ZFIN ID: ZDB-PUB-170629-3
A structural variant in the 5'-flanking region of the TWIST2 gene affects melanocyte development in belted cattle
Awasthi Mishra, N., Drögemüller, C., Jagannathan, V., Keller, I., Wüthrich, D., Bruggmann, R., Beck, J., Schütz, E., Brenig, B., Demmel, S., Moser, S., Signer-Hasler, H., Pieńkowska-Schelling, A., Schelling, C., Sande, M., Rongen, R., Rieder, S., Kelsh, R.N., Mercader, N., Leeb, T.
Date: 2017
Source: PLoS One   12: e0180170 (Journal)
Registered Authors: Kelsh, Robert, Mercader Huber, Nadia
Keywords: Cattle, Embryos, Melanocytes, Zebrafish, Neural crest, Haplotypes, Phenotypes, Fluorescence imaging
MeSH Terms:
  • 5' Flanking Region/genetics*
  • 5' Flanking Region/physiology
  • Animals
  • Animals, Genetically Modified/genetics
  • Cattle/genetics*
  • Cattle/growth & development
  • DNA Copy Number Variations/genetics*
  • DNA Copy Number Variations/physiology
  • Female
  • Male
  • Melanocytes/physiology*
  • Phenotype
  • Polymerase Chain Reaction
  • Skin Pigmentation/genetics
  • Twist-Related Protein 2/genetics*
  • Twist-Related Protein 2/physiology
  • Zebrafish/genetics
PubMed: 28658273 Full text @ PLoS One
Belted cattle have a circular belt of unpigmented hair and skin around their midsection. The belt is inherited as a monogenic autosomal dominant trait. We mapped the causative variant to a 37 kb segment on bovine chromosome 3. Whole genome sequence data of 2 belted and 130 control cattle yielded only one private genetic variant in the critical interval in the two belted animals. The belt-associated variant was a copy number variant (CNV) involving the quadruplication of a 6 kb non-coding sequence located approximately 16 kb upstream of the TWIST2 gene. Increased copy numbers at this CNV were strongly associated with the belt phenotype in a cohort of 333 cases and 1322 controls. We hypothesized that the CNV causes aberrant expression of TWIST2 during neural crest development, which might negatively affect melanoblasts. Functional studies showed that ectopic expression of bovine TWIST2 in neural crest in transgenic zebrafish led to a decrease in melanocyte numbers. Our results thus implicate an unsuspected involvement of TWIST2 in regulating pigmentation and reveal a non-coding CNV underlying a captivating Mendelian character.