Bilaterally asymmetric effects of quantitative trait loci (QTLs): QTLs that affect laxity in the right versus left coxofemoral (hip) joints of the dog (Canis familiaris)

Abstract

In dogs hip joint laxity that can lead to degenerative joint disease (DJD) is frequent and heritable, providing a genetic model for some aspects of the human disease. We have used Portuguese water dogs (PWDs) to identify Quantitative trait loci (QTLs) that regulate laxity in the hip joint. A population of 286 PWDs, each characterized by ca. 500 molecular genetic markers, was analyzed for subluxation of the hip joint as measured by the Norberg angle, a quantitative radiographic measure of laxity. A significant directed asymmetry was observed, such that greater laxity was observed in the left than the right hip. This asymmetry was not heritable. However, the average Norberg angle was highly heritable as were the Norberg angles of either the right or left hips. After correction for pedigree effects, two QTLs were identified using the metrics of the left and right hips as separate data sets. Both are on canine chromosome 1 (CFA1), separated by about 95 Mb. One QTL, associated with the SSR marker FH2524 was significant for the left, but not the right hip. The other, associated with FH2598, was significant for the right but not the left hip. For both QTLs, some extreme phenotypes were best explained by specific interactions between haplotypes.

Fig. 1

Radiographs (ventrodorsal) illustrating Norberg angles for: (a) a dog with almost no subluxation in the coxofemoral joint, and (b) a dog with very much subluxation in the coxofemoral joint. Because of the ventrodorsal position of the animals, the left hip is on the right side of the radiographs.

Fig. 2

Values of the Norberg angles of the 286 dogs in the Portuguese water dog (PWD) population. The cumulative distributions of values (X-axis) for the right (o) and left hips (◆) are shown.

Fig. 3

An ideogram of canine chromosome 1 (CFA01) highlighting locations of FH2524 and FH2598. Mapping data is based on a radiation hybrid map of CFA01 (Guyon et al., 2003, submitted) using the Multimap [Matise et al., 1994] and TSP Concorde Software programs [Agarwala et al., 2000]. Excerpts of markers neighboring FH2524 and FH2598 (underlined) are shown with inter-marker distances in TSP units between the markers. For CFA01, one unit corresponds to approximately 11 kb. The total length of CFA01 is 12,353 U or 137 Mb. Markers (AHTK338 and AHTH304) assigned to chromosomes by previous FISH mapping studies link the DAPI-banded ideogram to the RH map and are shown within a box [Breen et al., 2001]. FH2524 was mapped subsequent to other markers and is located between REN136G19 and FH3413 (as indicated).

Fig. 4

Distributions of Norberg angle metrics associated with particular genotypes of the markers FH2524 (a and b) and FH2598 (c and d). The left (top) and right (bottom) hip joints are shown. See Table II for additional information as well as additional genotypes. The collection of infrequent genotypes containing the FH2598 “G” allele (see text) has been denoted as NG. Genotypes are listed in descending order corresponding to the order from left to right in which their distributions occur.

Fig. 5

Scatter graph of the pedigree corrected estimates of genotypic means (X-axis) graphed against the best fit to an additive model (a and b) for FH2598 and FH2524 (see “Materials and Methods”); or (c) graphed against an additive model with simple dominance for FH2524. Error bars for the standard deviation were estimated using the jackknife procedure (; see “Materials and Methods”).