostrander's group at the NIH has recently completed a scan using 500 microsatellite
markers spanning the entire canine genome in 350 Bernese mountain dogs both affected
and unaffected, coming from the USA, France, NL and several other European countries
Focusing on a subset of 55 Bernese diagnosed before the age of 8 and 125 unaffected
Bernese over the age of 10, we have identified four regions of the genome that are likely
to contain MH susceptibility genes. The combination of our findings and the results
obtained by Dr. Andre et al at the University of Rennes based on an extended family of
Bernese highlights two highly significant regions that are currently under investigation.
We are working on fine mapping in these regions in order to find the specific genes that
are responsible for the disease while at the same time applying new SNP genotyping
technologies to our population samples in order to verify our findings and identify
additional loci
Furthermore, tumors that are rapidly frozen (or 3 mm particles put in a vials containing a
special solution RNA later) are being examined by Dr. Breen et al at North Carolina State
University using the high-tech cytogenetic technique, comparative genomic hybridization
(CGH) With dozens of tumors thus analyzed, common patterns, such as genomic
amplification or translocation or deletion of specific chromosomal areas, can be
deciphered. Identification of such regions may help both in the localization of important
genes and also in discovering the mechanisms behind cancer development. From NIL a
shipment of about 35 samples will be shipped to NCSU next month for extension of the
CGH analysis.
In addition, combination of data from the above NIL cases with data from archives from
collaborating laboratories from the past 15 years, will be used to assemble a group of >
300 MH/HS cases, to be examined for possible differences of disease manifestation (MH
versus HS) or age of occurrence between families.
In the coming years, the collaborating scientists will call on societies, breeders and
owners to continue to inform other BMD owners to report dogs suspected of developing
malignancies and to provide the study with blood and tissue. Great urgency also exists
with respect to the entry of veteran BMD into the control group. Unaffected dogs can
enter the study as controls by providing data on their health together with a blood sample.
Acknowledgement:
The authors are grateful for the help from owners and breeders of BMD and the national
BMD societies, in the collection of data and material. Also, they wish to thank
veterinarians from many European countries and the USA, who - often without putting in
a charge - enabled collection of blood and tissues.
-------------------------------------------------------------------------------------------------------------
Gerard R. Rutteman, PhD
Utrecht University Clinic of Companion Animals
POX 80.154
3508 TD Utrecht and
Veterinary Specialist Centre De Wagenrenk
6705 BN, Wageningen, The Netherlands
E-mail : gerrjeak@tele2.ni
1978: DVM-degree, University of Utrecht, "cum laude"
From 1980 employed at the Utrecht University Clinic of Companion Animals; first as scientific investigator ("fellow"),
from 1986 till present as assistant Professor. In 1988 PhD degree (thesis: Investigations on the pathogenesis of canine
mammary tumors) at University of Utrecht.
1991: Specialist Internal Medicine of Companion Animals (Royal Dutch Society of Veterinary Medicine).
1997: Diplomate of the European College of Veterinary Internat Medicine (ECVIM-CA)
2005: Specialist Oncology (ECVIM-CA)
From 1996 onward part-time employed at the Veterinary Specialist Center "De Wagenrenk"
==============================
Creation of and presentation of the 2007 Alberto Vittone
Award
Societa Italiana Bovaro del Bernese (SIBB) is creating an annual award in the memory of
Alberto Vittone, recently deceased friend and President of the Society. The purpose of
this award is to financially support studies regarding the most common pathologies found
in the Bernese Mountain Dog. Thus stimulating scientific research in diagnostic,
therapeutic, and preventative activities concerning such pathologies.
For 2007 ten projects were evaluated, 8 from Italy, 1 from France and 1 from Slovenja (+
Neatherlands and UK). Project subjects included 4 genetic, 3 orthopedic, 1 semen
cryopreservation and 1 psychology/ cognitive abilities.
Two awards are made for 2007:
1. Dr. Benoit Hedan (10,000 Euros) – The search of the genetic causes of Malignant
Histiocytosis in the Bernese Mountain Dog.
2. Dr. Johan de Vos, Prof Dr. Janos Butinar, and Dr Malcolm Brearley (5,000 Euros)
– Peri-articular histiocytic sarcoma in Bernese Mountain Dogs: a multi-center
retrospective investigation of the prevalence of this tumor and possible
association with previously diseased joints.
This years Symposium at Burgdorf was funded from the estate of Alberto Vittone.
Considerations: All people that, in the period taken into consideration for awarding the
prize, will start or develop a scientific research project concerning the health of this
breed, are entitled to apply for the award.
Applicants, such as universities, boards, Bernese Mountain dog societies and
clubs, private associations, individuals, should submit their application for
the award providing the following documentation for their research project :
- Curriculum vitae,
- Purpose of the research,
- Scientific program,
- Length of the study and development on the time of the planning work,
- Application form .
The submitted projects will be evaluated by a scientific commission composed of: 3
SIBB board members, the President of the International Working Group; and Mrs Martha
Cehrs , member of the B-IWG and President of KBS , but here involved as private person
and Vittone’s friend.
For further details see:
http://www.berner-iwg.org/docs/av_award.pdf
========================
Progress report on activities of the Bernese International
Working Group
Delivered by Steve Green (BMDCGB), newly elected President IWG.
The Bernese IWG comprises of an informal and flexible group of individuals, some
representing breed clubs and others independent, who have the common desire to
improve the health and longevity of the Bernese Mountain Dog
We have a wish to make the average age at death of the breed at least 10 years, we refer
to this as “Objective 10”.
We aim to reach this objective in many ways but including:




Collecting scientific studies / articles about health and breeding healthy BMDs
Encouraging the sharing of Bernese health information from our different
countries (statistics etc)
Sharing experiences of projects relevant to the Bernese
Helping to establish international co-operation
We are not a club, association or any other formally structured organisation, we do not
have a constitution, officers or committee. We have no bank account or membership fee
and have no financial or other disposable assets. We do not have any interest or ambition
to register puppies, organise shows, appoint or assess judges, grade dogs, authorise
breeding or have influence in any area of dog activity organised by the FCI, national
Kennel Clubs or breed clubs. By keeping this non official structure we hope to reduce the
problems for breed clubs with rules regarding associating with non FCI or other nonaffiliated bodies.
Most of our activity is via the internet and our meetings will be held no more than
annually. These meetings will be held in a spirit of co-operation, education, friendliness
and mutual aid and anyone who shares our “Objective 10” and can offer useful
information to help the Bernese Mountain Dog is welcome.
Update:
The Bernese IWG is composed of representatives from 25 countries and continues to
want to help coordinate health efforts globally to avoid duplicate effort. In 2006 the
Bernese IWG website was established, (see: http://www.berner-iwg.org/about.htm). The
IWG website is meant to be a clearing house for BMD health information. International
data needs are of foremost concern now. IWG supports and emphasizes the need for all
clubs to support health schemes.
Action Item: Steve Green spoke with me following the meeting and asked that the
BMDCA consider appointing a standing member to the Bernese IWG. Steve Green can
be contacted at: waldershelfbernese@doglovers.co.uk
Symposium closing business:
The 2008 Symposium will be held in Denmark, September 2008.
The 2009 Symposium will be held in Italy, April 2009.
Respectfully submitted
Steve Dudley
September 11, 2007.