Mutation profiling of a limbless pig reveals genome-wide regulation of RNA processing related to bone development.

Abstract

Mutation is the basis of phenotypic changes and serves as the source of natural selection. The development of limbs has been the milestone in vertebrate evolution. Several limb and bone-related genes were verified experimentally, but other indirect and regulatory factors of limb development remained untested, especially very few cases were observed in natural environment. We report a naturally born serpentized pig without hindlimbs. Whole genome sequencing followed by comparative genomic analysis revealed multiple interesting patterns on the handicapped pig-specific mutations. Although the bone-related genes are not directly subjected to mutations, other regulatory factors such as the RNA deaminase genes Adar are damaged in the handicapped pig, leading to the abolished A-to-I deamination in many functional, conserved genes as well as the bone-related genes. This is a precious case that the limbless phenotype is observed in naturally born non-model organisms. Our study broadened the generality of the limbless phenotype across mammals and extended the regulation of hindlimb development to other non-bone-related genes. Our knowledge of limb and bone-related mutations and regulation would also contribute to human genetics.