By comparing mammalian genomes, we and others have identified actively transcribed Ty3/gypsy retrotransposon-derived genes with highly conserved DNA sequences and insertion sites. To elucidate the functions of evolutionarily conserved retrotransposon-derived genes in mammalian development, we produced mice that lack one of these genes, Peg10 (paternally expressed 10), which is a paternally expressed imprinted gene on mouse proximal chromosome 6. The Peg10 knockout mice showed early embryonic lethality owing to defects in the placenta. This indicates that Peg10 is critical for mouse parthenogenetic development and provides the first direct evidence of an essential role of an evolutionarily conserved retrotransposon-derived gene in mammalian development.
"Little is known about this gene, but studies in the mouse demonstrate that it is an imprinted, retrotransposon-derived gene. Peg10 knockout mice showed early embryonic lethality, which indicates its critical role in mouse development . Ras-related Protein RAB22A, a member of the RAB family of small GTPases was identified within the second PACG associated locus in the BH. "
[Show abstract][Hide abstract] ABSTRACT: Primary angle-closure glaucoma (PACG) in dogs is usually caused by the gradual collapse of the iridocorneal angle and cleft, eventually leading to aqueous humor (AH) outflow obstruction. The condition occurs in several breeds of dogs and the prognosis for affected animals is typically poor. We have identified several basset hound (BH) pedigrees, as well as unrelated cases with characteristic PACG that in many aspects recapitulates PACG in human patients. The goal of this study was to utilize the BH PACG model to characterize the genetics of PACG, and potentially discover genetic factors contributing to PACG in humans and animals.
We conducted a genome-wide logistic regression test for association using 37 PACG cases and 41 unaffected controls. Population stratification and cryptic relatedness were assessed using a multidimensional scaling analysis. The expression of two candidate genes within the target tissues of the BH eye was assessed by immunohistochemistry.
We report significant associations at two novel loci, specifically BICF2P31912 in COL1A2 on chromosome 14 with a per-allele odds ratio (OR, 95% confidence interval [CI]) of 3.35 (1.73-6.51), P genome=3.6×10(-4); and BICF2P893476 residing in proximity to RAB22A on chromosome 24 with a per-allele OR (95% CI) of 3.93 (1.78-8.66), P genome=4.9×10(-4). COL1A2 and RAB22A demonstrated widespread expression throughout the eye and were prominently noted in the ciliary body (CB), trabecular meshwork (TM), and iris.
Our finding of two genetic associations supports the potential segregation of PACG risk-conferring variants in the BH. The genetic associations identified may contribute to mechanisms underlying the pathogenesis of PACG, which remain to be elucidated.
"PEG10 also interacts with the transforming growth factor (TGF)-β type I receptor, activin receptor-like kinase (ALK) 1 (16). Additionally, knockdown of PEG10 inhibits the proliferation of pancreatic carcinoma and HepG2 HCC cells (13), while knockout of the PEG gene causes early embryonic lethality (17). This evidence indicates that PEG10 may play a crucial role in carcinogenesis and tumor cell growth. "
[Show abstract][Hide abstract] ABSTRACT: The clinicopathological characteristics of squamous cell/adenosquamous carcinoma (SC/ASC) are currently not well documented, and as the prevalence of SC/ASC is uncommon in gallbladder cancers, a prognostic marker has not yet been found. In the present study, the expression of tumor susceptibility gene (TSG) 101 and paternally expressed gene (PEG) 10 was assessed in 46 SC/ASCs and 80 adenocarcinomas (ACs) using immunohistochemistry, and the samples were further analyzed to examine correlations with the clinicopathological characteristics. It was demonstrated that positive TSG101 and PEG10 expression were significantly associated with large tumor size, high tumor-node-metastasis (TNM) stage, lymph node metastasis, invasion and no resection (only biopsy) of SC/ASC and AC. The univariate Kaplan-Meier analysis showed that positive TSG101 and PEG10 expression, and differentiation, tumor size, TNM stage, lymph node metastasis, invasion and surgical curability, is closely associated with a decreased overall survival in SC/ASC and AC patients (P<0.05 or P<0.001). The multivariate Cox regression analysis identified that positive TSG101 and PEG10 expression are independent factors for a poor-prognosis in SC/ASC and AC patients. The present study indicates that positive TSG101 and PEG10 expression are closely associated with the clinical, pathological and biological behaviors, and a poor prognosis in gallbladder cancer.
"Consistent with this hypothesis, our genome structure and sequence comparison analyses revealed that the UTF1 gene is indeed specific to placental mammals. There are other examples of recently evolved genes with a role in placental development, such as PEG10 and PEG11
–. Both of these genes are derived from an LTR-type retrotransposon; PEG10 after the divergence of therian mammals which separates from monotremes and PEG11 after the divergence separating from marsupials, although the ancestral retrotransposon from which it is derived is present in the marsupial genome. "
[Show abstract][Hide abstract] ABSTRACT: Embryogenesis in placental mammals is sustained by exquisite interplay between the embryo proper and placenta. UTF1 is a developmentally regulated gene expressed in both cell lineages. Here, we analyzed the consequence of loss of the UTF1 gene during mouse development. We found that homozygous UTF1 mutant newborn mice were significantly smaller than wild-type or heterozygous mutant mice, suggesting that placental insufficiency caused by the loss of UTF1 expression in extra-embryonic ectodermal cells at least in part contributed to this phenotype. We also found that the effects of loss of UTF1 expression in embryonic stem cells on their pluripotency were very subtle. Genome structure and sequence comparisons revealed that the UTF1 gene exists only in placental mammals. Our analyses of a family of genes with homology to UTF1 revealed a possible mechanism by which placental mammals have evolved the UTF1 genes.
PLoS ONE 07/2013; 8(7):e68119. DOI:10.1371/journal.pone.0068119 · 3.23 Impact Factor
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