Genetic analysis of anal atresia in pigs: evidence for segregation at two main loci

Abstract

Anal atresia is a relatively common congenital malformation that occurs in about 1 out of 5000 infants, caused by abnormal hindgut development of the embryo, often associated with other developmental anomalies (e.g., Currarino, Townes-Brock, Pallister-Hall syndromes, and VATER association). Genetic analysis in human families is exceedingly difficult due to the multifactorial nature of the trait. In pigs, anal atresia occurs at a higher incidence (0.18%) than in humans. A complete genome scan (165 microsatellite markers) was performed using a backcross pedigree previously obtained by crossing affected animals from a partially inbred line, selected for a high incidence of anal atresia, with an unaffected male of a different breed (Meishan). The data set was analyzed with classical linkage (TWOPOINT) and nonparametric genetic methods (NPL, Non-Parametric Linkage, and TDT, Transmission Disequilibrium Test). Both methods support association of the trait with two loci on Chromosomes 9 and 15. GLI2 (GLI-Kruppel family member GLI2) was identified as a positional candidate gene based on comparative mapping; radiation hybrid mapping confirmed that this locus is located within the QTL region.

Increased heritability of certain types of anorectal malformations

“…For example, lines of mice [13,14] and pigs [15] with inherited ARMs have been described, and there is recent evidence of increased incidence of ARMs in certain breeds of dogs [16]. Although, to date, the specific mutations have not been studied in the mouse lines, a recent report has identified several regions of the pig genome that are linked to the ARM phenotype [17]. Furthermore, gene targeting in mice has demonstrated the importance of a number of genes, singly or in combination, for normal hindgut development.…”

Multiphasic and tissue-specific roles of sonic hedgehog in cloacal septation and external genitalia development

“…Interestingly, many of the animal models of ARM have been linked to the Shh pathway. The anal atresia in pigs documented by Van der Putte and Neeteson (Van der Putte and Neeteson, 1984) has been traced to a heritable mutation on chromosome 15 that maps near the location of Gli2 (Cassini et al, 2005). Both the Shh and Gli2/3 mouse mutants have been suggested as models of the VACTERL complex (Arsic et al, 2002;Kim et al, 2001;Mo et al, 2001), and ARMs caused by treatment with either retinoic acid or etretinate (a vitamin A derivative) produce ARM that resemble the phenotypes presented here (Dawrant et al, 2008;Ioannides et al, 2003;Kubota et al, 2000;Kubota et al, 1998;.…”

Complete Diphallia, Imperforate Ani (Type 2 Atresia Ani), and an Accessory Scrotum in a 5-Day-Old Calf

“…8 Atresia ani occurs in all species and is commonly reported in ruminants 13 and pigs. 4 This manuscript describes the gross pathologic appearance of a rare case of complete diphallia, imperforate ani (type 2 atresia ani), and an accessory scrotum in a 5-day-old Angus calf.…”