Mammalian genome : official journal of the International Mammalian Genome Society最新文献

{"title":"Population-based dose-response analysis of liver transcriptional response to trichloroethylene in mouse.","authors":"Abhishek Venkatratnam,&nbsp;John S House,&nbsp;Kranti Konganti,&nbsp;Connor McKenney,&nbsp;David W Threadgill,&nbsp;Weihsueh A Chiu,&nbsp;David L Aylor,&nbsp;Fred A Wright,&nbsp;Ivan Rusyn","doi":"10.1007/s00335-018-9734-y","DOIUrl":"https://doi.org/10.1007/s00335-018-9734-y","url":null,"abstract":"<p><p>Studies of gene expression are common in toxicology and provide important clues to mechanistic understanding of adverse effects of chemicals. Most prior studies have been performed in a single strain or cell line; however, gene expression is heavily influenced by the genetic background, and these genotype-expression differences may be key drivers of inter-individual variation in response to chemical toxicity. In this study, we hypothesized that the genetically diverse Collaborative Cross mouse population can be used to gain insight and suggest mechanistic hypotheses for the dose- and genetic background-dependent effects of chemical exposure. This hypothesis was tested using a model liver toxicant trichloroethylene (TCE). Liver transcriptional responses to TCE exposure were evaluated 24 h after dosing. Transcriptomic dose-responses were examined for both TCE and its major oxidative metabolite trichloroacetic acid (TCA). As expected, peroxisome- and fatty acid metabolism-related pathways were among the most dose-responsive enriched pathways in all strains. However, nearly half of the TCE-induced liver transcriptional perturbation was strain-dependent, with abundant evidence of strain/dose interaction, including in the peroxisomal signaling-associated pathways. These effects were highly concordant between the administered TCE dose and liver levels of TCA. Dose-response analysis of gene expression at the pathway level yielded points of departure similar to those derived from the traditional toxicology studies for both non-cancer and cancer effects. Mapping of expression-genotype-dose relationships revealed some significant associations; however, the effects of TCE on gene expression in liver appear to be highly polygenic traits that are challenging to positionally map. This study highlights the usefulness of mouse population-based studies in assessing inter-individual variation in toxicological responses, but cautions that genetic mapping may be challenging because of the complexity in gene exposure-dose relationships.</p>","PeriodicalId":412165,"journal":{"name":"Mammalian genome : official journal of the International Mammalian Genome Society","volume":" ","pages":"168-181"},"PeriodicalIF":2.5,"publicationDate":"2018-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/s00335-018-9734-y","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35754378","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic variation in sensitivity to estrogens and breast cancer risk.","authors":"D Joseph Jerry,&nbsp;James D Shull,&nbsp;Darryl L Hadsell,&nbsp;Monique Rijnkels,&nbsp;Karen A Dunphy,&nbsp;Sallie S Schneider,&nbsp;Laura N Vandenberg,&nbsp;Prabin Dhangada Majhi,&nbsp;Celia Byrne,&nbsp;Amy Trentham-Dietz","doi":"10.1007/s00335-018-9741-z","DOIUrl":"https://doi.org/10.1007/s00335-018-9741-z","url":null,"abstract":"<p><p>Breast cancer risk is intimately intertwined with exposure to estrogens. While more than 160 breast cancer risk loci have been identified in humans, genetic interactions with estrogen exposure remain to be established. Strains of rodents exhibit striking differences in their responses to endogenous ovarian estrogens (primarily 17β-estradiol). Similar genetic variation has been observed for synthetic estrogen agonists (ethinyl estradiol) and environmental chemicals that mimic the actions of estrogens (xenoestrogens). This review of literature highlights the extent of variation in responses to estrogens among strains of rodents and compiles the genetic loci underlying pathogenic effects of excessive estrogen signaling. Genetic linkage studies have identified a total of the 35 quantitative trait loci (QTL) affecting responses to 17β-estradiol or diethylstilbestrol in five different tissues. However, the QTL appear to act in a tissue-specific manner with 9 QTL affecting the incidence or latency of mammary tumors induced by 17β-estradiol or diethylstilbestrol. Mammary gland development during puberty is also exquisitely sensitive to the actions of endogenous estrogens. Analysis of mammary ductal growth and branching in 43 strains of inbred mice identified 20 QTL. Regions in the human genome orthologous to the mammary development QTL harbor loci associated with breast cancer risk or mammographic density. The data demonstrate extensive genetic variation in regulation of estrogen signaling in rodent mammary tissues that alters susceptibility to tumors. Genetic variants in these pathways may identify a subset of women who are especially sensitive to either endogenous estrogens or environmental xenoestrogens and render them at increased risk of breast cancer.</p>","PeriodicalId":412165,"journal":{"name":"Mammalian genome : official journal of the International Mammalian Genome Society","volume":" ","pages":"24-37"},"PeriodicalIF":2.5,"publicationDate":"2018-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/s00335-018-9741-z","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35869211","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Voluntary exposure to a toxin: the genetic influence on ethanol consumption.","authors":"Paula L Hoffman,&nbsp;Laura M Saba,&nbsp;Lauren A Vanderlinden,&nbsp;Boris Tabakoff","doi":"10.1007/s00335-017-9726-3","DOIUrl":"https://doi.org/10.1007/s00335-017-9726-3","url":null,"abstract":"<p><p>Ethyl alcohol is a toxin that, when consumed at high levels, produces organ damage and death. One way to prevent or ameliorate this damage in humans is to reduce the exposure of organs to alcohol by reducing alcohol ingestion. Both the propensity to consume large volumes of alcohol and the susceptibility of human organs to alcohol-induced damage exhibit a strong genetic influence. We have developed an integrative genetic/genomic approach to identify transcriptional networks that predispose complex traits, including propensity for alcohol consumption and propensity for alcohol-induced organ damage. In our approach, the phenotype is assessed in a panel of recombinant inbred (RI) rat strains, and quantitative trait locus (QTL) analysis is performed. Transcriptome data from tissues/organs of naïve RI rat strains are used to identify transcriptional networks using Weighted Gene Coexpression Network Analysis (WGCNA). Correlation of the first principal component of transcriptional coexpression modules with the phenotype across the rat strains, and overlap of QTLs for the phenotype and the QTLs for the coexpression modules (module eigengene QTL) provide the criteria for identification of the functionally related groups of genes that contribute to the phenotype (candidate modules). While we previously identified a brain transcriptional module whose QTL overlapped with a QTL for levels of alcohol consumption in HXB/BXH RI rat strains and 12 selected rat lines, this module did not account for all of the genetic variation in alcohol consumption. Our search for QTL overlap and correlation of coexpression modules with phenotype can, however, be applied to any organ in which the transcriptome has been measured, and this represents a holistic approach in the search for genetic contributors to complex traits. Previous work has implicated liver/brain interactions, particularly involving inflammatory/immune processes, as influencing alcohol consumption levels. We have now analyzed the liver transcriptome of the HXB/BXH RI rat panel in relation to the behavioral trait of alcohol consumption. We used RNA-Seq and microarray data to construct liver transcriptional networks, and identified a liver candidate transcriptional coexpression module that explained 24% of the genetic variance in voluntary alcohol consumption. The transcripts in this module focus attention on liver secretory products that influence inflammatory and immune signaling pathways. We propose that these liver secretory products can interact with brain mechanisms that affect alcohol consumption, and targeting these pathways provides a potential approach to reducing high levels of alcohol intake and also protecting the integrity of the liver and other organs.</p>","PeriodicalId":412165,"journal":{"name":"Mammalian genome : official journal of the International Mammalian Genome Society","volume":" ","pages":"128-140"},"PeriodicalIF":2.5,"publicationDate":"2018-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/s00335-017-9726-3","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35211331","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Introduction to mammalian genome special issue: the combined role of genetics and environment relevant to human disease outcomes.","authors":"Ivan Rusyn,&nbsp;Steven R Kleeberger,&nbsp;Kimberly A McAllister,&nbsp;John E French,&nbsp;Karen L Svenson","doi":"10.1007/s00335-018-9740-0","DOIUrl":"https://doi.org/10.1007/s00335-018-9740-0","url":null,"abstract":"","PeriodicalId":412165,"journal":{"name":"Mammalian genome : official journal of the International Mammalian Genome Society","volume":" ","pages":"1-4"},"PeriodicalIF":2.5,"publicationDate":"2018-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/s00335-018-9740-0","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35845197","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ageing in relation to skeletal muscle dysfunction: redox homoeostasis to regulation of gene expression.","authors":"Katarzyna Goljanek-Whysall, Lesley A Iwanejko, Aphrodite Vasilaki, Vanja Pekovic-Vaughan, Brian McDonagh","doi":"10.1007/s00335-016-9643-x","DOIUrl":"10.1007/s00335-016-9643-x","url":null,"abstract":"<p><p>Ageing is associated with a progressive loss of skeletal muscle mass, quality and function-sarcopenia, associated with reduced independence and quality of life in older generations. A better understanding of the mechanisms, both genetic and epigenetic, underlying this process would help develop therapeutic interventions to prevent, slow down or reverse muscle wasting associated with ageing. Currently, exercise is the only known effective intervention to delay the progression of sarcopenia. The cellular responses that occur in muscle fibres following exercise provide valuable clues to the molecular mechanisms regulating muscle homoeostasis and potentially the progression of sarcopenia. Redox signalling, as a result of endogenous generation of ROS/RNS in response to muscle contractions, has been identified as a crucial regulator for the adaptive responses to exercise, highlighting the redox environment as a potentially core therapeutic approach to maintain muscle homoeostasis during ageing. Further novel and attractive candidates include the manipulation of microRNA expression. MicroRNAs are potent gene regulators involved in the control of healthy and disease-associated biological processes and their therapeutic potential has been researched in the context of various disorders, including ageing-associated muscle wasting. Finally, we discuss the impact of the circadian clock on the regulation of gene expression in skeletal muscle and whether disruption of the peripheral muscle clock affects sarcopenia and altered responses to exercise. Interventions that include modifying altered redox signalling with age and incorporating genetic mechanisms such as circadian- and microRNA-based gene regulation, may offer potential effective treatments against age-associated sarcopenia.</p>","PeriodicalId":412165,"journal":{"name":"Mammalian genome : official journal of the International Mammalian Genome Society","volume":" ","pages":"341-57"},"PeriodicalIF":0.0,"publicationDate":"2016-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4935741/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34407075","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetics of aging bone.","authors":"Douglas J Adams,&nbsp;David W Rowe,&nbsp;Cheryl L Ackert-Bicknell","doi":"10.1007/s00335-016-9650-y","DOIUrl":"https://doi.org/10.1007/s00335-016-9650-y","url":null,"abstract":"<p><p>With aging, the skeleton experiences a number of changes, which include reductions in mass and changes in matrix composition, leading to fragility and ultimately an increase of fracture risk. A number of aspects of bone physiology are controlled by genetic factors, including peak bone mass, bone shape, and composition; however, forward genetic studies in humans have largely concentrated on clinically available measures such as bone mineral density (BMD). Forward genetic studies in rodents have also heavily focused on BMD; however, investigations of direct measures of bone strength, size, and shape have also been conducted. Overwhelmingly, these studies of the genetics of bone strength have identified loci that modulate strength via influencing bone size, and may not impact the matrix material properties of bone. Many of the rodent forward genetic studies lacked sufficient mapping resolution for candidate gene identification; however, newer studies using genetic mapping populations such as Advanced Intercrosses and the Collaborative Cross appear to have overcome this issue and show promise for future studies. The majority of the genetic mapping studies conducted to date have focused on younger animals and thus an understanding of the genetic control of age-related bone loss represents a key gap in knowledge.</p>","PeriodicalId":412165,"journal":{"name":"Mammalian genome : official journal of the International Mammalian Genome Society","volume":" ","pages":"367-80"},"PeriodicalIF":2.5,"publicationDate":"2016-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/s00335-016-9650-y","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34457928","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Platelet function and ageing.","authors":"Chris I Jones","doi":"10.1007/s00335-016-9629-8","DOIUrl":"https://doi.org/10.1007/s00335-016-9629-8","url":null,"abstract":"<p><p>There are clear age-related changes in platelet count and function, driven by changes in hematopoietic tissue, the composition of the blood and vascular health. Platelet count remains relatively stable during middle age (25-60 years old) but falls in older people. The effect of age on platelet function is slightly less clear. The longstanding view is that platelet reactivity increases with age in an almost linear fashion. There are, however, serious limitations to the data supporting this dogma. We can conclude that platelet function increases during middle age, but little evidence exists on the changes in platelet responsiveness in old age (>75 years old). This change in platelet function is driven by differential mRNA and microRNA expression, an increase in oxidative stress and changes in platelet receptors. These age-related changes in platelets are particularly pertinent given that thrombotic disease and use of anti-platelet drugs is much more prevalent in the elderly population, yet the majority of platelet research is carried out in young to middle-aged (20-50 years old) human volunteers and young mice (2-6 months old). We know relatively little about exactly how platelets from people over 75 years old differ from those of middle-aged subjects, and we know even less about the mechanisms that drive these changes. Addressing these gaps in our knowledge will provide substantial understanding in how cell signalling changes during ageing and will enable the development of more precise anti-platelet therapies.</p>","PeriodicalId":412165,"journal":{"name":"Mammalian genome : official journal of the International Mammalian Genome Society","volume":" ","pages":"358-66"},"PeriodicalIF":2.5,"publicationDate":"2016-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/s00335-016-9629-8","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34453497","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Mammalian Genome special issue on ageing.","authors":"Paul K Potter","doi":"10.1007/s00335-016-9652-9","DOIUrl":"10.1007/s00335-016-9652-9","url":null,"abstract":"","PeriodicalId":412165,"journal":{"name":"Mammalian genome : official journal of the International Mammalian Genome Society","volume":" ","pages":"257-8"},"PeriodicalIF":0.0,"publicationDate":"2016-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34470395","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cellular ageing mechanisms in osteoarthritis.","authors":"P K Sacitharan,&nbsp;T L Vincent","doi":"10.1007/s00335-016-9641-z","DOIUrl":"https://doi.org/10.1007/s00335-016-9641-z","url":null,"abstract":"<p><p>Age is the strongest independent risk factor for the development of osteoarthritis (OA) and for many years this was assumed to be due to repetitive microtrauma of the joint surface over time, the so-called 'wear and tear' arthritis. As our understanding of OA pathogenesis has become more refined, it has changed our appreciation of the role of ageing on disease. Cartilage breakdown in disease is not a passive process but one involving induction and activation of specific matrix-degrading enzymes; chondrocytes are exquisitely sensitive to changes in the mechanical, inflammatory and metabolic environment of the joint; cartilage is continuously adapting to these changes by altering its matrix. Ageing influences all of these processes. In this review, we will discuss how ageing affects tissue structure, joint use and the cellular metabolism. We describe what is known about pathways implicated in ageing in other model systems and discuss the potential value of targeting these pathways in OA.</p>","PeriodicalId":412165,"journal":{"name":"Mammalian genome : official journal of the International Mammalian Genome Society","volume":" ","pages":"421-9"},"PeriodicalIF":2.5,"publicationDate":"2016-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/s00335-016-9641-z","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34407073","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unraveling the message: insights into comparative genomics of the naked mole-rat.","authors":"Kaitlyn N Lewis,&nbsp;Ilya Soifer,&nbsp;Eugene Melamud,&nbsp;Margaret Roy,&nbsp;R Scott McIsaac,&nbsp;Matthew Hibbs,&nbsp;Rochelle Buffenstein","doi":"10.1007/s00335-016-9648-5","DOIUrl":"https://doi.org/10.1007/s00335-016-9648-5","url":null,"abstract":"<p><p>Animals have evolved to survive, and even thrive, in different environments. Genetic adaptations may have indirectly created phenotypes that also resulted in a longer lifespan. One example of this phenomenon is the preternaturally long-lived naked mole-rat. This strictly subterranean rodent tolerates hypoxia, hypercapnia, and soil-based toxins. Naked mole-rats also exhibit pronounced resistance to cancer and an attenuated decline of many physiological characteristics that often decline as mammals age. Elucidating mechanisms that give rise to their unique phenotypes will lead to better understanding of subterranean ecophysiology and biology of aging. Comparative genomics could be a useful tool in this regard. Since the publication of a naked mole-rat genome assembly in 2011, analyses of genomic and transcriptomic data have enabled a clearer understanding of mole-rat evolutionary history and suggested molecular pathways (e.g., NRF2-signaling activation and DNA damage repair mechanisms) that may explain the extraordinarily longevity and unique health traits of this species. However, careful scrutiny and re-analysis suggest that some identified features result from incorrect or imprecise annotation and assembly of the naked mole-rat genome: in addition, some of these conclusions (e.g., genes involved in cancer resistance and hairlessness) are rejected when the analysis includes additional, more closely related species. We describe how the combination of better study design, improved genomic sequencing techniques, and new bioinformatic and data analytical tools will improve comparative genomics and ultimately bridge the gap between traditional model and nonmodel organisms.</p>","PeriodicalId":412165,"journal":{"name":"Mammalian genome : official journal of the International Mammalian Genome Society","volume":" ","pages":"259-78"},"PeriodicalIF":2.5,"publicationDate":"2016-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/s00335-016-9648-5","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34624421","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}