Regulatory mutations in TBX3 disrupt asymmetric hair pigmentation that underlies Dun camouflage color in horses

Imsland, Freyja; McGowan, Kelly A.; Rubin, Carl-Johan; Hénégar, Corneliu; Sundström, Elisabeth; Berglund, J. Andrew; Schwochow, Doreen; Gustafson, Ulla; Imsland, Páll; Lindblad‐Toh, Kerstin; Lindgren, Gabriella; Mikko, Sofia; Millon, L. V.; Wade, Claire M.; Schubert, Mikkel; Orlando, Ludovic; Penedo, M. C. T.; Barsh, Gregory S.; Andersson, Leif

doi:10.1038/ng.3475

Cited by 67 publications

(76 citation statements)

References 32 publications

(35 reference statements)

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“…The median age at diagnosis of ocular SCC or carcinoma in situ in this sample was 11 years (range: 5-27 years). The median age at the time of examination of the control group was 15 years (range: [13][14][15][16][17][18][19][20][21][22][23][24][25]. The median age of the affected group was significantly younger than that of the control group (U = 101, P = 0.002).…”

Section: Resultsmentioning

confidence: 99%

A missense mutation in damage‐specific DNA binding protein 2 is a genetic risk factor for ocular squamous cell carcinoma in Belgian horses

Knickelbein

Lassaline

Singer-Berk

et al. 2019

Equine Veterinary Journal

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Summary Background Belgian horses are commonly affected with ocular squamous cell carcinoma (SCC), the most common cancer of the equine eye. A missense mutation in damage‐specific DNA binding protein 2 (DDB2 c.1013C>T, p.Thr338Met) has been established as a recessive genetic risk factor for ocular SCC in the Haflinger breed. A sample of Belgian horses with unknown SCC phenotype was shown to possess this variant at a similar frequency to the Haflinger breed. Retrospective studies indicate that chestnut coat colour may predispose to the development of SCC. Objectives To determine if DDB2 c.1013C>T is a risk factor for ocular SCC in a strictly phenotyped sample of Belgian horses. To investigate associations between coat colour loci genotypes and ocular SCC. Study design Retrospective and prospective case identification, genetic investigation. Methods Genomic DNA was isolated from blood, hair or formalin‐fixed paraffin‐embedded tissue from 25 Belgian horses with histologically confirmed ocular SCC and 18 unaffected Belgian horses. Association testing of 34 single nucleotide variants from 11 genomic loci and genotyping for DDB2 c.1013C>T and coat colour alleles were performed. Exons of DDB2 were sequenced in four cases and two controls. Associations were analysed by Chi‐square or Fisher's exact tests and relative risk was calculated. Results Homozygosity for DDB2 c.1013C>T was significantly associated with ocular SCC (P = 7.4 × 10−7). Seventy‐six per cent of affected horses were homozygous for the variant. Relative risk for homozygous horses developing SCC was 4.0 (P = 1.0 × 10−4). Sequencing DDB2 did not identify a variant more concordant with disease phenotype. An association between disease and coat colour loci was not identified. Main limitations Phenotyping was determined at a single timepoint. Each included horse genotyped as chestnut, so association with this MC1R variant could not be investigated. Conclusions A missense variant, DDB2 c.1013C>T, p.Thr338Met, is a risk factor for ocular SCC in Belgian horses. A genetic risk test is commercially available.

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Section: Resultsmentioning

confidence: 99%

A missense mutation in damage‐specific DNA binding protein 2 is a genetic risk factor for ocular squamous cell carcinoma in Belgian horses

Knickelbein

Lassaline

Singer-Berk

et al. 2019

Equine Veterinary Journal

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“…), segments of the Dun insertion (represented by 45 probes, Imsland et al . ) and the Y chromosome (76 probes, Schubert et al . ; Der Sarkissian et al .…”

Section: Methodsmentioning

confidence: 99%

Experimental conditions improving in‐solution target enrichment for ancient DNA

Dávalos

Llamas

Gaunitz

et al. 2016

Molecular Ecology Resources

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High-throughput sequencing has dramatically fostered ancient DNA research in recent years. Shotgun sequencing, however, does not necessarily appear as the best-suited approach due to the extensive contamination of samples with exogenous environmental microbial DNA. DNA capture-enrichment methods represent cost-effective alternatives that increase the sequencing focus on the endogenous fraction, whether it is from mitochondrial or nuclear genomes, or parts thereof. Here, we explored experimental parameters that could impact the efficacy of MYbaits in-solution capture assays of ~5000 nuclear loci or the whole genome. We found that varying quantities of the starting probes had only moderate effect on capture outcomes. Starting DNA, probe tiling, the hybridization temperature and the proportion of endogenous DNA all affected the assay, however. Additionally, probe features such as their GC content, number of CpG dinucleotides, sequence complexity and entropy and self-annealing properties need to be carefully addressed during the design stage of the capture assay. The experimental conditions and probe molecular features identified in this study will improve the recovery of genetic information extracted from degraded and ancient remains.

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“…Transcription factor TBX3 is expressed in the outer cuticular layer and asymmetrically in hair cortex of Dun hair follicles, but only in the outer cuticular layer of non‐Dun hair follicles in Dun horses. This asymmetric expression pattern of TBX3 in the growing hairs results in pigment dilution and asymmetric pattern of pigment in hairs, indicating that hair cortex keratinocytes can regulate melanocyte location and hair pigmentation.…”

Section: Regulation Of Mcscs By Keratinocytesmentioning

confidence: 99%

Regulation of melanocyte stem cells in the pigmentation of skin and its appendages: Biological patterning and therapeutic potentials

Qiu

Chuong

Lei

2019

Experimental Dermatology

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Skin evolves essential appendages and indispensable types of cells that synergistically insulate the body from environmental insults. Residing in the specific regions in the skin such as epidermis, dermis and hair follicle, melanocytes perform an array of vital functions including defending the ultraviolet radiation and diversifying animal appearance. As one of the adult stem cells, melanocyte stem cells in the hair follicle bulge niche can proliferate, differentiate and keep quiescence to control and coordinate tissue homeostasis, repair and regeneration. In synchrony with hair follicle stem cells, melanocyte stem cells in the hair follicles undergo cyclic activation, degeneration and resting phases, to pigment the hairs and to preserve the stem cells. Disorder of melanocytes results in severe skin problems such as canities, vitiligo and even melanoma. Here, we compare and summarize recent discoveries about melanocyte in the skin, particularly in the hair follicle. A better understanding of the physiological and pathological regulation of melanocyte and melanocyte stem cell behaviours will help to guide the clinical applications in regenerative medicine.

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Regulatory mutations in TBX3 disrupt asymmetric hair pigmentation that underlies Dun camouflage color in horses

Cited by 67 publications

References 32 publications

A missense mutation in damage‐specific DNA binding protein 2 is a genetic risk factor for ocular squamous cell carcinoma in Belgian horses

A missense mutation in damage‐specific DNA binding protein 2 is a genetic risk factor for ocular squamous cell carcinoma in Belgian horses

Experimental conditions improving in‐solution target enrichment for ancient DNA

Regulation of melanocyte stem cells in the pigmentation of skin and its appendages: Biological patterning and therapeutic potentials

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