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Athma A Pai, Golshid Baharian, Ariane Pagé Sabourin, Jessica F Brinkworth, Yohann Nédélec, Joseph W Foley, Jean-Christophe Grenier, Katherine J Siddle, Anne Dumaine, Vania Yotova, Zachary P Johnson, Robert E Lanford, Christopher B Burge, Luis B Barreiro
The contribution of pre-mRNA processing mechanisms to the regulation of immune responses remains poorly studied despite emerging examples of their role as regulators of immune defenses. We sought to investigate the role of mRNA processing in the cellular responses of human macrophages to live bacterial infections. Here, we used mRNA sequencing to quantify gene expression and isoform abundances in primary macrophages from 60 individuals, before and after infection with Listeria monocytogenes and Salmonella typhimurium...
September 2016: PLoS Genetics
Yun Chen, Athma A Pai, Jan Herudek, Michal Lubas, Nicola Meola, Aino I Järvelin, Robin Andersson, Vicent Pelechano, Lars M Steinmetz, Torben Heick Jensen, Albin Sandelin
Mammalian transcriptomes are complex and formed by extensive promoter activity. In addition, gene promoters are largely divergent and initiate transcription of reverse-oriented promoter upstream transcripts (PROMPTs). Although PROMPTs are commonly terminated early, influenced by polyadenylation sites, promoters often cluster so that the divergent activity of one might impact another. Here we found that the distance between promoters strongly correlates with the expression, stability and length of their associated PROMPTs...
September 2016: Nature Genetics
Tuhin Samanta, Shyam Sarkar, Venkata N K B Adusumalli, Athma E Praveen, Venkataramanan Mahalingam
We report the enhancement of both visible and near infrared (NIR) emissions from Nd(3+) ions via Ce(3+) sensitization in colloidal nanocrystals for the first time. This is achieved in citrate capped Nd(3+)-doped CeF3 nanocrystals under ultraviolet (UV) irradiation (λex = 282 nm). The lasing transition ((4)F3/2 → (4)I11/2) at 1064 nm from Nd(3+)-doped CeF3 nanocrystals has much higher emission intensity via Ce(3+) ion sensitization compared to the direct excitation of Nd(3+) ions. The nanocrystals were prepared using a simple microwave irradiation route...
January 7, 2016: Dalton Transactions: An International Journal of Inorganic Chemistry
Alain Pacis, Ludovic Tailleux, Alexander M Morin, John Lambourne, Julia L MacIsaac, Vania Yotova, Anne Dumaine, Anne Danckaert, Francesca Luca, Jean-Christophe Grenier, Kasper D Hansen, Brigitte Gicquel, Miao Yu, Athma Pai, Chuan He, Jenny Tung, Tomi Pastinen, Michael S Kobor, Roger Pique-Regi, Yoav Gilad, Luis B Barreiro
DNA methylation is an epigenetic mark thought to be robust to environmental perturbations on a short time scale. Here, we challenge that view by demonstrating that the infection of human dendritic cells (DCs) with a live pathogenic bacteria is associated with rapid and active demethylation at thousands of loci, independent of cell division. We performed an integrated analysis of data on genome-wide DNA methylation, histone mark patterns, chromatin accessibility, and gene expression, before and after infection...
December 2015: Genome Research
Athma A Pai, Jonathan K Pritchard, Yoav Gilad
It is now well established that noncoding regulatory variants play a central role in the genetics of common diseases and in evolution. However, until recently, we have known little about the mechanisms by which most regulatory variants act. For instance, what types of functional elements in DNA, RNA, or proteins are most often affected by regulatory variants? Which stages of gene regulation are typically altered? How can we predict which variants are most likely to impact regulation in a given cell type? Recent studies, in many cases using quantitative trait loci (QTL)-mapping approaches in cell lines or tissue samples, have provided us with considerable insight into the properties of genetic loci that have regulatory roles...
January 2015: PLoS Genetics
Athma A Pai, Yoav Gilad
It has become increasingly clear that changes in gene regulation have played an important role in adaptive evolution both between and within species. Over the past five years, comparative studies have moved beyond simple characterizations of differences in gene expression levels within and between species to studying variation in regulatory mechanisms. We still know relatively little about the precise chain of events that lead to most regulatory adaptations, but we have taken significant steps towards understanding the relative importance of changes in different mechanisms of gene regulatory evolution...
December 2014: Current Opinion in Genetics & Development
Machika Moriya, Shinya Oda, Masaki Nakane, Kaneyuki Kawamae
We experienced severe asthmatic crisis during general anesthesia in a 45-year-old man with IgG4-related disease, COPD and athma undergoing removal of submandibular gland. The ventilatiory failure was caused by the stimulation of the operation, sputum, and neostigmine. His serum IgG4 level was extremely high. IgG4 related disease is a recently emerging entity characterized by a diffuse or mass forming inflammatory reaction rich in IgG4-positive plasma cells associated with fibrosclerosis and obliterative phlebitis...
April 2014: Masui. the Japanese Journal of Anesthesiology
Athma Ram Bhandari, William Powrie
Legislation in some parts of the world now requires municipal solid waste (MSW) to be processed prior to landfilling to reduce its biodegradability and hence its polluting potential through leachate and fugitive emission of greenhouse gases. This pre-processing may be achieved through what is generically termed mechanical-biological-treatment (MBT). One of the major concerns relating to MBT wastes is that the strength of the material may be less than for raw MSW, owing to the removal of sheet, stick and string-like reinforcing elements during processing...
April 2013: Waste Management
Daniel J Gaffney, Graham McVicker, Athma A Pai, Yvonne N Fondufe-Mittendorf, Noah Lewellen, Katelyn Michelini, Jonathan Widom, Yoav Gilad, Jonathan K Pritchard
Nucleosomes are important for gene regulation because their arrangement on the genome can control which proteins bind to DNA. Currently, few human nucleosomes are thought to be consistently positioned across cells; however, this has been difficult to assess due to the limited resolution of existing data. We performed paired-end sequencing of micrococcal nuclease-digested chromatin (MNase-seq) from seven lymphoblastoid cell lines and mapped over 3.6 billion MNase-seq fragments to the human genome to create the highest-resolution map of nucleosome occupancy to date in a human cell type...
2012: PLoS Genetics
Athma A Pai, Carolyn E Cain, Orna Mizrahi-Man, Sherryl De Leon, Noah Lewellen, Jean-Baptiste Veyrieras, Jacob F Degner, Daniel J Gaffney, Joseph K Pickrell, Matthew Stephens, Jonathan K Pritchard, Yoav Gilad
Recent gene expression QTL (eQTL) mapping studies have provided considerable insight into the genetic basis for inter-individual regulatory variation. However, a limitation of all eQTL studies to date, which have used measurements of steady-state gene expression levels, is the inability to directly distinguish between variation in transcription and decay rates. To address this gap, we performed a genome-wide study of variation in gene-specific mRNA decay rates across individuals. Using a time-course study design, we estimated mRNA decay rates for over 16,000 genes in 70 Yoruban HapMap lymphoblastoid cell lines (LCLs), for which extensive genotyping data are available...
2012: PLoS Genetics
Rebecca C Iskow, Omer Gokcumen, Alexej Abyzov, Joanna Malukiewicz, Qihui Zhu, Ann T Sukumar, Athma A Pai, Ryan E Mills, Lukas Habegger, Darren A Cusanovich, Meagan A Rubel, George H Perry, Mark Gerstein, Anne C Stone, Yoav Gilad, Charles Lee
Gene expression differences are shaped by selective pressures and contribute to phenotypic differences between species. We identified 964 copy number differences (CNDs) of conserved sequences across three primate species and examined their potential effects on gene expression profiles. Samples with copy number different genes had significantly different expression than samples with neutral copy number. Genes encoding regulatory molecules differed in copy number and were associated with significant expression differences...
July 31, 2012: Proceedings of the National Academy of Sciences of the United States of America
Jacob F Degner, Athma A Pai, Roger Pique-Regi, Jean-Baptiste Veyrieras, Daniel J Gaffney, Joseph K Pickrell, Sherryl De Leon, Katelyn Michelini, Noah Lewellen, Gregory E Crawford, Matthew Stephens, Yoav Gilad, Jonathan K Pritchard
The mapping of expression quantitative trait loci (eQTLs) has emerged as an important tool for linking genetic variation to changes in gene regulation. However, it remains difficult to identify the causal variants underlying eQTLs, and little is known about the regulatory mechanisms by which they act. Here we show that genetic variants that modify chromatin accessibility and transcription factor binding are a major mechanism through which genetic variation leads to gene expression differences among humans. We used DNase I sequencing to measure chromatin accessibility in 70 Yoruba lymphoblastoid cell lines, for which genome-wide genotypes and estimates of gene expression levels are also available...
February 16, 2012: Nature
Daniel J Gaffney, Jean-Baptiste Veyrieras, Jacob F Degner, Roger Pique-Regi, Athma A Pai, Gregory E Crawford, Matthew Stephens, Yoav Gilad, Jonathan K Pritchard
BACKGROUND: Expression quantitative trait loci (eQTLs) are likely to play an important role in the genetics of complex traits; however, their functional basis remains poorly understood. Using the HapMap lymphoblastoid cell lines, we combine 1000 Genomes genotypes and an extensive catalogue of human functional elements to investigate the biological mechanisms that eQTLs perturb. RESULTS: We use a Bayesian hierarchical model to estimate the enrichment of eQTLs in a wide variety of regulatory annotations...
2012: Genome Biology
Darren A Cusanovich, Christine Billstrand, Xiang Zhou, Claudia Chavarria, Sherryl De Leon, Katelyn Michelini, Athma A Pai, Carole Ober, Yoav Gilad
Recent genome-wide association studies (GWAS) have identified a number of novel genetic associations with complex human diseases. In spite of these successes, results from GWAS generally explain only a small proportion of disease heritability, an observation termed the 'missing heritability problem'. Several sources for the missing heritability have been proposed, including the contribution of many common variants with small individual effect sizes, which cannot be reliably found using the standard GWAS approach...
May 1, 2012: Human Molecular Genetics
Luis B Barreiro, Ludovic Tailleux, Athma A Pai, Brigitte Gicquel, John C Marioni, Yoav Gilad
Tuberculosis (TB) is a major public health problem. One-third of the world's population is estimated to be infected with Mycobacterium tuberculosis (MTB), the etiological agent causing TB, and active disease kills nearly 2 million individuals worldwide every year. Several lines of evidence indicate that interindividual variation in susceptibility to TB has a heritable component, yet we still know little about the underlying genetic architecture. To address this, we performed a genome-wide mapping study of loci that are associated with functional variation in immune response to MTB...
January 24, 2012: Proceedings of the National Academy of Sciences of the United States of America
Athma A Pai, Jordana T Bell, John C Marioni, Jonathan K Pritchard, Yoav Gilad
The modification of DNA by methylation is an important epigenetic mechanism that affects the spatial and temporal regulation of gene expression. Methylation patterns have been described in many contexts within and across a range of species. However, the extent to which changes in methylation might underlie inter-species differences in gene regulation, in particular between humans and other primates, has not yet been studied. To this end, we studied DNA methylation patterns in livers, hearts, and kidneys from multiple humans and chimpanzees, using tissue samples for which genome-wide gene expression data were also available...
February 2011: PLoS Genetics
Klara Stefflova, Matthew C Dulik, Jill S Barnholtz-Sloan, Athma A Pai, Amy H Walker, Timothy R Rebbeck
BACKGROUND: The ancestry of African-descended Americans is known to be drawn from three distinct populations: African, European, and Native American. While many studies consider this continental admixture, few account for the genetically distinct sources of ancestry within Africa--the continent with the highest genetic variation. Here, we dissect the within-Africa genetic ancestry of various populations of the Americas self-identified as having primarily African ancestry using uniparentally inherited mitochondrial DNA...
2011: PloS One
Jordana T Bell, Athma A Pai, Joseph K Pickrell, Daniel J Gaffney, Roger Pique-Regi, Jacob F Degner, Yoav Gilad, Jonathan K Pritchard
BACKGROUND: DNA methylation is an essential epigenetic mechanism involved in gene regulation and disease, but little is known about the mechanisms underlying inter-individual variation in methylation profiles. Here we measured methylation levels at 22,290 CpG dinucleotides in lymphoblastoid cell lines from 77 HapMap Yoruba individuals, for which genome-wide gene expression and genotype data were also available. RESULTS: Association analyses of methylation levels with more than three million common single nucleotide polymorphisms (SNPs) identified 180 CpG-sites in 173 genes that were associated with nearby SNPs (putatively in cis, usually within 5 kb) at a false discovery rate of 10%...
2011: Genome Biology
Joseph K Pickrell, Athma A Pai, Yoav Gilad, Jonathan K Pritchard
While the majority of multiexonic human genes show some evidence of alternative splicing, it is unclear what fraction of observed splice forms is functionally relevant. In this study, we examine the extent of alternative splicing in human cells using deep RNA sequencing and de novo identification of splice junctions. We demonstrate the existence of a large class of low abundance isoforms, encompassing approximately 150,000 previously unannotated splice junctions in our data. Newly-identified splice sites show little evidence of evolutionary conservation, suggesting that the majority are due to erroneous splice site choice...
2010: PLoS Genetics
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