Genetic effects on gene expression across human tissues

Characterization of the molecular function of the human genome and its variation across individuals is essential for identifying the cellular mechanisms that underlie human genetic traits and diseases. The Genotype-Tissue Expression (GTEx) project aims to characterize variation in gene expression levels across individuals and diverse tissues of the human body, many of which are not easily accessible. Here we describe genetic effects on gene expression levels across 44 human tissues. We find that local genetic variation affects gene expression levels for the majority of genes, and we further identify inter-chromosomal genetic effects for 93 genes and 112 loci. On the basis of the identified genetic effects, we characterize patterns of tissue specificity, compare local and distal effects, and evaluate the functional properties of the genetic effects. We also demonstrate that multi-tissue, multi-individual data can be used to identify genes and pathways affected by human disease-associated variation, enabling a mechanistic interpretation of gene regulation and the genetic basis of diseas

Integrated pest management of Tuta absoluta: practical implementations across different world regions

The South American tomato pinworm, Tuta absoluta (Meyrick) (Lepidoptera: Gelechiidae), has invaded most Afro-Eurasian countries and is threatening worldwide tomato production. Various strategies have been developed and implemented to manage this pest. Here, we present a timely review on the up-to-date development and practical implementation of integrated pest management (IPM) programs for tomato crops across different world regions infested by T. absoluta. While insecticide resistance is a growing concern, biological control via releasing or conserving arthropod natural enemies and sex pheromone-based biotechnical control are the most successful management practices. Agronomic control-related research is an emerging area where the soil fertilization and/or irrigation, as well as breeding of resistant cultivars, has the potential to enhance IPM effectiveness. Grower survey responses in the native areas (i.e., South America), early-invaded areas (i.e., first report between 2006 and 2012) and newly invaded areas (i.e., first report after 2012) showed that the control programs evolved along with the areas and time since invasion. Growers in the early-invaded areas shifted more rapidly from chemical control to biological control compared to those from the native area. In all concerned regions, the pest control failure risk following chemical insecticide applications and the high cost associated with either biological or biotechnical control methods have been the greatest concerns for growers. The information gathered from the native and/or early-invaded areas may help achieve a more effective management in newly invaded areas. Lastly, researchers are expected to break the bottlenecks of some key issues that would enable lowering application cost of novel biorational alternative management options

Population- and individual-specific regulatory variation in Sardinia

Genetic studies of complex traits have mainly identified associations with noncoding variants. To further determine the contribution of regulatory variation, we combined whole-genome and transcriptome data for 624 individuals from Sardinia to identify common and rare variants that influence gene expression and splicing. We identified 21,183 expression quantitative trait loci (eQTLs) and 6,768 splicing quantitative trait loci (sQTLs), including 619 new QTLs. We identified high-frequency QTLs and found evidence of selection near genes involved in malarial resistance and increased multiple sclerosis risk, reflecting the epidemiological history of Sardinia. Using family relationships, we identified 809 segregating expression outliers (median z score of 2.97), averaging 13.3 genes per individual. Outlier genes were enriched for proximal rare variants, providing a new approach to study large-effect regulatory variants and their relevance to traits. Our results provide insight into the effects of regulatory variants and their relationship to population history and individual genetic risk.M.P. is supported by the European Union’s Horizon 2020 Research and Innovation Programme under grant agreement 633964 (ImmunoAgeing). Z.Z. is supported by the National Science Foundation (NSF) GRFP (DGE- 114747) and by the Stanford Center for Computational, Evolutionary, and Human Genomics (CEHG). Z.Z., J.R.D., and G.T.H. also acknowledge support from the Stanford Genome Training Program (SGTP; NIH/NHGRI T32HG000044). J.R.D. is supported by the Stanford Graduate Fellowship. K.R.K. is supported by Department of Defense, Air Force Office of Scientific Research, National Defense Science and Engineering Graduate (NDSEQ) Fellowship 32 CFR 168a. S.J.S. is supported by the NIHR Cambridge Biomedical Research Centre. The SardiNIA project is supported in part by the intramural program of the National Institute on Aging through contract HHSN271201100005C to the Consiglio Nazionale delle Ricerche of Italy. The RNA sequencing was supported by the PB05 InterOmics MIUR Flagship grant; by the FaReBio2011 “Farmaci e Reti Biotecnologiche di Qualità” grant; and by Sardinian Autonomous Region (L.R. no. 7/2009) grant cRP3-154 to F. Cucca, who is also supported by the Italian Foundation for Multiple Sclerosis (FISM 2015/R/09) and by the Fondazione di Sardegna (ex Fondazione Banco di Sardegna, Prot. U1301.2015/AI.1157.BE Prat. 2015-1651). S.B.M. is supported by the US National Institutes of Health through R01HG008150, R01MH101814, U01HG007436, and U01HG009080. All of the authors would like to thank the CRS4 and the SCGPM for the computational infrastructure supporting this project

Genetic effects on gene expression across human tissues

Characterization of the molecular function of the human genome and its variation across individuals is essential for identifying the cellular mechanisms that underlie human genetic traits and diseases. The Genotype-Tissue Expression (GTEx) project aims to characterize variation in gene expression levels across individuals and diverse tissues of the human body, many of which are not easily accessible. Here we describe genetic effects on gene expression levels across 44 human tissues. We find that local genetic variation affects gene expression levels for the majority of genes, and we further identify inter-chromosomal genetic effects for 93 genes and 112 loci. On the basis of the identified genetic effects, we characterize patterns of tissue specificity, compare local and distal effects, and evaluate the functional properties of the genetic effects. We also demonstrate that multi-tissue, multi-individual data can be used to identify genes and pathways affected by human disease-associated variation, enabling a mechanistic interpretation of gene regulation and the genetic basis of disease

Hepatitis C virus infection in pregnancy.

Abstract: Objectives To evaluate the clinical aspects of hepatitis C virus (HCV) liver disease in anti-HCV+ve mothers, both during pregnancy and six months after delivery, and to assess the outcome of pregnancy. Setting Obstetric department for high risk pregnancies of the University of Padova, Italy. Participants Seventeen hundred consecutive pregnant women were studied. Methods Each woman underwent the following: 1. serological screening for hepatitis surface antigen (HBsAg), antibodies to HCV (anti-HCV), antibodies to human immunodeficiency virus type 1 (HIV1) within the first trimester of pregnancy; and 2. clinico-biochemical assessment in order to ascertain previous or active liver disease and risk factors for viral infections. Results Twenty-nine (1.7%) of the 1700 women were found anti-HCV positive. Eight of them had an associated positivity for HIV infection. HCV-RNA was positive in 64.2% of anti-HCV positive women. Liver function tests (included transaminases) were within the normal range in 27 mothers (both during and six months after delivery). Only 2/29 women had a slight increase in AST/ALT; liver biopsy in these cases was compatible with mild chronic active hepatitis. Tn all women the outcome of pregnancy was favourable (12/29 anti-HCV positive mothers underwent caesarean delivery for causes independent from HCV infection). Conclusions A substantial proportion of anti-HCV positive pregnant mothers, even if asymptomatic, have circulating HCV-RNA. The pregnancy does not induce a deterioration of liver disease, and vice versa, HCV infection does not increase the risk of obstetric complication

Quantitative in vitro and in vivo characterization of the human P32T mutant ITPase

International audienceHuman ITPase, encoded by the gene, and its orthologs (RdgB in and HAM1 in ) exclude noncanonical nucleoside triphosphates (NTPs) from NTP pools. Deoxyinosine triphosphate (dITP) and 2'-deoxy--6-hydroxylaminopurine triphosphate are both hydrolyzed by ITPase to yield the corresponding deoxynucleoside monophosphate and pyrophosphate. In addition, metabolites of thiopurine drugs such as azathioprine have been shown to be substrates for ITPase. The 94C>A [P32T] variant is one of two polymorphisms associated with decreased ITPase activity. Furthermore, the 94C>A [P32T] variant is associated with an increased risk of adverse drug reactions for patients treated with azathioprine. The nature of the observed phenotypes for 94C>A [P32T] variant individuals is currently unclear. Our biochemical assays indicate the P32T ITPase has 55% activity with dITP compared to wild-type ITPase. Complementation experiments at 37C show that -6-hydroxylaminopurine sensitivity of mutants is reduced with a plasmid bearing the 94C>A [P32T] gene approximately 50% less than with a plasmid bearing the wild-type gene. The reduction in sensitivity is less at 42C. Experiments with synthetic lethal (ts) mutants show that the 94C>A [P32T] gene also complements the (ts) growth deficiency at 42C approximately 40% lower than wild-type gene Western blot analysis indicates the expression level of P32T ITPase is reduced in these cells relative to wild-type. Our data support the idea that P32T ITPase is a functional protein, albeit with a reduced rate of noncanonical NTP pyrophosphohydrolase activity and reduced protein stability