A cis-acting regulatory mutation causes premature hair graying and susceptibility to melanoma in the horse

Pielberg, Gerli; Golovko, Anna; Sundström, Elisabeth; Čurik, Ino; Lennartsson, Johan; Seltenhammer, Monika; Druml, Thomas; Binns, M. M.; Fitzsimmons, Carolyn; Lindgren, Gabriella; Sandberg, K.; Baumung, Roswitha; Vetterlein, M.; Strömberg, Sara; Grabherr, Manfred; Wade, Claire M.; Lindblad‐Toh, Kerstin; Pontén, Fredrik; Heldin, Carl‐Henrik; Sölkner, Johann; Andersson, Leif

doi:10.1038/ng.185

Cited by 257 publications

(189 citation statements)

References 25 publications

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“…Another famous example is white horses caused by the Greying‐with‐age in Syntaxin 17 , which have had a huge impact on human culture worldwide (Rosengren Pielberg et al . 2008). …”

Section: Discussionmentioning

confidence: 99%

Microphthalmia‐associated transcription factor mutations are associated with white‐spotted coat color in swamp buffalo

et al. 2015

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SummaryA candidate gene analysis of the microphthalmia‐associated transcription factor (MITF) gene was used in an attempt to identify the genetic basis for a white‐spotted coat color phenotype in the Asian swamp buffalo (Bubalus bubalis carabanensis). Ninety‐three buffaloes—32 solid, 38 spotted and 23 white individuals—were Sanger‐sequenced for all MITF exons as well as highly conserved intronic and flanking regions. MITF cDNA representing skin and iris tissue from six spotted, nine solid and one white buffaloes was also Sanger‐sequenced to confirm detected mutations. Two independent loss‐of‐function mutations, a premature stop codon (c.328C>T, p.Arg110*) and a donor splice‐site mutation (c.840+2T>A, p.Glu281_Leu282Ins8), both of which cause white‐spotted coat color in swamp buffaloes, were identified. The nonsense mutation leads to a premature stop codon in exon 3, and likely removal of the resulting mRNA via nonsense‐mediated decay pathway, whereas the donor splice‐site mutation leads to aberrant splicing of exon 8 that encodes part of a highly conserved region of MITF. The resulting insertion of eight amino acid residues is expected to perturb the leucine zipper part in the basic helix‐loop‐helix leucine zipper (bHLH‐Zip) domain and will most likely influence dimerization and DNA binding capacity. Electrophoretic mobility shift assay was performed using mutant and wild‐type MITF proteins and showed that the mutant MITF protein resulting from the splice‐site mutation decreased in vitro DNA binding capacity compared to wild‐type MITF. White‐spotted buffalo bulls are sacrificed in funeral ceremonies in Tana Toraja, Indonesia, because they are considered holy, and our results show that genetic variation causes a tie to the cultural use of these buffaloes.

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“…Another famous example is white horses caused by the Greying‐with‐age in Syntaxin 17 , which have had a huge impact on human culture worldwide (Rosengren Pielberg et al . 2008). …”

Section: Discussionmentioning

confidence: 99%

Microphthalmia‐associated transcription factor mutations are associated with white‐spotted coat color in swamp buffalo

et al. 2015

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“…Structural changes may underlie phenotypic variation, as extensively documented in domestic animals. For instance, dominant white colour in pigs (Moller et al, 1996), the hair ridge in Rhodesian Ridgeback dogs , greying with age in horses (Rosengren Pielberg et al, 2008) and familial Shar-Pei fever (Olsson et al, 2011) are all caused by duplications.…”

Section: Copy Number Variation (Cnv) In Dogsmentioning

confidence: 99%

LUPA: A European initiative taking advantage of the canine genome architecture for unravelling complex disorders in both human and dogs

Lequarré

Andersson

André

et al. 2011

The Veterinary Journal

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a b s t r a c tThe domestic dog offers a unique opportunity to explore the genetic basis of disease, morphology and behaviour. Humans share many diseases with our canine companions, making dogs an ideal model organism for comparative disease genetics. Using newly developed resources, genome-wide association studies in dog breeds are proving to be exceptionally powerful. Towards this aim, veterinarians and geneticists from 12 European countries are collaborating to collect and analyse the DNA from large cohorts of dogs suffering from a range of carefully defined diseases of relevance to human health. This project, named LUPA, has already delivered considerable results. The consortium has collaborated to develop a new high density single nucleotide polymorphism (SNP) array. Mutations for four monogenic diseases have been identified and the information has been utilised to find mutations in human patients. Several complex diseases have been mapped and fine mapping is underway. These findings should ultimately lead to a better understanding of the molecular mechanisms underlying complex diseases in both humans and their best friend.

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“…Because CNVs represent a change in genetic content (ie, deletions and duplications), they may have the potential to greatly impact many phenotypes. A 4.6‐kb duplication in an intron has been associated with graying and melanomas in horses 75. A 16.1‐kb duplication has been shown to cause wrinkling of the skin in Shar‐Pei dogs 76.…”

Section: Copy Number Variantsmentioning

confidence: 99%

Genetic Susceptibility to Rhodococcus equi

McQueen

Dindot

2015

Veterinary Internal Medicne

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Rhodococcus equi pneumonia is a major cause of morbidity and mortality in neonatal foals. Much effort has been made to identify preventative measures and new treatments for R. equi with limited success. With a growing focus in the medical community on understanding the genetic basis of disease susceptibility, investigators have begun to evaluate the interaction of the genetics of the foal with R. equi. This review describes past efforts to understand the genetic basis underlying R. equi susceptibility and tolerance. It also highlights the genetic technology available to study horses and describes the use of this technology in investigating R. equi. This review provides readers with a foundational understanding of candidate gene approaches, single nucleotide polymorphism‐based, and copy number variant‐based genome‐wide association studies, and next generation sequencing (both DNA and RNA).

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A cis-acting regulatory mutation causes premature hair graying and susceptibility to melanoma in the horse

Cited by 257 publications

References 25 publications

Microphthalmia‐associated transcription factor mutations are associated with white‐spotted coat color in swamp buffalo

Microphthalmia‐associated transcription factor mutations are associated with white‐spotted coat color in swamp buffalo

LUPA: A European initiative taking advantage of the canine genome architecture for unravelling complex disorders in both human and dogs

Genetic Susceptibility to Rhodococcus equi

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