Donnelly M.P.,Yale University |
Paschou P.,Democritus University of Thrace |
Grigorenko E.,Yale University |
Gurwitz D.,National Laboratory for the Genetics of Israeli Populations |
And 20 more authors.
American Journal of Human Genetics | Year: 2010
The polymorphic inversion on 17q21, sometimes called the microtubular associated protein tau (MAPT) inversion, is an ∼900 kb inversion found primarily in Europeans and Southwest Asians. We have identified 21 SNPs that act as markers of the inverted, i.e., H2, haplotype. The inversion is found at the highest frequencies in Southwest Asia and Southern Europe (frequencies of ∼30%); elsewhere in Europe, frequencies vary from < 5%, in Finns, to 28%, in Orcadians. The H2 inversion haplotype also occurs at low frequencies in Africa, Central Asia, East Asia, and the Americas, though the East Asian and Amerindian alleles may be due to recent gene flow from Europe. Molecular evolution analyses indicate that the H2 haplotype originally arose in Africa or Southwest Asia. Though the H2 inversion has many fixed differences across the ∼900 kb, short tandem repeat polymorphism data indicate a very recent date for the most recent common ancestor, with dates ranging from 13,600 to 108,400 years, depending on assumptions and estimation methods. This estimate range is much more recent than the 3 million year age estimated by Stefansson et al. in 2005.1. © 2010 The American Society of Human Genetics.
PD-0332991, a potent and selective inhibitor of cyclin-dependent kinase 4/6, demonstrates inhibition of proliferation in renal cell carcinoma at nanomolar concentrations and molecular markers predict for sensitivity
Logan J.E.,Urologic |
Bui P.H.,Molecular Cytogenetics Laboratory |
Christensen J.G.,Pfizer |
Belldegrun A.S.,Urologic |
Anticancer Research | Year: 2013
Background: PD-0332991 is an inhibitor of cyclindependent kinases (CDK) 4 and 6, and was evaluated to determine its anti-proliferative effects in 25 renal cell carcinoma (RCC) cell lines. Materials and Methods: Half-maximal inhibitory concentrations (IC50) of PD-0332991 were determined with cell line proliferation assays, as were its effects on the cell cycle, apoptosis, and retinoblastoma (RB) phosphorylation. Molecular markers for response prediction, including p16, p15, cyclin D1 (CCND1), cyclin E1 (CCNE1), E2F transcription factor 1 (E2F1), RB, CDK4 and CDK6, were studied using array comparative genomic hybridization (CGH) and gene expression. Results: IC50 values for PD-0332991 ranged from 25.0 nM to 700 nM, and the agent demonstrated G0/G1 cell-cycle arrest, induction of late apoptosis, and blockade of RB phosphorylation. Through genotype and expression data p16, p15 and E2F1 were identified as having significant association between loss and sensitivity to PD-0332991: p16 (p=0.021), p15 (p=0.047), and E2F1 (p=0.041). Conclusion: PD-0332991 has antiproliferative activity in RCC cell lines, and molecular markers predict for sensitivity to this agent.
News Article | April 14, 2016
The research team found a group of DNA sequences in pine trees, spruces and other conifers had been transferred to an ancestor of those trees from insects about 340 million years ago, said Dr. Claudio Casola, an AgriLife Research forest genomics assistant professor in the Texas A&M University ecosystem science and management department in College Station. "Loblolly pine is an important economic resource across the southeastern U.S., including Texas," Casola said. "We are just now starting to understand the different parts that form the very large genome of this pine tree and other conifers. Xuan Lin, one of Casola's doctoral students, and Dr. Nurul Faridi, leader of the U.S. Department of Agriculture Forest Service's Molecular Cytogenetics Laboratory and a collaborating faculty member, were other members of the team. Their work, "An Ancient Trans-Kingdom Horizontal Transfer of Penelope-like Retroelements from Arthropods to Conifers," was published recently in the Genome Biology and Evolution journal. "We called these conifer DNA sequences 'Dryads' after the Greek mythological nymphs that inhabit trees," Casola said. "Dryads are one of the many groups of DNA sequences known as DNA repeats." He said DNA repeats, also known as transposable elements, are particularly good at making new copies of themselves. As a result, they ended up forming more than half of the genome in some species, including conifers and other plants. "We know from studies in other plants that transposable elements affect both the activity and the structure of genes, and ultimately have a role in shaping certain traits, from the color of some grape varieties to the oval shape of some tomatoes." He said because transposable elements make up a lot of the conifers' DNA, it is important to gather a better understanding of what they are and how they influence conifer genes and phenotypic traits. "You can think of transposable elements as 'genomic parasites,'" Casola explained. "They spread into new genomes kind of like viruses spread between people. Unlike flu and other viral disease, these 'genomic infections' occur rarely, but once established, they can persist for millions of years." The similarities between some transposable elements and viruses are not only superficial, he said. For example retroviruses, the group of viruses that includes the HIV, evolved from transposable elements long ago. On the other hand, Casola said, many transposable elements known as endogenous retroviruses, or ERVs, represent "DNA fossils" of retroviruses that once infected primates and other mammals. "No less than 8 percent of our own genome is made of ERVs," he said. "Retroviruses, ERVs and other DNA repeats such as Penelope-like sequences share a unique way to make new copies of themselves." In this process, a single DNA repeat acts as a template to make many molecules called RNAs, and these RNAs are then transformed back into just as many DNA copies that are sort of stitched back in the host genome, he explained. Because the generation of new DNA copies from RNAs is called retroposition, transposable elements that amplify through this mechanism are known as retroelements, Casola said. By looking at some specific features in the DNA of retroelements, it is possible to classify them into different families and subfamilies. "Dryads represent a conifer-specific subfamily within the larger family of Penelope-like retroelements, hence the manuscript's title," Casola said. "Before we described Dryads, Penelope-like retroelements were known only in animals. "We thought that Dryads could have derived from Penelope-like retroelements that were somehow introduced into conifer genomes long ago," he said. "To confirm that, we computationally analyzed the genome sequences from 1,029 species that were neither animals nor conifers. "Some of these other species seemed to contain Penelope-like retroelements; however, after thorough inspections of these DNA sequences, we concluded that they were due to DNA contamination from either animals or conifers." Casola said they also did a lot of other analyses to confirm that Dryads are not artifacts and to show they are likely derived from insect Penelope-like retroelements. "One of the techniques used is called fluorescence in situ hybridization, or FISH, and allowed to visualize the position of Dryad DNA sequences on the loblolly pine chromosomes," Faridi said. Other lab experiments showed that Dryads do not occur in plants closely related to conifers, such as cycads and ginkgo, he said. "This helped us in timing the origin of Dryads between the separation of conifers' ancestors from other plants and the radiation of modern conifer groups known to have occurred about 340 million years ago," Casola said. The consequences of Dryads invasion for conifers evolution remain unclear, he said. When DNA repeats like Dryads amplify in a genome, they can change the structure of chromosomes and alter the activity of genes, with potential negative consequences for the organism, Casola said. Most species have evolved genetic mechanisms that slow down the amplification of DNA repeats, but when they jump into new host genomes, these defense mechanisms are not in place yet and a new cycle of amplification ensues, he said. The same likely happened in Dryads, which generated hundreds of thousands of new copies in the past 340 million years but now seem to have a relatively low activity, at least in loblolly pine, Casola said. "We think that Dryads changed significantly the genome landscape of ancestral conifers and possibly are still introducing important changes into the DNA of these trees," he said. "The next step in our research will be to understand how conifer chromosomes, and especially genes, were affected by the amplification of Dryads since their invasion of these plants," Casola said. "Additionally, we want to know if Dryads and other DNA repeats show differences between loblolly pine trees that are associated with trait differences, for example drought tolerance and pest resistance. Both these aspects will be the focus of future research in our labs." Explore further: Huge DNA code of the Christmas tree being revealed More information: Xuan Lin et al. An Ancient Trans-Kingdom Horizontal Transfer of -like Retroelements from Arthropods to Conifers , Genome Biology and Evolution (2016). DOI: 10.1093/gbe/evw076