Awasthi Mishra Nivedita, Drögemüller Cord, Jagannathan Vidhya, Keller Irene, Wüthrich Daniel, Bruggmann Rémy, Beck Julia, Schütz Ekkehard, Brenig Bertram, Demmel Steffi, Moser Simon, Signer-Hasler Heidi, Pieńkowska-Schelling Aldona, Schelling Claude, Sande Marcos, Rongen Ronald, Rieder Stefan, Kelsh Robert N, Mercader Nadia, Leeb Tosso
Institute of Genetics, Vetsuisse Faculty, University of Bern, Bern, Switzerland.
DermFocus, Vetsuisse Faculty, University of Bern, Bern, Switzerland.
PLoS One. 2017 Jun 28;12(6):e0180170. doi: 10.1371/journal.pone.0180170. eCollection 2017.
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.
带纹牛在其腹部有一圈无色素毛发和皮肤的环形带纹。该带纹作为单基因常染色体显性性状遗传。我们将致病变异定位到牛3号染色体上一个37 kb的片段。对2头带纹牛和130头对照牛的全基因组序列数据进行分析，在这2头带纹动物的关键区间仅发现一个私有遗传变异。与带纹相关的变异是一个拷贝数变异（CNV），涉及位于TWIST2基因上游约16 kb处一个6 kb非编码序列的四倍重复。在一个由333例病例和1322例对照组成的队列中，该CNV处拷贝数增加与带纹表型密切相关。我们推测该CNV在神经嵴发育过程中导致TWIST2异常表达，这可能对黑素母细胞产生负面影响。功能研究表明，在转基因斑马鱼的神经嵴中异位表达牛TWIST2会导致黑素细胞数量减少。因此，我们的结果表明TWIST2在调节色素沉着中有着意想不到的作用，并揭示了一个迷人的孟德尔性状背后的非编码CNV。
