Comparison of DNA variants in the PRNP and NF1 regions between bovine spongiform encephalopathy and control cattle

Abstract

DNA from 252 bovine spongiform encephalopathy (BSE) cattle and 376 non-diseased control cattle were genotyped for nine loci in the prion protein (PRNP) gene region, three loci in the neurofibromin 1 (NF1) region and four control loci on different chromosomes. The allele and genotype frequencies of the control loci were similar in BSE and control cattle. In the analysed 7.4 Mb PRNP region, the largest differences between BSE and control cattle were found for the loci REG2, R16 and R18, which are located between +300 and +5600 bp, spanning PRNP introns 1 to 2. Carriers of the REG2 genotype 128/128 were younger at BSE diagnosis than those with the other genotypes (128/140 or 140/140). The predominant haplotype REG2 128 bp-R18 173 bp occurred more frequently (P < 0.001), and the second-most frequent haplotype (REG2 140 bp-R18 175 bp) occurred less frequently (P < 0.05) in BSE than in control cattle. The largest frequency differences between BSE and control groups were observed in the Brown Swiss breed. Across all breeds, most of the same alleles and haplotypes of the PRNP region were associated with BSE. In the 23-cM NF1 region, associations with BSE incidence were found for the RM222 allele and for the DIK4009 genotype frequencies. Cattle carrying RM222 genotypes with the 127- or 129-bp alleles were about half a year older at BSE incidence than those with other genotypes. Across the breeds, different alleles and genotypes of the NF1 region were associated with BSE. The informative DNA markers were used to localize the genetic disposition to BSE and may be useful for the identification of the causative DNA variants.

PRNP promoter polymorphisms are associated with BSE susceptibility in Swiss and German cattle

“…An association of BSE susceptibility with respect to PRNP genotypes at the 23 bp indel polymorphism in the 5'flanking region and the 12 bp indel polymorphism within intron 1 of the PRNP gene was demonstrated in a small sample of animals. Recently, similar associations were confirmed in larger replicating association studies using German and British cattle [21-23]. It has to be mentioned that the design of the previous and the present association studies does not allow to determine whether a difference between the genotype frequencies of BSE-affected animals and controls is due to a genetic effect on susceptibility to BSE or to differences in the BSE incubation time.…”

“…In the D-D haplotype this repression cannot take place and the resulting PRNP expression is higher than in the I-I haplotype [20]. The effect of the 12 bp indel polymorphism was recently confirmed in independent studies using German and English cattle [21-23]. …”

Populationwide Investigation of Two Indel Polymorphisms at the Prion Protein Gene in Polish Holstein–Friesian Cattle

“…In recent years, scientific centers in many countries have been involved in research on the genetic structure and indel polymorphism of healthy and also, if possible, affected cattle, including breeds in Germany (Sander et al 2004;Geldermann et al 2006;Haase et al 2007), Great Britain (Juling et al 2006), Switzerland (Haase et al 2007), the United States (Seabury et al 2004;Clawson et al 2006;Brunelle et al 2008b), Japan (Nakamitsu et al 2006), South Korea (Jeong et al 2006), and Poland (Czarnik et al 2007). The reported results indicate that Holstein-Friesian cattle bred in the United States (Brunelle et al 2008b) are characterized by the lowest frequencies of the 23del/del genotype (0.31) and the deletion allele (0.57) at the polymorphic locus of the promoter (23 bp).…”

“…Research results published by Sander et al (2004) came as a major breakthrough in the search for a causative mutation responsible for cattle susceptibility or resistance to the disease; the authors pointed to a correlation between indel polymorphism in the promoter (23indel) and intron 1 (12indel) sequences, and also displaying the features of the PRNP gene promoter, and susceptibility to BSE. The effect of this indel polymorphism on the frequency of BSE occurrence was validated by successive independent studies (Geldermann et al 2006;Juling et al 2006;Haase et al 2007). …”

Polymorphisms of Two Indels at the PRNP Gene in Three Beef Cattle Herds

“…In a study that analyzed 388 PRNP polymorphisms, Clawson et al (2006) verified that this gene could be classified into two distinct regions defined by high and low frequencies of linkage disequilibrium (LD) and observed that both 12 and 23 bp indels lie on the region of high LD. Geldermann et al (2006) analyzed a total of 252 BSE animals and 376 controls and did not find an effect of the 12 bp indel on BSE susceptibility. Nakamitsu et al (2006) did not find differences in allele frequencies in both indels between healthy and affected animals, but this last study analyzed a small number of BSE-affected Holstein cattle (six animals).…”