Gordon JI

References (12)

Title : Genetic determinants of in vivo fitness and diet responsiveness in multiple human gut Bacteroides - Wu_2015_Science_350_aac5992
Author(s) : Wu M , McNulty NP , Rodionov DA , Khoroshkin MS , Griffin NW , Cheng J , Latreille P , Kerstetter RA , Terrapon N , Henrissat B , Osterman AL , Gordon JI
Ref : Science , 350 :aac5992 , 2015
Abstract : Libraries of tens of thousands of transposon mutants generated from each of four human gut Bacteroides strains, two representing the same species, were introduced simultaneously into gnotobiotic mice together with 11 other wild-type strains to generate a 15-member artificial human gut microbiota. Mice received one of two distinct diets monotonously, or both in different ordered sequences. Quantifying the abundance of mutants in different diet contexts allowed gene-level characterization of fitness determinants, niche, stability, and resilience and yielded a prebiotic (arabinoxylan) that allowed targeted manipulation of the community. The approach described is generalizable and should be useful for defining mechanisms critical for sustaining and/or approaches for deliberately reconfiguring the highly adaptive and durable relationship between the human gut microbiota and host in ways that promote wellness.
ESTHER : Wu_2015_Science_350_aac5992
PubMedSearch : Wu_2015_Science_350_aac5992
PubMedID: 26430127
Gene_locus related to this paper: bactn-BT2379 , 9bace-a0a0p0g3y7

Title : Bacteria from diverse habitats colonize and compete in the mouse gut - Seedorf_2014_Cell_159_253
Author(s) : Seedorf H , Griffin NW , Ridaura VK , Reyes A , Cheng J , Rey FE , Smith MI , Simon GM , Scheffrahn RH , Woebken D , Spormann AM , Van Treuren W , Ursell LK , Pirrung M , Robbins-Pianka A , Cantarel BL , Lombard V , Henrissat B , Knight R , Gordon JI
Ref : Cell , 159 :253 , 2014
Abstract : To study how microbes establish themselves in a mammalian gut environment, we colonized germ-free mice with microbial communities from human, zebrafish, and termite guts, human skin and tongue, soil, and estuarine microbial mats. Bacteria from these foreign environments colonized and persisted in the mouse gut; their capacity to metabolize dietary and host carbohydrates and bile acids correlated with colonization success. Cohousing mice harboring these xenomicrobiota or a mouse cecal microbiota, along with germ-free "bystanders," revealed the success of particular bacterial taxa in invading guts with established communities and empty gut habitats. Unanticipated patterns of ecological succession were observed; for example, a soil-derived bacterium dominated even in the presence of bacteria from other gut communities (zebrafish and termite), and human-derived bacteria colonized germ-free bystander mice before mouse-derived organisms. This approach can be generalized to address a variety of mechanistic questions about succession, including succession in the context of microbiota-directed therapeutics.
ESTHER : Seedorf_2014_Cell_159_253
PubMedSearch : Seedorf_2014_Cell_159_253
PubMedID: 25284151
Gene_locus related to this paper: 9firm-a0a0j1g143

Title : The impact of a consortium of fermented milk strains on the gut microbiome of gnotobiotic mice and monozygotic twins - McNulty_2011_Sci.Transl.Med_3_106ra106
Author(s) : McNulty NP , Yatsunenko T , Hsiao A , Faith JJ , Muegge BD , Goodman AL , Henrissat B , Oozeer R , Cools-Portier S , Gobert G , Chervaux C , Knights D , Lozupone CA , Knight R , Duncan AE , Bain JR , Muehlbauer MJ , Newgard CB , Heath AC , Gordon JI
Ref : Sci Transl Med , 3 :106ra106 , 2011
Abstract : Understanding how the human gut microbiota and host are affected by probiotic bacterial strains requires carefully controlled studies in humans and in mouse models of the gut ecosystem where potentially confounding variables that are difficult to control in humans can be constrained. Therefore, we characterized the fecal microbiomes and metatranscriptomes of adult female monozygotic twin pairs through repeated sampling 4 weeks before, 7 weeks during, and 4 weeks after consumption of a commercially available fermented milk product (FMP) containing a consortium of Bifidobacterium animalis subsp. lactis, two strains of Lactobacillus delbrueckii subsp. bulgaricus, Lactococcus lactis subsp. cremoris, and Streptococcus thermophilus. In addition, gnotobiotic mice harboring a 15-species model human gut microbiota whose genomes contain 58,399 known or predicted protein-coding genes were studied before and after gavage with all five sequenced FMP strains. No significant changes in bacterial species composition or in the proportional representation of genes encoding known enzymes were observed in the feces of humans consuming the FMP. Only minimal changes in microbiota configuration were noted in mice after single or repeated gavage with the FMP consortium. However, RNA-Seq analysis of fecal samples and follow-up mass spectrometry of urinary metabolites disclosed that introducing the FMP strains into mice results in significant changes in expression of microbiome-encoded enzymes involved in numerous metabolic pathways, most prominently those related to carbohydrate metabolism. B. animalis subsp. lactis, the dominant persistent member of the FMP consortium in gnotobiotic mice, up-regulates a locus in vivo that is involved in the catabolism of xylooligosaccharides, a class of glycans widely distributed in fruits, vegetables, and other foods, underscoring the importance of these sugars to this bacterial species. The human fecal metatranscriptome exhibited significant changes, confined to the period of FMP consumption, that mirror changes in gnotobiotic mice, including those related to plant polysaccharide metabolism. These experiments illustrate a translational research pipeline for characterizing the effects of FMPs on the human gut microbiome.
ESTHER : McNulty_2011_Sci.Transl.Med_3_106ra106
PubMedSearch : McNulty_2011_Sci.Transl.Med_3_106ra106
PubMedID: 22030749
Gene_locus related to this paper: lacda-q1g8l1 , lacdl-pip , lacla-menX

Title : Characterizing a model human gut microbiota composed of members of its two dominant bacterial phyla - Mahowald_2009_Proc.Natl.Acad.Sci.U.S.A_106_5859
Author(s) : Mahowald MA , Rey FE , Seedorf H , Turnbaugh PJ , Fulton RS , Wollam A , Shah N , Wang C , Magrini V , Wilson RK , Cantarel BL , Coutinho PM , Henrissat B , Crock LW , Russell A , VerBerkmoes NC , Hettich RL , Gordon JI
Ref : Proc Natl Acad Sci U S A , 106 :5859 , 2009
Abstract : The adult human distal gut microbial community is typically dominated by 2 bacterial phyla (divisions), the Firmicutes and the Bacteroidetes. Little is known about the factors that govern the interactions between their members. Here, we examine the niches of representatives of both phyla in vivo. Finished genome sequences were generated from Eubacterium rectale and E. eligens, which belong to Clostridium Cluster XIVa, one of the most common gut Firmicute clades. Comparison of these and 25 other gut Firmicutes and Bacteroidetes indicated that the Firmicutes possess smaller genomes and a disproportionately smaller number of glycan-degrading enzymes. Germ-free mice were then colonized with E. rectale and/or a prominent human gut Bacteroidetes, Bacteroides thetaiotaomicron, followed by whole-genome transcriptional profiling, high-resolution proteomic analysis, and biochemical assays of microbial-microbial and microbial-host interactions. B. thetaiotaomicron adapts to E. rectale by up-regulating expression of a variety of polysaccharide utilization loci encoding numerous glycoside hydrolases, and by signaling the host to produce mucosal glycans that it, but not E. rectale, can access. E. rectale adapts to B. thetaiotaomicron by decreasing production of its glycan-degrading enzymes, increasing expression of selected amino acid and sugar transporters, and facilitating glycolysis by reducing levels of NADH, in part via generation of butyrate from acetate, which in turn is used by the gut epithelium. This simplified model of the human gut microbiota illustrates niche specialization and functional redundancy within members of its major bacterial phyla, and the importance of host glycans as a nutrient foundation that ensures ecosystem stability.
ESTHER : Mahowald_2009_Proc.Natl.Acad.Sci.U.S.A_106_5859
PubMedSearch : Mahowald_2009_Proc.Natl.Acad.Sci.U.S.A_106_5859
PubMedID: 19321416
Gene_locus related to this paper: eube2-c4z2j4 , eube2-c4z5d5 , eube2-c4z6k4 , eube2-c4z179 , eube2-c4z180 , eubr3-c4z8a6 , eubr3-c4zfm2 , eubr3-c4zhp3 , eubr3-c4zf28

Title : Evolution of symbiotic bacteria in the distal human intestine - Xu_2007_PLoS.Biol_5_e156
Author(s) : Xu J , Mahowald MA , Ley RE , Lozupone CA , Hamady M , Martens EC , Henrissat B , Coutinho PM , Minx P , Latreille P , Cordum H , Van Brunt A , Kim K , Fulton RS , Fulton LA , Clifton SW , Wilson RK , Knight RD , Gordon JI
Ref : PLoS Biol , 5 :e156 , 2007
Abstract : The adult human intestine contains trillions of bacteria, representing hundreds of species and thousands of subspecies. Little is known about the selective pressures that have shaped and are shaping this community's component species, which are dominated by members of the Bacteroidetes and Firmicutes divisions. To examine how the intestinal environment affects microbial genome evolution, we have sequenced the genomes of two members of the normal distal human gut microbiota, Bacteroides vulgatus and Bacteroides distasonis, and by comparison with the few other sequenced gut and non-gut Bacteroidetes, analyzed their niche and habitat adaptations. The results show that lateral gene transfer, mobile elements, and gene amplification have played important roles in affecting the ability of gut-dwelling Bacteroidetes to vary their cell surface, sense their environment, and harvest nutrient resources present in the distal intestine. Our findings show that these processes have been a driving force in the adaptation of Bacteroidetes to the distal gut environment, and emphasize the importance of considering the evolution of humans from an additional perspective, namely the evolution of our microbiomes.
ESTHER : Xu_2007_PLoS.Biol_5_e156
PubMedSearch : Xu_2007_PLoS.Biol_5_e156
PubMedID: 17579514
Gene_locus related to this paper: 9bace-b6w170 , 9bace-c6z6f2 , 9bace-e1z049 , 9porp-c7xbp3 , 9porp-c7xci2 , 9porp-c7xdx2 , bacv8-a6kwf6 , bacv8-a6kzc1 , bacv8-a6kze8 , bacv8-a6l0d9 , bacv8-a6l1d0 , bacv8-a6l1u9 , bacv8-a6l7p9 , bacv8-a6l7w1 , bacv8-a6l018 , bacv8-a6l378 , bacv8-a6l415 , bacv8-a6l715 , pard8-a6lc23 , pard8-a6lca7 , pard8-a6ld87 , pard8-a6le10 , pard8-a6le63 , pard8-a6lfj2 , pard8-a6lgh2 , pard8-a6lgi6 , pard8-a6lgn7 , pard8-a6lhe1 , pard8-a6li91 , bacv8-a6l3w9

Title : Genomic and metabolic adaptations of Methanobrevibacter smithii to the human gut - Samuel_2007_Proc.Natl.Acad.Sci.U.S.A_104_10643
Author(s) : Samuel BS , Hansen EE , Manchester JK , Coutinho PM , Henrissat B , Fulton R , Latreille P , Kim K , Wilson RK , Gordon JI
Ref : Proc Natl Acad Sci U S A , 104 :10643 , 2007
Abstract : The human gut is home to trillions of microbes, thousands of bacterial phylotypes, as well as hydrogen-consuming methanogenic archaea. Studies in gnotobiotic mice indicate that Methanobrevibacter smithii, the dominant archaeon in the human gut ecosystem, affects the specificity and efficiency of bacterial digestion of dietary polysaccharides, thereby influencing host calorie harvest and adiposity. Metagenomic studies of the gut microbial communities of genetically obese mice and their lean littermates have shown that the former contain an enhanced representation of genes involved in polysaccharide degradation, possess more archaea, and exhibit a greater capacity to promote adiposity when transplanted into germ-free recipients. These findings have led to the hypothesis that M. smithii may be a therapeutic target for reducing energy harvest in obese humans. To explore this possibility, we have sequenced its 1,853,160-bp genome and compared it to other human gut-associated M. smithii strains and other Archaea. We have also examined M. smithii's transcriptome and metabolome in gnotobiotic mice that do or do not harbor Bacteroides thetaiotaomicron, a prominent saccharolytic bacterial member of our gut microbiota. Our results indicate that M. smithii is well equipped to persist in the distal intestine through (i) production of surface glycans resembling those found in the gut mucosa, (ii) regulated expression of adhesin-like proteins, (iii) consumption of a variety of fermentation products produced by saccharolytic bacteria, and (iv) effective competition for nitrogenous nutrient pools. These findings provide a framework for designing strategies to change the representation and/or properties of M. smithii in the human gut microbiota.
ESTHER : Samuel_2007_Proc.Natl.Acad.Sci.U.S.A_104_10643
PubMedSearch : Samuel_2007_Proc.Natl.Acad.Sci.U.S.A_104_10643
PubMedID: 17563350
Gene_locus related to this paper: mets3-a5ujk2 , metsm-d2zrn4

Title : The complete genome sequence of a chronic atrophic gastritis Helicobacter pylori strain: evolution during disease progression - Oh_2006_Proc.Natl.Acad.Sci.U.S.A_103_9999
Author(s) : Oh JD , Kling-Backhed H , Giannakis M , Xu J , Fulton RS , Fulton LA , Cordum HS , Wang C , Elliott G , Edwards J , Mardis ER , Engstrand LG , Gordon JI
Ref : Proc Natl Acad Sci U S A , 103 :9999 , 2006
Abstract : Helicobacter pylori produces acute superficial gastritis in nearly all of its human hosts. However, a subset of individuals develops chronic atrophic gastritis (ChAG), a condition characterized in part by diminished numbers of acid-producing parietal cells and increased risk for development of gastric adenocarcinoma. Previously, we used a gnotobiotic transgenic mouse model with an engineered ablation of parietal cells to show that loss of parietal cells provides an opportunity for a H. pylori isolate from a patient with ChAG (HPAG1) to bind to, enter, and persist within gastric stem cells. This finding raises the question of how ChAG influences H. pylori genome evolution, physiology, and tumorigenesis. Here we describe the 1,596,366-bp HPAG1 genome. Custom HPAG1 Affymetrix GeneChips, representing 99.6% of its predicted ORFs, were used for whole-genome genotyping of additional H. pylori ChAG isolates obtained from Swedish patients enrolled in a case-control study of gastric cancer, as well as ChAG- and cancer-associated isolates from an individual who progressed from ChAG to gastric adenocarcinoma. The results reveal a shared gene signature among ChAG strains, as well as genes that may have been lost or gained during progression to adenocarcinoma. Whole-genome transcriptional profiling of HPAG1's response to acid during in vitro growth indicates that genes encoding components of metal uptake and utilization pathways, outer membrane proteins, and virulence factors are among those associated with H. pylori's adaptation to ChAG.
ESTHER : Oh_2006_Proc.Natl.Acad.Sci.U.S.A_103_9999
PubMedSearch : Oh_2006_Proc.Natl.Acad.Sci.U.S.A_103_9999
PubMedID: 16788065
Gene_locus related to this paper: helpy-o25061

Title : Identification of genes subject to positive selection in uropathogenic strains of Escherichia coli: a comparative genomics approach - Chen_2006_Proc.Natl.Acad.Sci.U.S.A_103_5977
Author(s) : Chen SL , Hung CS , Xu J , Reigstad CS , Magrini V , Sabo A , Blasiar D , Bieri T , Meyer RR , Ozersky P , Armstrong JR , Fulton RS , Latreille JP , Spieth J , Hooton TM , Mardis ER , Hultgren SJ , Gordon JI
Ref : Proc Natl Acad Sci U S A , 103 :5977 , 2006
Abstract : Escherichia coli is a model laboratory bacterium, a species that is widely distributed in the environment, as well as a mutualist and pathogen in its human hosts. As such, E. coli represents an attractive organism to study how environment impacts microbial genome structure and function. Uropathogenic E. coli (UPEC) must adapt to life in several microbial communities in the human body, and has a complex life cycle in the bladder when it causes acute or recurrent urinary tract infection (UTI). Several studies designed to identify virulence factors have focused on genes that are uniquely represented in UPEC strains, whereas the role of genes that are common to all E. coli has received much less attention. Here we describe the complete 5,065,741-bp genome sequence of a UPEC strain recovered from a patient with an acute bladder infection and compare it with six other finished E. coli genome sequences. We searched 3,470 ortholog sets for genes that are under positive selection only in UPEC strains. Our maximum likelihood-based analysis yielded 29 genes involved in various aspects of cell surface structure, DNA metabolism, nutrient acquisition, and UTI. These results were validated by resequencing a subset of the 29 genes in a panel of 50 urinary, periurethral, and rectal E. coli isolates from patients with UTI. These studies outline a computational approach that may be broadly applicable for studying strain-specific adaptation and pathogenesis in other bacteria.
ESTHER : Chen_2006_Proc.Natl.Acad.Sci.U.S.A_103_5977
PubMedSearch : Chen_2006_Proc.Natl.Acad.Sci.U.S.A_103_5977
PubMedID: 16585510
Gene_locus related to this paper: ecoli-Aes , ecoli-rutD , ecoli-bioh , ecoli-C0410 , ecoli-C2429 , ecoli-C2451 , ecoli-C4836 , ecoli-dlhh , ecoli-entf , ecoli-fes , ecoli-IROD , ecoli-IROE , ecoli-pldb , ecoli-ptrb , ecoli-yafa , ecoli-yaim , ecoli-ybff , ecoli-ycfp , ecoli-ycjy , ecoli-yeiG , ecoli-YFBB , ecoli-yghX , ecoli-yhet , ecoli-yiel , ecoli-yjfp , ecoli-YNBC , ecoli-ypfh , ecoli-ypt1 , ecoli-yqia , ecoli-YfhR , ecout-q1r7l6 , yerpe-YBTT

Title : A genomic view of the human-Bacteroides thetaiotaomicron symbiosis - Xu_2003_Science_299_2074
Author(s) : Xu J , Bjursell MK , Himrod J , Deng S , Carmichael LK , Chiang HC , Hooper LV , Gordon JI
Ref : Science , 299 :2074 , 2003
Abstract : The human gut is colonized with a vast community of indigenous microorganisms that help shape our biology. Here, we present the complete genome sequence of the Gram-negative anaerobe Bacteroides thetaiotaomicron, a dominant member of our normal distal intestinal microbiota. Its 4779-member proteome includes an elaborate apparatus for acquiring and hydrolyzing otherwise indigestible dietary polysaccharides and an associated environment-sensing system consisting of a large repertoire of extracytoplasmic function sigma factors and one- and two-component signal transduction systems. These and other expanded paralogous groups shed light on the molecular mechanisms underlying symbiotic host-bacterial relationships in our intestine.
ESTHER : Xu_2003_Science_299_2074
PubMedSearch : Xu_2003_Science_299_2074
PubMedID: 12663928
Gene_locus related to this paper: bacth-BT1008 , bacth-BT1087 , bacth-BT1121 , bacth-BT1192 , bacth-BT1400 , bacth-BT1838 , bacth-BT2436 , bacth-BT3100 , bacth-BT4214 , bactn-BT0152 , bactn-BT0587 , bactn-BT1114 , bactn-BT1261 , bactn-BT2379 , bactn-BT2525 , bactn-BT3084 , bactn-BT3112 , bactn-BT3254 , bactn-BT3286 , bactn-BT3608 , bactn-BT4077 , bactn-BT4193 , bactn-q8a7t0

Title : Tissue-specific expression, developmental regulation, and chromosomal mapping of the lecithin: cholesterol acyltransferase gene. Evidence for expression in brain and testes as well as liver - Warden_1989_J.Biol.Chem_264_21573
Author(s) : Warden CH , Langner CA , Gordon JI , Taylor BA , McLean JW , Lusis AJ
Ref : Journal of Biological Chemistry , 264 :21573 , 1989
Abstract : Lecithin:cholesterol acyltransferase (LCAT) catalyzes the esterification of cholesterol in high density lipoproteins, thereby facilitating transport of excess cholesterol from peripheral tissues to liver. We report here studies of the developmental, dietary, and genetic control of LCAT gene expression. In adult male Sprague-Dawley rats fed a standard chow diet LCAT mRNA was most abundant in liver, a major source of the plasma enzyme, but appreciable levels were also present in brain and testes. Since both brain and testes are isolated from blood by tight cellular barriers, undoubtedly greatly reducing the level of plasma-derived LCAT in cerebrospinal fluid and testes, the production of LCAT in these tissues may be important for removal of excess cholesterol. Noteworthy changes in the expression of LCAT mRNA were observed during development of both rodents and humans. On the other hand, LCAT mRNA levels were relatively resistant to dietary challenge or to drugs affecting cholesterol metabolism. Since human epidemiological studies have suggested an association between LCAT levels and variations of high density lipoprotein cholesterol, we examined LCAT gene polymorphisms in a mouse animal model. Mapping of the LCAT gene (Lcat) to mouse Chromosome 8 within 2 centimorgans of the Es-2 locus indicates that it does not correspond to any previously mapped loci affecting high density lipoprotein phenotypes in the mouse.
ESTHER : Warden_1989_J.Biol.Chem_264_21573
PubMedSearch : Warden_1989_J.Biol.Chem_264_21573
PubMedID: 2600083
Gene_locus related to this paper: mouse-lcat

Title : The fatty liver dystrophy (fld) mutation. A new mutant mouse with a developmental abnormality in triglyceride metabolism and associated tissue-specific defects in lipoprotein lipase and hepatic lipase activities - Langner_1989_J.Biol.Chem_264_7994
Author(s) : Langner CA , Birkenmeier EH , Ben-Zeev O , Schotz MC , Sweet HO , Davisson MT , Gordon JI
Ref : Journal of Biological Chemistry , 264 :7994 , 1989
Abstract : An autosomal recessive mutation, termed fatty liver dystrophy (fld), can be identified in neonatal mice by their enlarged and fatty liver (Sweet, H. O., Birkenmeier, E. H., and Davisson, M. T. (1988) Mouse News Letter 81, 69). We have examined the underlying metabolic abnormalities in fld/fld mice from postnatal days 3-40. Serum and hepatic triglyceride levels were elevated 5-fold in suckling fld/fld mice compared to their +/? littermates but abruptly resolved at the suckling/weaning transition. Blot hybridization analysis of liver and intestinal RNAs revealed a liver-specific increase in apolipoprotein (apo) A-IV and C-II mRNA concentrations (100- and 6-fold, respectively) that was limited to the suckling and early weaning stages in fld/fld mice. Resolution of these differences during the weaning period could not be delayed by prolonging suckling to the 20th postnatal day nor could the mutant phenotype be elicited in young adult animals with a high fat diet. Lipoprotein lipase (LPL) activity was reduced 16-fold in the white adipose tissue of fld/fld mice until the onset of weaning. Heart activity was decreased less than 2-fold, but there were no deficits in brown adipose tissue or liver. Hepatic lipase (HL) mRNA levels and activity were significantly reduced in fld/fld livers and sera, respectively, during the suckling period. Mapping studies show the fld locus to be distinct from loci encoding LPL, HL, and apoA-IV, and those responsible for the combined lipase deficiencies in cld/cld and W/Wv mice. These data suggest that the fld mutation is associated with developmentally programmed tissue-specific defects in the neonatal expression of LPL and HL activities and provide evidence for a new regulatory locus which affects these lipase activities. This mutation could serve as a useful model for (i) analyzing the homeostatic mechanisms controlling lipid metabolism in newborn mice and (ii) understanding and treating certain inborn errors in human triglyceride metabolism.
ESTHER : Langner_1989_J.Biol.Chem_264_7994
PubMedSearch : Langner_1989_J.Biol.Chem_264_7994
PubMedID: 2722772

Title : Genetic and developmental regulation of the lipoprotein lipase gene: loci both distal and proximal to the lipoprotein lipase structural gene control enzyme expression - Kirchgessner_1989_J.Biol.Chem_264_1473
Author(s) : Kirchgessner TG , LeBoeuf RC , Langner CA , Zollman S , Chang CH , Taylor BA , Schotz MC , Gordon JI , Lusis AJ
Ref : Journal of Biological Chemistry , 264 :1473 , 1989
Abstract : We report here a study of the developmental and genetic control of tissue-specific expression of lipoprotein lipase, the enzyme responsible for hydrolysis of triglycerides in chylomicrons and very low density lipoproteins. Lipoprotein lipase (LPL) mRNA is present in a wide variety of adult rat and mouse tissues examined, albeit at very different levels. A remarkable increase in the levels of LPL mRNA occurs in heart over a period of several weeks following birth, closely paralleling developmental changes in lipase activity and myocardial beta-oxidation capacity. Large increases in LPL mRNA also occur during differentiation of 3T3L1 cells to adipocytes. As previously reported, at least two separate genetic loci control the tissue-specific expression of LPL activity in mice. One of the loci, controlling LPL activity in heart, is associated with an alteration in LPL mRNA size, while the other, controlling LPL activity in adipose tissue, appears to affect the translation or post-translational expression of LPL. To examine whether these genetic variations are due to mutations of the LPL structural locus, we mapped the LPL gene to a region of mouse chromosome 8 using restriction fragment-length polymorphisms and analysis of hamster-mouse somatic cell hybrids. This region is homologous to the region of human chromosome 8 which contains the human LPL gene as judged by the conservation of linked genetic markers. Genetic variations affecting LPL expression in heart cosegregated with the LPL gene, while variations affecting LPL expression in adipose tissue did not. Furthermore, Southern blotting analysis indicates that LPL is encoded by a single gene and, thus, the genetic differences are not a consequence of independent regulation of two separate genes in the two tissues. These results suggest the existence of cis-acting elements for LPL gene expression that operate in heart but not adipose tissue. Our results also indicate that two genetic mutations resulting in deficiencies of LPL in mice, the W mutation on chromosome 5 and the cld mutation on mouse chromosome 17, do not involve the LPL structural gene locus. Finally, we show that the gene for hepatic lipase, a member of a gene family with LPL, is unlinked to the gene for LPL. This indicates that combined deficiencies of LPL and hepatic lipase, observed in humans as well as in certain mutant strains of mice, do not result from focal disruptions of a cluster of lipase genes.
ESTHER : Kirchgessner_1989_J.Biol.Chem_264_1473
PubMedSearch : Kirchgessner_1989_J.Biol.Chem_264_1473
PubMedID: 2563260
Gene_locus related to this paper: mouse-1hlip