A de novo frameshift mutation in ZEB2 causes polledness, abnormal skull shape, small body stature and subfertility in Fleckvieh cattle

Doris Seichter,Alexander Graf,Kristin Heidrich,Georg Thaller,Maulik Upadhyay,Helmut Blum,Stefan Krebs,Frank Weber,Holm Zerbe,Ivica Medugorac,Aurélien Capitan,Elisabeth Kunz,Lilian J. Gehrke,Daniela Klaus-Halla

doi:10.1038/s41598-020-73807-5

Abstract

Polledness in cattle is an autosomal dominant trait. Previous studies have revealed allelic heterogeneity at the polled locus and four different variants were identified, all in intergenic regions. In this study, we report a case of polled bull (FV-Polled1) born to horned parents, indicating a de novo origin of this polled condition. Using 50K genotyping and whole genome sequencing data, we identified on chromosome 2 an 11-bp deletion (AC_000159.1:g.52364063_52364073del; Del11) in the second exon of ZEB2 gene as the causal mutation for this de novo polled condition. We predicted that the deletion would shorten the protein product of ZEB2 by almost 91%. Moreover, we showed that all animals carrying Del11 mutation displayed symptoms similar to Mowat-Wilson syndrome (MWS) in humans, which is also associated with genetic variations in ZEB2. The symptoms in cattle include delayed maturity, small body stature and abnormal shape of skull. This is the first report of a de novo dominant mutation affecting only ZEB2 and associated with a genetic absence of horns. Therefore our results demonstrate undoubtedly that ZEB2 plays an important role in the process of horn ontogenesis as well as in the regulation of overall development and growth of animals.

Highlights

Polledness in cattle is an autosomal dominant trait
We present the genetic and clinical characterization of a new genetic condition attributed to a de novo deletion in ZEB2 gene that first arose in a Fleckvieh sire (FV-Polled1) and was later passed onto its offspring
Historical findings of the ancient paintings in Egypt suggest that polledness is a trait existing since several thousand years in the generally horned Bovinae[41]

Summary

Introduction

Polledness in cattle is an autosomal dominant trait. Previous studies have revealed allelic heterogeneity at the polled locus and four different variants were identified, all in intergenic regions. We showed that all animals carrying Del[11] mutation displayed symptoms similar to Mowat-Wilson syndrome (MWS) in humans, which is associated with genetic variations in ZEB2. The symptoms in cattle include delayed maturity, small body stature and abnormal shape of skull. This is the first report of a de novo dominant mutation affecting only ZEB2 and associated with a genetic absence of horns. The bony core of the horn originates from a separate ossification center in the dermis. As it grows, it progressively fuses with the frontal bone and becomes pneumatized by the action of osteoclasts coming from the frontal sinuses. Polledness is a trait of great importance for the cattle industry and livestock science[19] and it is constantly under scrutiny by the broad consumer community and animal welfare legislation[20]

Methods

Results

Conclusion