Archivi categoria: PLOS

Discovery and fine-mapping of adiposity loci using high density imputation of genome-wide association studies in individuals of African ancestry: African ancestry anthropometry genetics consortium

by Maggie C. Y. Ng, Mariaelisa Graff, Yingchang Lu, Anne E. Justice, Poorva Mudgal, Ching-Ti Liu, Kristin Young, Lisa R. Yanek, Mary F. Feitosa, Mary K. Wojczynski, Kristin Rand, Jennifer A. Brody, Brian E. Cade, Latchezar Dimitrov, Qing Duan, Xiuqing Guo, Leslie A. Lange, Michael A. Nalls, Hayrettin Okut, Salman M. Tajuddin, Bamidele O. Tayo, Sailaja Vedantam, Jonathan P. Bradfield, Guanjie Chen, Wei-Min Chen, Alessandra Chesi, Marguerite R. Irvin, Badri Padhukasahasram, Jennifer A. Smith, Wei Zheng, Matthew A. Allison, Christine B. Ambrosone, Elisa V. Bandera, Traci M. Bartz, Sonja I. Berndt, Leslie Bernstein, William J. Blot, Erwin P. Bottinger, John Carpten, Stephen J. Chanock, Yii-Der Ida Chen, David V. Conti, Richard S. Cooper, Myriam Fornage, Barry I. Freedman, Melissa Garcia, Phyllis J. Goodman, Yu-Han H. Hsu, Jennifer Hu, Chad D. Huff, Sue A. Ingles, Esther M. John, Rick Kittles, Eric Klein, Jin Li, Barbara McKnight, Uma Nayak, Barbara Nemesure, Adesola Ogunniyi, Andrew Olshan, Michael F. Press, Rebecca Rohde, Benjamin A. Rybicki, Babatunde Salako, Maureen Sanderson, Yaming Shao, David S. Siscovick, Janet L. Stanford, Victoria L. Stevens, Alex Stram, Sara S. Strom, Dhananjay Vaidya, John S. Witte, Jie Yao, Xiaofeng Zhu, Regina G. Ziegler, Alan B. Zonderman, Adebowale Adeyemo, Stefan Ambs, Mary Cushman, Jessica D. Faul, Hakon Hakonarson, Albert M. Levin, Katherine L. Nathanson, Erin B. Ware, David R. Weir, Wei Zhao, Degui Zhi, The Bone Mineral Density in Childhood Study (BMDCS) Group , Donna K. Arnett, Struan F. A. Grant, Sharon L. R. Kardia, Olufunmilayo I. Oloapde, D. C. Rao, Charles N. Rotimi, Michele M. Sale, L. Keoki Williams, Babette S. Zemel, Diane M. Becker, Ingrid B. Borecki, Michele K. Evans, Tamara B. Harris, Joel N. Hirschhorn, Yun Li, Sanjay R. Patel, Bruce M. Psaty, Jerome I. Rotter, James G. Wilson, Donald W. Bowden, L. Adrienne Cupples, Christopher A. Haiman, Ruth J. F. Loos, Kari E. North

Genome-wide association studies (GWAS) have identified >300 loci associated with measures of adiposity including body mass index (BMI) and waist-to-hip ratio (adjusted for BMI, WHRadjBMI), but few have been identified through screening of the African ancestry genomes. We performed large scale meta-analyses and replications in up to 52,895 individuals for BMI and up to 23,095 individuals for WHRadjBMI from the African Ancestry Anthropometry Genetics Consortium (AAAGC) using 1000 Genomes phase 1 imputed GWAS to improve coverage of both common and low frequency variants in the low linkage disequilibrium African ancestry genomes. In the sex-combined analyses, we identified one novel locus (TCF7L2/HABP2) for WHRadjBMI and eight previously established loci at P < 5×10−8: seven for BMI, and one for WHRadjBMI in African ancestry individuals. An additional novel locus (SPRYD7/DLEU2) was identified for WHRadjBMI when combined with European GWAS. In the sex-stratified analyses, we identified three novel loci for BMI (INTS10/LPL and MLC1 in men, IRX4/IRX2 in women) and four for WHRadjBMI (SSX2IP, CASC8, PDE3B and ZDHHC1/HSD11B2 in women) in individuals of African ancestry or both African and European ancestry. For four of the novel variants, the minor allele frequency was low (<5%). In the trans-ethnic fine mapping of 47 BMI loci and 27 WHRadjBMI loci that were locus-wide significant (P < 0.05 adjusted for effective number of variants per locus) from the African ancestry sex-combined and sex-stratified analyses, 26 BMI loci and 17 WHRadjBMI loci contained ≤ 20 variants in the credible sets that jointly account for 99% posterior probability of driving the associations. The lead variants in 13 of these loci had a high probability of being causal. As compared to our previous HapMap imputed GWAS for BMI and WHRadjBMI including up to 71,412 and 27,350 African ancestry individuals, respectively, our results suggest that 1000 Genomes imputation showed modest improvement in identifying GWAS loci including low frequency variants. Trans-ethnic meta-analyses further improved fine mapping of putative causal variants in loci shared between the African and European ancestry populations.
Tratto da: www.plos.org.
All site content, except where otherwise noted, is licensed under a Creative Commons Attribution (CC BY) license.

Correction: The Subclonal Architecture of Metastatic Breast Cancer: Results from a Prospective Community-Based Rapid Autopsy Program "CASCADE"

by Peter Savas, Zhi Ling Teo, Christophe Lefevre, Christoffer Flensburg, Franco Caramia, Kathryn Alsop, Mariam Mansour, Prudence A. Francis, Heather A. Thorne, Maria Joao Silva, Nnennaya Kanu, Michelle Dietzen, Andrew Rowan, Maik Kschischo, Stephen Fox, David D. Bowtell, Sarah-Jane Dawson, Terence P. Speed, Charles Swanton, Sherene Loi


Tratto da: www.plos.org.
All site content, except where otherwise noted, is licensed under a Creative Commons Attribution (CC BY) license.

Lethality of mice bearing a knockout of the <i>Ngly1</i>-gene is partially rescued by the additional deletion of the <i>Engase</i> gene

by Haruhiko Fujihira, Yuki Masahara-Negishi, Masaru Tamura, Chengcheng Huang, Yoichiro Harada, Shigeharu Wakana, Daisuke Takakura, Nana Kawasaki, Naoyuki Taniguchi, Gen Kondoh, Tadashi Yamashita, Yoko Funakoshi, Tadashi Suzuki

The cytoplasmic peptide:N-glycanase (Ngly1 in mammals) is a de-N-glycosylating enzyme that is highly conserved among eukaryotes. It was recently reported that subjects harboring mutations in the NGLY1 gene exhibited severe systemic symptoms (NGLY1-deficiency). While the enzyme obviously has a critical role in mammals, its precise function remains unclear. In this study, we analyzed Ngly1-deficient mice and found that they are embryonic lethal in C57BL/6 background. Surprisingly, the additional deletion of the gene encoding endo-β-N-acetylglucosaminidase (Engase), which is another de-N-glycosylating enzyme but leaves a single GlcNAc at glycosylated Asn residues, resulted in the partial rescue of the lethality of the Ngly1-deficient mice. Additionally, we also found that a change in the genetic background of C57BL/6 mice, produced by crossing the mice with an outbred mouse strain (ICR) could partially rescue the embryonic lethality of Ngly1-deficient mice. Viable Ngly1-deficient mice in a C57BL/6 and ICR mixed background, however, showed a very severe phenotype reminiscent of the symptoms of NGLY1-deficiency subjects. Again, many of those defects were strongly suppressed by the additional deletion of Engase in the C57BL/6 and ICR mixed background. The defects observed in Ngly1/Engase-deficient mice (C57BL/6 background) and Ngly1-deficient mice (C57BL/6 and ICR mixed background) closely resembled some of the symptoms of patients with an NGLY1-deficiency. These observations strongly suggest that the Ngly1- or Ngly1/Engase-deficient mice could serve as a valuable animal model for studies related to the pathogenesis of the NGLY1-deficiency, and that cytoplasmic ENGase represents one of the potential therapeutic targets for this genetic disorder.
Tratto da: www.plos.org.
All site content, except where otherwise noted, is licensed under a Creative Commons Attribution (CC BY) license.

Three distinct mechanisms of long-distance modulation of gene expression in yeast

by Manyu Du, Qian Zhang, Lu Bai

Recent Hi-C measurements have revealed numerous intra- and inter-chromosomal interactions in various eukaryotic cells. To what extent these interactions regulate gene expression is not clear. This question is particularly intriguing in budding yeast because it has extensive long-distance chromosomal interactions but few cases of gene regulation over-a-distance. Here, we developed a medium-throughput assay to screen for functional long-distance interactions that affect the average expression level of a reporter gene as well as its cell-to-cell variability (noise). We ectopically inserted an insulated MET3 promoter (MET3pr) flanked by ~1kb invariable sequences into thousands of genomic loci, allowing it to make contacts with different parts of the genome, and assayed the MET3pr activity in single cells. Changes of MET3pr activity in this case necessarily involve mechanisms that function over a distance. MET3pr has similar activities at most locations. However, at some locations, they deviate from the norm and exhibit three distinct patterns including low expression / high noise, low expression / low noise, and high expression / low noise. We provided evidence that these three patterns of MET3pr expression are caused by Sir2-mediated silencing, transcriptional interference, and 3D clustering. The clustering also occurs in the native genome and enhances the transcription of endogenous Met4-targeted genes. Overall, our results demonstrate that a small fraction of long-distance chromosomal interactions can affect gene expression in yeast.
Tratto da: www.plos.org.
All site content, except where otherwise noted, is licensed under a Creative Commons Attribution (CC BY) license.

Bioenergetic status modulates motor neuron vulnerability and pathogenesis in a zebrafish model of spinal muscular atrophy

by Penelope J. Boyd, Wen-Yo Tu, Hannah K. Shorrock, Ewout J. N. Groen, Roderick N. Carter, Rachael A. Powis, Sophie R. Thomson, Derek Thomson, Laura C. Graham, Anna A. L. Motyl, Thomas M. Wishart, J. Robin Highley, Nicholas M. Morton, Thomas Becker, Catherina G. Becker, Paul R. Heath, Thomas H. Gillingwater

Degeneration and loss of lower motor neurons is the major pathological hallmark of spinal muscular atrophy (SMA), resulting from low levels of ubiquitously-expressed survival motor neuron (SMN) protein. One remarkable, yet unresolved, feature of SMA is that not all motor neurons are equally affected, with some populations displaying a robust resistance to the disease. Here, we demonstrate that selective vulnerability of distinct motor neuron pools arises from fundamental modifications to their basal molecular profiles. Comparative gene expression profiling of motor neurons innervating the extensor digitorum longus (disease-resistant), gastrocnemius (intermediate vulnerability), and tibialis anterior (vulnerable) muscles in mice revealed that disease susceptibility correlates strongly with a modified bioenergetic profile. Targeting of identified bioenergetic pathways by enhancing mitochondrial biogenesis rescued motor axon defects in SMA zebrafish. Moreover, targeting of a single bioenergetic protein, phosphoglycerate kinase 1 (Pgk1), was found to modulate motor neuron vulnerability in vivo. Knockdown of pgk1 alone was sufficient to partially mimic the SMA phenotype in wild-type zebrafish. Conversely, Pgk1 overexpression, or treatment with terazosin (an FDA-approved small molecule that binds and activates Pgk1), rescued motor axon phenotypes in SMA zebrafish. We conclude that global bioenergetics pathways can be therapeutically manipulated to ameliorate SMA motor neuron phenotypes in vivo.
Tratto da: www.plos.org.
All site content, except where otherwise noted, is licensed under a Creative Commons Attribution (CC BY) license.