High mobility group A2 (HMGA2) deficiency in pigs leads to dwarfism, abnormal fetal resource allocation, and cryptorchidism.

Abstract

Expression ofis strongly associated with body size and growth in mice and humans. In mice, inactivation of one or both alleles ofresults in body-size reductions of 20% and 60%, respectively. In humans, microdeletions involving thelocus result in short stature, suggesting the function of the HMGA2 protein is conserved among mammals. To test this hypothesis, we generated HMGA2-deficient pigs via gene editing and somatic cell nuclear transfer (SCNT). Examination of growth parameters revealed thatmale and female pigs were on average 20% lighter and smaller thanmatched controls (< 0.05).boars showed significant size reduction ranging from 35 to 85% of controls depending on age (< 0.05), and organ weights were also affected (< 0.05).2gilts and boars exhibited normal reproductive development and fertility, whileboars were sterile due to undescended testes (cryptorchidism). Crossbreedingboars and gilts produced litters lacking thegenotype. However, analysis of day (D) D40 and D78 pregnancies indicated thatfetuses were present at the expected Mendelian ratio, but placental abnormalities were seen in the D78concepti. Additionally,embryos generated by gene editing and SCNT produced multiple pregnancies and viable offspring, indicating that lack of HMGA2 is not lethal per se. Overall, our results show that the effect ofwith respect to growth regulation is highly conserved among mammals and opens up the possibility of regulating body and organ size in a variety of mammalian species including food and companion animals.