Genome-wide linkage analysis of inherited hydrocephalus in the H-Tx rat

Abstract

Inherited hydrocephalus in humans has received very little attention, most probably because known occurrences are sporadic and systematic investigation is difficult. The H-Tx rat, one of a number of rodent strains with inherited hydrocephalus, has a complex inheritance with more than one postulated susceptibility gene and 40% penetrance. The aim of this study was to perform a genome-wide scan on backcross progeny derived from H-Tx and Fisher F344 rats, to identify genomic regions associated with hydrocephalus. Penetrance of hydrocephalus in (H-Tx x F344) F1 x H-Tx was 12.3%. All severely hydrocephalic progeny (n = 185) and a subset of normal progeny (n = 128) were screened with 110 simple sequence length polymorphisms (SSLPs) with 83% coverage of the genome. A significant susceptibility locus was found on chromosome (Chr) 11 (LOD = 3.1). Three loci with suggestive linkage were found on Chr 17 (LOD = 2.4), on Chr 9 (LOD = 1.94), and on Chr 19 (LOD = 1.91). For the loci on Chr 11 and 19, hydrocephalus was associated with the heterozygous genotype, while the other two were recessive. Although none of the four loci was essential for the hydrocephalic phenotype, the additive effects of two, three, or four loci increased the penetrance in a linear fashion. Altogether these four loci accounted for 13.5% of the total variance. It is concluded that hydrocephalus in the H-Tx rat is associated with two, possibly four genetic loci, but that there may be additional undefined genetic and environmental influences.

Hereditary hydrocephalus internus in a laboratory strain of golden hamsters (Mesocricetus auratus)

“…There are two known mutations in rats: one line (H-Tx) with a high rate of inherited hydrocephalus was derived from one mating (Cai et al, 2000;Jones et al, 2000Jones et al, , 2001Jones et al, and 2002 and the other strain (LEW/Jms) was derived from an inbred strain of Wistar-Lewis rats (Jones et al, 2003). Both mutations seem to have a complex mode of inheritance probably involving more than one gene (Jones et al, 2003).…”

Single and multiple congenic strains for hydrocephalus in the H-Tx rat

“…In addition, more polymorphic markers were identified for Chr10, 11, and 17 to obtain a denser coverage for these chromosomes containing the hydrocephalus loci. Markers for these chromosomes were mapped in the backcross experiment used for linkage analysis (Jones et al 2001a(Jones et al , 2001b. Amplification of the DNA repeats by PCR and electrophoretic separation on 5% agarose gels were performed according to the methods published previously (Jones et al 2000b).…”

“…The two marker sets together gave a genome coverage of 90%. Additionally, the number of markers on the chromosomes containing the loci was increased to refine the interval and ensure it was as large as, or larger than, the LOD ± confidence interval as shown by MAPMAKER (Jones et al 2001b. After four backcrosses, the heterozygous N 5 rats were intercrossed, the progeny genotyped, and the best rats selected to make the first-generation homozygous congenic lines.…”

“…Quantitative trait locus (QTL) mapping was performed with a backcross experiment in which H-Tx rats were bred with Fischer F344 rats, a nonhydrocephalic strain, and the N 1 offspring backcrossed to the H-Tx hydrocephalic strain. The backcross generated 1500 N 2 offspring of which 12.3% had severe hydrocephalus and a further 5% had a mild form that was detected after examination of the fixed brains (Jones et al 2000b(Jones et al , 2001b. A genomewide scan was performed on all the hydrocephalic pups and on a subset of the non/ hydrocephalic pups using 110 DNA markers (SSLPs).…”

“…A genomewide scan was performed on all the hydrocephalic pups and on a subset of the non/ hydrocephalic pups using 110 DNA markers (SSLPs). Linkage analysis demonstrated three loci with significant linkage on Chromosomes 10,11, and 17 and three more loci with suggestive linkage on Chromosomes 4, 9, and 19 (Jones et al 2001a(Jones et al , 2001b. Hydrocephalus loci on Chromosomes 10 and 11 were most frequently associated with the heterozygous genotype (one allele from each strain), whereas the hydrocephalus locus on Chromosome 17 was predominantly associated with the H-Tx homozygous genotype.…”