Haplotype variability in the bovine MITF gene and association with piebaldism in Holstein and Simmental cattle breeds.
ABSTRACT Candidate gene analysis, quantitative trait locus mapping in outbreed and experimental cross-populations and a genomewide association study in Holstein have reported that a few chromosome regions contribute to great variability in the degree of white/black spotting in cattle. In particular, an important region affecting this trait was localized on bovine chromosome 22 in the region containing the microphthalmia-associated transcription factor (MITF) gene. We sequenced a total of 7258 bp of the MITF gene in 40 cattle of different breeds, including 20 animals from spotted breeds (10 Italian Holstein and 10 Italian Simmental) and 20 animals from solid coloured breeds (10 Italian Brown and 10 Reggiana), and identified 17 single nucleotide polymorphisms (SNPs). The allele frequencies of one polymorphism (g.32386957A>T) were clearly different between spotted (A = 0.875; T = 0.125) and non-spotted breeds (A = 0.125; T = 0.875) (P = 8.2E-12). This result was confirmed by genotyping additional animals of these four breeds (P < 1.0E-20). A total of 21 different haplotypes were inferred from the sequenced animals. Considering similarities among haplotypes, spotted and non-spotted groups of cattle showed significant differences in their haplotype distribution (P = 0.001), which was further supported by the analysis of molecular variance (amova) of two genotyped SNPs in an enlarged sample of cattle. Variability in the MITF gene clearly explained the differences between spotted and non-spotted phenotypes but, at the same time, it is evident that this gene is not the only genetic factor determining piebaldism in Italian Holstein and Italian Simmental cattle breeds.
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ABSTRACT: Waardenburg syndrome type 2 (WS2) is a dominantly inherited disorder characterized by a pigmentation anomaly and hearing impairment due to lack of melanocyte. Previous work has linked a subset of families with WS2 (WS2A) to the MITF gene that encodes a transcription factor with a basic-helix-loop-helix-leucine zipper (bHLH-Zip) motif and that is involved in melanocyte differentiation. Several splice-site and missense mutations have been reported in individuals affected with WS2A. In this report, we have identified two novel point mutations in the MITF gene in affected individuals from two different families with WS2A. The two mutations (C760--> T and C895--> T) create stop codons in exons 7 and 8, respectively. Corresponding mutant alleles predict the truncated proteins lacking HLH-Zip or Zip structure. To understand how these mutations cause WS2 in heterozygotes, we generated mutant MITF cDNAs and used them for DNA-binding and luciferase reporter assays. The mutated MITF proteins lose the DNA-binding activity and fail to transactivate the promoter of tyrosinase, a melanocyte-specific enzyme. However, these mutated proteins do not appear to interfere with the activity of wild-type MITF protein in these assays, indicating that they do not show a dominant-negative effect. These findings suggest that the phenotypes of the two families with WS2A in the present study are caused by loss-of-function mutations in one of the two alleles of the MITF gene, resulting in haploinsufficiency of the MITF protein, the protein necessary for normal development of melanocytes.The American Journal of Human Genetics 07/1996; 59(1):76-83. · 11.20 Impact Factor
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ABSTRACT: The proportion of unpigmented coat on the trunk was determined from photographs of 38 German Simmental and 627 German Holstein bulls distributed over three generations. All 665 animals were members of 18 Holstein and 3 Simmental half-sib families. A Bayesian estimation of heritability yielded a posterior mean of 0.88 and a standard error of 0.08. A quantitative trait loci (QTL) scan over all chromosomes covered by 229 microsatellite marker loci (2926 cM) was performed by fitting a multiple marker regression model to 625 observations from the youngest generation in 18 families. On chromosome 6 a QTL for the proportion of white coat with large effects (experiment-wise error probability < .0001) was found and a less important one on chromosome 3 (chromosome-wise error probability < .009). Chromosome 6 is known to harbor the KIT locus (receptor tyrosinase kinase), which is associated with various depigmentation phenotypes in mice, humans, and pigs. Similarity of phenotypic KIT effects in other species and synteny with the reported QTL suggest that KIT is a serious candidate gene for the degree of spotting in cattle. The results are also discussed with respect to resistance to solar radiation, heat stress, and photosensitization.Journal of Heredity 01/1999; 90(6):629-34. · 2.00 Impact Factor
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ABSTRACT: In this report, we compare and contrast three previously published Bayesian methods for inferring haplotypes from genotype data in a population sample. We review the methods, emphasizing the differences between them in terms of both the models ("priors") they use and the computational strategies they employ. We introduce a new algorithm that combines the modeling strategy of one method with the computational strategies of another. In comparisons using real and simulated data, this new algorithm outperforms all three existing methods. The new algorithm is included in the software package PHASE, version 2.0, available online (http://www.stat.washington.edu/stephens/software.html).The American Journal of Human Genetics 12/2003; 73(5):1162-9. · 11.20 Impact Factor