Abstract
The Creeper trait, a classical monogenic phenotype of chicken, is controlled by a dominant semi-lethal gene. This trait has been widely cited in the genetics and molecular biology textbooks for illustrating autosomal dominant semi-lethal inheritance over decades. However, the genetic basis of the Creeper trait remains unknown. Here we have utilized ultra-deep sequencing and extensive analysis for targeting causative mutation controlling the Creeper trait. Our results indicated that the deletion of Indian hedgehog (IHH) gene was only found in the whole-genome sequencing data of lethal embryos and Creeper chickens. Large scale segregation analysis demonstrated that the deletion of IHH was fully linked with early embryonic death and the Creeper trait. Expression analysis showed a much lower expression of IHH in Creeper than wild-type chickens. We therefore suggest the deletion of IHH to be the causative mutation for the Creeper trait in chicken. Our findings unravel the genetic basis of the longstanding Creeper phenotype mystery in chicken as the same gene also underlies bone dysplasia in human and mouse, and thus highlight the significance of IHH in animal development and human haploinsufficiency disorders.
Highlights
One critical issue in biology is to understand the mechanism underlying phenotype formation
We have performed whole-genome sequencing to demonstrate that early embryonic death and the Creeper trait are caused by the deletion of Indian hedgehog (IHH), leading to a decreased expression of IHH during cartilage development, which is responsible for condensation, growth, and differentiation of cartilage
The results were consistent with our first incubation experiment, as summarized in Supplementary Table S1. These results suggested that Creeper chickens were heterozygotes and the Creeper trait was controlled by a single dominant gene
Summary
One critical issue in biology is to understand the mechanism underlying phenotype formation. Genetic studies suggested that the Creeper trait was determined by a single autosomal dominant semi-lethal gene (Cp) in chicken. Due to its dominant semi-lethal characteristic and historic significance, the Cp gene has been widely cited in genetics and molecular biology textbooks[15,16]. We have performed whole-genome sequencing to demonstrate that early embryonic death and the Creeper trait are caused by the deletion of Indian hedgehog (IHH), leading to a decreased expression of IHH during cartilage development, which is responsible for condensation, growth, and differentiation of cartilage. Our results dissect the molecular basis of the Creeper trait and early embryo death in chicken, and highlight the significance of IHH deletion as a dominant semi-lethal mutation in natural chicken populations. This study emphasizes the pivotal role of IHH in animal development and provides an ideal and valuable in vitro model for the study of IHH function and haploinsufficiency diseases
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