Transcript Keeshond Club Genetic Counselling Scheme

Keeshond Club
Genetic Counselling
Scheme
December 4, 2009
Stephen J.G. Hall
University of Lincoln
Background
• The idea of a genetic tendency to epilepsy was first
published in 1964. EEG investigations (1970s) proved
fruitless.
• In late 1980s the late Dr. Margaret Wallace carried out
pedigree analysis of 15 animals diagnosed by vets as
epileptic and of 34 litters that didn’t show the condition.
• The simplest hypothesis – a single non-sex-linked
recessive gene – was tested by assuming both parents
of an affected pup were carriers.
• For 26 litters of which both parents were thought to be
carriers, numbers of normal and affected progeny were
known (91 and 29 respectively). This is the same,
statistically, as a 3:1 ratio which is what would be
expected from the hypothesis proposed. All the fitters
were found to be inbred to either a dog born in 1971, or
to his great grandsire.
Operation of the scheme
• In 1989 following a lecture by Dr. Wallace the
Keeshond Club decided to start a genetic
counselling scheme and when Dr. Wallace
retired, I continued with it.
• Veterinary practice and genetic counselling have
been completely separate; I play no part in
diagnosis and will only enter an animal on the
list of carriers if it is a parent of an epileptic and
if this is communicated to me by the Club’s
scheme co-ordinator.
Uptake of the scheme
• Breeders who anticipate using specific
animals for breeding, provide pedigree
details to the co-ordinator who forwards
them to SJGH.
• Numbers of these notifications, and of
requests for advice, fluctuate from year to
year (next slide, where trend lines are also
given).
Numbers of advices requested
and of animals notified to the
scheme
40
35
Advices requested
30
25
Animals notified
20
Linear (Advices
requested)
Linear (Animals
notified)
15
10
5
20
09
20
07
20
05
20
03
20
01
19
99
19
97
19
95
19
93
19
91
0
Criteria for approval of matings
• Advice on matings is based purely on a calculation of
the probability that a resulting pup will be a carrier.
Other factors, such as inbreeding, are not taken into
account.
• A threshold was set at the start of the scheme; a
calculated probability of greater than 0.26 (26%) would
disqualify the mating.
• The rationale behind this threshold was explained in a
scientific publication (Hall & Wallace, 1996*).
• Generally, a high proportion of matings are approved
(next slide, with trend line).
*Vet. Rec. (1996) 138, 358
Percentages of proposed
matings that were approved
100
90
80
70
60
50
40
30
20
10
0
1989
1994
1999
2004
2009
Trends in calculated carrier
probabilities
• The next slide shows a possible downward trend
in the carrier probabilities of proposed matings.
• However, this is not strong evidence of a
reduction in the frequency of the recessive gene.
• Perhaps breeders are making their own
calculations or estimates and are no longer
submitting matings for advice that are likely to
be very near the threshold.
Average carrier probabilities of
proposed matings
0.3
0.25
0.2
0.15
0.1
0.05
20
09
20
07
20
05
20
03
20
01
19
99
19
97
19
95
19
93
19
91
0
Is the scheme working (1)?
• In addition to the trend implied in the
previous slide, there is a downward
tendency in the carrier probabilities of
animals being notified to the scheme
• This would suggest the frequency of the
recessive gene is declining, at least in the
segment of the breed that uses the
scheme
Average carrier probabilities of
all animals notified to scheme
0.6
0.5
0.4
0.3
0.2
0.1
19
80
19
82
19
84
19
86
19
88
19
90
19
92
19
94
19
96
19
98
20
00
20
02
20
04
0
Year of birth of dog
Is the scheme working (2)?
• There is more powerful evidence for a beneficial
effect. This was found in a project funded by the
Canine Supporters’ Charity.
• KC records were examined in 2004. It was found
that many of the matings had not been referred
to the scheme.
• Carrier probabilities were calculated for all
registered litters.
• Evidently (next slide), over the breed as a whole
carrier probability is declining, i.e. the frequency
of the recessive gene is declining.
Average carrier probabilities of
all KC registered Keeshond
litters
19
89
19
90
19
91
19
92
19
93
19
94
19
95
19
96
19
97
19
98
19
99
20
00
20
01
20
02
20
03
0.5
0.45
0.4
0.35
0.3
0.25
0.2
0.15
0.1
0.05
0
Next steps
• Ideally, there would be a direct DNA test by which carrier animals
would be identified.
• However, this would require a sample of at least 12 epileptic animals
and also of non-epileptics.
• Repeated efforts have been made to contact the worker at
Cambridge University reported to be particularly interested in a
direct DNA test, with a view to coordinating the scheme with
proposed research work, but these attempts have been rebuffed.
• However, if a DNA test does appear, it will be much easier to put it
into effect if the frequency of the recessive gene has already been
reduced. Accordingly, it is suggested that the current scheme
continues to offer real benefits to the breed and should continue to
be supported.
SJGH 4 December 2009