Founder analysis of Cardiomyopathy

 Founder analysis is an attempt to identify the founder responsible for an autosomal recessive disease.  We start by making the assumption that the defective gene (allele) was introduced by one and only one founder.

Figure 1 gives an overview of the cardiomyopathy population and it's ancestors.  Each square represents a dog.  The display is arranged vertically by generation with the founders at the top and the most recent dogs at the bottom.  The red squares represent known affecteds.  Under the assumption that the disease is an autosomal recessive, the blue squares (parents of affecteds) are known carriers.  All of the remaining black squares are involved in at least one of the pedigrees of the affected dogs.
 

Figure 1
Cardiomyopathy
The Cardiomyopathy affected population and all known ancestors, as displayed by the "Georgie" program.  The affected dogs are indicated by red squares.  The implicated carriers are indicated by light blue squares.  The blue lines show two potential paths of the recessive gene; from the implicated founder, Taro, to an affected PWD. 
 
Figure 1 shows that 18 different founders are in the pedigrees of the cardiomyopathy affecteds.  In order to discriminate between the 18 founders we can ask: We will answer these questions in terms of consanguinity.  The consanguinity between any two dogs is the probability that those two dogs will share an allele that is identical by descent.  Two dogs that are completely unrelated will have a consanguinity of 0.  The consanguinity between any two founders is assumed to be 0.  The consanguinity between a founder and its child is 0.25
 
Table 1 
Cardiomyopathy 
Founder Average consanguinity to entire population Average consanguinity to the group of carriers Minimum consanguinity to the group of carriers
TARO 0.0863 0.097 0.039
TABU 0.0844 0.086 0
RIA(AD) 0.0758 0.063 0.034
LONTRA 0.0546 0.054 0.006
CIGANA 0.0546 0.054 0.006
SILVES 0.0513 0.043 0.023
DINA 0.0348 0.035 0.004
ESPERDICIO 0.0115 0.01 0.005
ALGARVIA 0.0115 0.01 0.005
LANDRIM 0.0075 0.007 0.001
TROIA 0.0075 0.007 0.001
TAMAR 0.0064 0.018 0
AGAPANTHA 0.0033 0.005 0
RUBY 0.0025 0.006 0
TUCHO 0.0017 0 0
JUCA 0.0013 0 0
FOFO 0.0009 0.001 0
SANDY 0.0005 0.002 0
DICK 0.0005 0.001 0
LINDA 0.0005 0.001 0
PIPA 0.0005 0 0
POPA 0.0001 0 0
Table 1 gives an overview of the founders, their relationship to the entire population and their relationship to the population of Cardiomyopathy carriers.  The founders are ordered according to their average consanguinity with the entire population (second column).  The third column shows the average consanguinity between the founders and the 34 dogs identified as Cardiomyopathy carriers.  The last column shows the minimum consangunity between each founder and the carrier group.

The second column is a measure of how widespread the genes of each founder are in the known population.  This is an important measure since the genes of "popular" founders will be expressed in more combinations.  Taro and Tabu are represented in almost all of the pedigrees in the population and thus have a high average consangunity to the entire population.  Note that Taro's average consangunity to the carrier group is higher that his consangunity with the entire population, this is evidence that Taro has introduced a gene responsible for the disease.

The asumption that the defective allele was introduced from one founder requires a path from the suspected founder to all of the known carriers.  Founders with a zero in the last column of table 1 could not have been solely responsible for the defective allele.  While Tabu is well represented in the carrier population, he could not have been the sole provider of the defective allele since at least one carrier exists which did not descended from him.
 
 

Table 2 
Cardiomyopathy 
Founder Average consanguinity to the group of carriers p-value of average consanguinity
TARO 0.097 <.001
TAMAR 0.018 0.08
RUBY 0.006 0.14
TABU 0.086 0.25
FOFO 0.001 0.27
AGAPANTHA 0.005 0.29
LINDA 0.001 0.44
DICK 0.001 0.47
SANDY 0.002 0.49
CIGANA 0.054 0.52
LONTRA 0.054 0.53
DINA 0.035 0.53
TROIA 0.007 0.54
LANDRIM 0.007 0.67
SILVES 0.043 0.76
ESPERDICIO 0.01 0.81
ALGARVIA 0.01 0.81
RIA(AD) 0.063 0.85

Table 2 shows the significance of the relationship between the founders and the carrier group.  The founders from table 1 that were not related to the carrier group were excluded from this analysis.  In this analysis a random group of 34 dogs was selected from the living population of breeding dogs.  The average consanguinity between the random group and each founder was recorded.  This process was repeated 1000 times.  The fraction of times the average consanguinity to the random group exceeded the average consanguinity to the carrier group is a measure of significance for the relationship between the founder and the carrier group.

According to this analysis Taro was a carrier of the gene which causes cardiomyopathy.