TY - JOUR
T1 - A structural variant in the 5′-flanking region of the TWIST2 gene affects melanocyte development in belted cattle
AU - Awasthi Mishra, Nivedita
AU - Droegemueller, Cord
AU - Jagannathan, Vidhya
AU - Keller, Irene
AU - Wuthrich, Daniel
AU - Bruggmann, Remy
AU - Beck, Julia
AU - Schuetz, Ekkehard
AU - Brenig, Bertram
AU - Demmel, Steffi
AU - Moser, Simon
AU - Signer-Hasler, Heidi
AU - Pienkowska-Schelling, Aldona
AU - Schelling, Claude
AU - Sande, Marcos
AU - Rongen, Ronald
AU - Rieder, Stefan
AU - Kelsh, Robert N.
AU - Mercader, Nadia
AU - Leeb, Tosso
PY - 2017/6/28
Y1 - 2017/6/28
N2 - 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.
AB - 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.
UR - https://doi.org/10.1371/journal.pone.0180170
U2 - 10.1101/077065
DO - 10.1101/077065
M3 - Article
SN - 1932-6203
VL - 12
JO - PLoS ONE
JF - PLoS ONE
IS - 6
M1 - e0180170
ER -