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Developmental biology - Genes that control development
HMGA2 gene controls body size in pigs - and humans
Researchers from North Carolina State University have demonstrated a connection between the function of gene HMGA2 and body size. Published online May 7, 2018 in the Proceedings of the National Academy of Sciences PNAS, the work demonstrates HMGA2's importance in body size regulation across mammal species, providing a target for gene modification.
"Essentially, HMGA2 is a gene that controls the total number of cells that an animal has. The gene is only active during fetal development and 'programs' in the number of cells that the animal will be able to generate. When the animal is born, it will only be able to grow to the size dictated by the number of cells it can produce."
The research team had previously studied HMGA2 in mice, finding mice have two different genes (HMGA1 and HMGA2) involved in mouse body mass and size. Pigs and humans only use HMGA2 to regulate growth in each of our species. The NC State study examined how body size in fetal pigs responds in situations where a variety of copies of HMGA2 - one copy (one from mom or one from dad), both copies (from mom and dad), or neither copy — exists.
"We found that the amount of the gene expressed is proportional to the size of the animal. If both copies were expressed the pig was 'normal' sized. If one copy was expressed the pig was roughly 25 percent smaller than normal, and if neither copy was expressed the pig was 75 percent smaller. The animals grow and develop normally, although boars with both copies of the gene deleted — were sterile. Overall, it seems that controlling the expression of HMGA2 is like using a dial to control body size.""
The researchers also found that deleting HMGA2 affected what resources pig fetuses received in utero. In litters containing mixed types of functioning HMGA2 such as litters with both: (A) fetuses with both maternal and paternal copies of HMGA2 deleted, mixed with (B) fetuses with one or more copies of the gene working — those fetuses with both copies of HMGA2 deleted died. But, if the litter only contained fetuses with both copies deleted, all the fetuses survived and developed normally.
We show that mutations in HMGA2 affect fetal resource allocation, testis descent, and the size of pigs and provides a target for gene modification that can be used to modulate size in other mammalian species. This can have implications in agriculture as well as in the development of new strains of companion animals. In addition, most xenograft pig donors have adult organs larger than those of humans. Recently, it has been shown that regulation of organ growth is donor-controlled, not host-controlled, resulting in organ overgrowth and damage after transplantation. We show here that the HMGA2 gene is a potential target for organ-size regulation in xenotransplantation.
Expression of HMGA2 is strongly associated with body size and growth in mice and humans. In mice, inactivation of one or both alleles of Hmga2 results in body size reductions of 20% and 60%, respectively. In humans, micro-deletions involving the HMGA2 locus 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 that HMGA2-/+ male and female pigs were on average 20% lighter and smaller than HMGA2+/+ matched controls (P<0.05). HMGA2 -/- boars showed significant size reduction ranging from 35-85% of controls depending on age (P<0.05), and organ weights were also affected (P<0.05). HMGA2 -/+ gilts and boars exhibited normal reproductive development and fertility, while HMGA2-/- boars were sterile due to undescended testes (cryptorchidism). Crossbreeding HMGA2-/+ boars and gilts produced litters lacking the HMGA2 -/- genotype. Yet analysis of D40 and D78 pregnancies indicated that HMGA2 -/- fetuses were present at the expected Mendelian ratio, but placental abnormalities were seen in the D78 HMGA2-/- concepti. Additionally, HMGA2 -/- 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 of HMGA2 with 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.
Authors: Jaewook Chung, Bruce Collins, Renan Sper, Katherine Gleason, Sean Simpson, Jeffrey Sommer, William Flowers, Robert Petters, Jorge A. Piedrahita, North Carolina State University; Xia Zhang, University of Missouri; Sehwon Koh, Duke University
The research was supported by the National Institutes of Health (grant R21-OD010553).
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The HMGA2 gene is strongly associated with body size and growth in mice and humans. In mice, inactivating one or both copies (one from mom and one from dad) results in reduced body size from 20% and 60%, respectively. In humans, micro-deletions of HMGA2 result in short stature, which suggests HMGA2 protein is conserved across mammal species. Image credit: in the public domain