UC Davis

The Suppressor of cytokine signaling 2 (Socs2) gene encodes the SOCS2 protein, a potent negative regulator of growth hormone receptor signaling. In mice, loss of SOCS2 function results in 30-50% increases in post-weaning growth without increases in birth or pre-weaning weight and without excessive adiposity or leanness. However, Socs2 KO also reduces fertility, increases mortality rate, and prolongs inflammation in response to infection in mice. In sheep, a naturally occurring point mutation in Socs2, that is predicted to eliminate SOCS2 function, is associated with increases in size, weight, and milk production, at the expense of susceptibility to mastitis. We aimed to test whether Socs2 knockout (KO) in a meat breed of sheep had detrimental effects on reproduction, and evaluate the growth, feed efficiency, survival, and carcass characteristics of Socs2 heterozygous KO lambs. Additionally, we aimed to characterize the genomic alterations created by electroporation of sheep zygotes with Clustered Regularly Interspersed Short Palindromic Repeats/CRISPR associated protein 9 (CRISPR/Cas9) ribonucleoprotein complexed with dual guide RNAs targeting an 85 base pair span of Socs2. Whole genome sequencing (WGS) of six genome edited sheep, revealed that three healthy lambs carried large deletion alleles that evaded detection by initial PCR and Sanger sequencing. All six genome edited lambs were compound heterozygotes for Socs2 mutations that were predicted to functionally ablate SOCS2 function and all the offspring of the two healthy genome edited rams were carriers for a Socs2 KO allele. The pre-weaning (including prenatal) mortality rate of Socs2(+/-) lambs was 57% compared to 20% for Socs2(+/+) lambs, which was a large effect that trended towards statistical significance (p = .052). Socs2(+/-) rams were 17% taller at birth and Socs2(+/-) genotype was associated with a 22% increase in male growth rate during the preweaning period and a 28% increase in female growth rate in the post-weaning period. Socs2(+/-) lambs did not differ significantly in feed efficiency and minor differences in carcass characteristics were observed. The modestly improved growth of Socs2 heterozygous KO sheep is unlikely to benefit commercial lamb production unless the detrimental reproductive and survival phenotypes observed in Socs2(+/-) sheep are addressed.