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Results for “genetic dissection”

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At least 127 records · Page 7Linked to original sources
PubMed2000

Genetic dissection of a rat model for rheumatoid arthritis: significant gender influences on autosomal modifier loci.

Rheumatoid arthritis (RA) is a common, chronic, autoimmune, inflammatory disease that is influenced by genetic factors including gender. Many studies suggest that the genetic risk for RA is determined by the MHC, in particular class II alleles with a 'shared epitope' (SE), and multiple non-MHC loci. Other studies indicate that RA and other autoimmune diseases, in particular insulin-dependent diabetes mellitus (IDDM) and autoimmune thyroid disease (ATD), share genetic risk factors. Rat collagen-induced arthritis (CIA) is an experimental model with many features that resemble RA. The spontaneous diabetes-resistant bio-breeding rat, BB(DR), is of interest because it is susceptible to experimentally induced CIA, IDDM and ATD, and it has an SE in its MHC class II allele. To explore the genetics of CIA, including potential gender influences and the genetic relationships between CIA and other autoimmune diseases, we conducted a genome-wide scan for CIA regulatory loci in the F(2) progeny of BB(DR) and CIA-resistant BN rats. We identified 10 quantitative trait loci (QTLs), including 5 new ones (Cia15, Cia16*, Cia17, Cia18* and Cia19 on chromosomes 9, 10, 18 and two on the X chromosome, respectively), that regulated CIA severity. We also identified four QTLs, including two new ones (Ciaa4* and Ciaa5* on chromosomes 4 and 5, respectively), that regulated autoantibody titer to rat type II collagen. Many of these loci appeared to be gender influenced, and most co-localized with several other autoimmune trait loci. Our data support the view that multiple autoimmune diseases may share genetic risk factors, and suggest that many of these loci are gender influenced.

Animals↗
PubMed2005

Genetic dissection of immunity in leprosy.

Leprosy is a chronic infectious disease caused by Mycobacterium leprae that affects an estimated 700,000 new individuals each year. A strong contribution of host genetics to susceptibility to leprosy has long been suggested to account for the considerable variability observed between individuals exposed to M. leprae. As there is no relevant animal model for human leprosy, forward genetics is the main strategy used to identify the genes and, consequently, the immunological pathways involved in protective immunity to M. leprae. With respect to genome-wide screens, a major breakthrough has been reported this year; variants in the regulatory region shared by PARK2 and PACRG have been identified as being common risk factors for leprosy.

Chronic Disease↗
PubMed1998

Genetic dissection of the molecular target(s) of anesthetics with the gene knockout approach in mice.

Techniques have recently been developed that enable the creation of mice that harbor specific, predetermined genetic changes. These 'gene knockout mice', which contain a single genetic modification that is determined by the investigator, can subsequently be analyzed with tests that span the molecular, cellular, and behavioral levels. Application of such a multi-level approach to mechanisms of drug action should ultimately allow general anesthetic responses to be properly attributed to a molecular site.

Anesthetics↗
PubMed1970

Genetic dissection of the Drosophila nervous system by means of mosaics.

Given a mutant having abnormal behavior, the anatomical domain responsible for the deficit may be identified by the use of genetic mosaicism. Individuals may be produced in which a portion of the body is mutant male while the rest is normal female. In such sex mosaics, or gynandromorphs, the division line between normal and mutant parts can occur in various orientations. Mutants of five different genes (cistrons) on the X-chromosome of Drosophila melanogaster, having various abnormalities in visual function, have been tested by this method. All of these have been found to be autonomous, i.e., a mutant eye always functions abnormally, regardless of the amount of normal tissue present elsewhere, indicating that the primary causes of the behavioral deficits in these mutants are within the eye.

Drosophila↗
PubMed2003

Recombinant congenic strains of mice: a new tool for the genetic dissection of efficacy and toxicity of adjuvants.

The efficacy of immunization of a vaccine depends on an antigen, an adjuvant, and on the expression of multiple genes in the host. The responsiveness of various strains of mice to adjuvants is therefore dependent on their genetic background present as a complex, multigenic trait similarly as in man. We have recently developed a gene-discovery platform, termed recombinant congenic strains (RCS), that greatly facilitates the dissection, localization and characterization of genes that mediate complex traits such as responsiveness to adjuvants. These recombinant congenic mice, which were constructed from two progenitor strains (A/J and C57BL/6) that are phenotypically different for several spontaneous or infectious diseases, were generated such that they carry 13.5% of the one genome in 85% of the other genome. The use of these RCS mice therefore enables a more efficient identification of genes that mediate the responsiveness of the adjuvant.

Adjuvants, Immunologic↗
PubMed2001

Genomic and genetic dissection of an archaeal regulon.

The extremely halophilic archaeon Halobacterium sp. NRC-1 can grow phototrophically by means of light-driven proton pumping by bacteriorhodopsin in the purple membrane. Here, we show by genetic analysis of the wild type, and insertion and double-frame shift mutants of Bat that this transcriptional regulator coordinates synthesis of a structural protein and a chromophore for purple membrane biogenesis in response to both light and oxygen. Analysis of the complete Halobacterium sp. NRC-1 genome sequence showed that the regulatory site, upstream activator sequence (UAS), the putative binding site for Bat upstream of the bacterio-opsin gene (bop), is also present upstream to the other Bat-regulated genes. The transcription regulator Bat contains a photoresponsive cGMP-binding (GAF) domain, and a bacterial AraC type helix-turn-helix DNA binding motif. We also provide evidence for involvement of the PAS/PAC domain of Bat in redox-sensing activity by genetic analysis of a purple membrane overproducer. Five additional Bat-like putative regulatory genes were found, which together are likely to be responsible for orchestrating the complex response of this archaeon to light and oxygen. Similarities of the bop-like UAS and transcription factors in diverse organisms, including a plant and a gamma-proteobacterium, suggest an ancient origin for this regulon capable of coordinating light and oxygen responses in the three major branches of the evolutionary tree of life. Finally, sensitivity of four of five regulon genes to DNA supercoiling is demonstrated and correlated to presence of alternating purine-pyrimidine sequences (RY boxes) near the regulated promoters.

Amino Acid Sequence↗
PubMed2001

Genetic dissection of retinoid dehydrogenases.

Biochemical studies indicate that alcohol dehydrogenase (ADH) metabolizes retinol to retinal, and that aldehyde dehydrogenase (ALDH) metabolizes retinal to retinoic acid, a molecule essential for growth and development. Summarized herein are several genetic studies supporting in vivo functions for ADH and ALDH in retinoic acid synthesis. Gene targeting was used to create knockout mice for either Adh1 or Adh4. Both knockout mice were viable and fertile without obvious defects. However, when wild-type and Adh4 knockout mice were subjected to vitamin A deficiency during gestation, the survival rate at birth was 3.3-fold lower for Adh4 knockout mice. When adult mice were examined for production of retinoic acid following retinol administration, Adh1 knockout mice exhibited 10-fold lower retinoic acid levels in liver compared with wild-type, whereas Adh4 knockout mice differed from wild-type by less than 2-fold. Thus, Adh1 plays a major role in the metabolism of a large dose of retinol to retinoic acid in adults, whereas Adh4 plays a role in maintaining sufficient retinol metabolism for development during retinol deficiency. ALDHs were examined by overexpression studies in frog embryos. Injection of mRNAs for either mouse Raldh1 or Raldh2 stimulated retinoic acid synthesis in frog embryos at the blastula stage when retinoic acid is normally undetectable. Overexpression of human ALDH2, human ALDH3, and mouse Aldh-pb did not stimulate retinoic acid production. In addition, Raldh2 knockout mice exhibit embryonic lethality with defects in retinoid-dependent tissues. Overall, these studies provide genetic evidence that Adh1, Adh4, Raldh1, and Raldh2 encode retinoid dehydrogenases involved in retinoic acid synthesis in vivo.

Alcohol Dehydrogenase↗
PubMed2005

Genetic dissection of photosensitivity and its relation to idiopathic generalized epilepsy.

Photosensitivity or photoparoxysmal response (PPR) is a common and highly heritable electroencephalographic trait characterized by an abnormal visual sensitivity of the brain in reaction to intermittent photic stimulation. PPR occurs frequently associated with idiopathic generalized epilepsies (IGEs). The present genomewide linkage scan was designed to map susceptibility loci for PPR and to explore their genetic relationship with IGE. The study included 60 families with at least two siblings displaying PPR. To dissect PPR-specific and IGE-related susceptibility loci, we defined two distinct family subgroups, comprising 19 families with predominantly pure PPR and photosensitive seizures (PPR-families) and 25 families, in which PPR was strongly associated with IGE (PPR/IGE-families). MOD score analyses provided significant evidence for linkage to the region 6p21.2 in the PPR-families (empirical p = 0.00004) and suggestive evidence for linkage to the region 13q31.3 in the PPR/IGE families (p = 0.00015), both with a best-fitting recessive mode of inheritance. In the PPR/IGE-families, linkage evidence was even stronger (p = 0.00003) when the trait definition was broadened by IGE traits. Our study shows two PPR-related susceptibility loci, depending on the familial background of IGE. The locus on 6p21.2 seems to predispose to PPR itself, whereas the locus on 13q31.3 also confers susceptibility to IGE.

Chromosomes, Human, Pair 13↗
PubMed2002

Genetic dissection of mammalian fertility pathways.

The world's population is increasing at an alarming rate and is projected to reach nine billion by 2050. Despite this, 15% of couples world-wide remain childless because of infertility. Few genetic causes of infertility have been identified in humans; nevertheless, genetic aetiologies are thought to underlie many cases of idiopathic infertility. Mouse models with reproductive defects as a major phenotype are being rapidly created and discovered and now total over 200. These models are helping to define mechanisms of reproductive function, as well as identify potential new contraceptive targets and genes involved in the pathophysiology of reproductive disorders. With this new information, men and women will continue to be confronted with difficult decisions on whether or not to use state-of-the-art technology and hormonal treatments to propagate their germline, despite the risks of transmitting mutant genes to their offspring.

Animals↗
PubMed2003

Genetic dissection of hybrid incompatibilities between Drosophila simulans and D. mauritiana. II. Mapping hybrid male sterility loci on the third chromosome.

Hybrid male sterility (HMS) is a rapidly evolving mechanism of reproductive isolation in Drosophila. Here we report a genetic analysis of HMS in third-chromosome segments of Drosophila mauritiana that were introgressed into a D. simulans background. Qualitative genetic mapping was used to localize 10 loci on 3R and a quantitative trait locus (QTL) procedure (multiple-interval mapping) was used to identify 19 loci on the entire chromosome. These genetic incompatibilities often show dominance and complex patterns of epistasis. Most of the HMS loci have relatively small effects and generally at least two or three of them are required to produce complete sterility. Only one small region of the third chromosome of D. mauritiana by itself causes a high level of infertility when introgressed into D. simulans. By comparison with previous studies of the X chromosome, we infer that HMS loci are only approximately 40% as dense on this autosome as they are on the X chromosome. These results are consistent with the gradual evolution of hybrid incompatibilities as a by-product of genetic divergence in allopatric populations.

Alleles↗
PubMed2002

[Genetic dissection of retinoic acid function in epidermis physiology].

The active metabolite of vitamin A (retinoic acid, RA) acts through the nuclear receptors RARalpha, beta and gamma and RXRalpha, beta and gamma. These receptors form RAR/RXR heterodimers, which bind to genetic regulatory DNA sequences and activate transcription of RA target genes. As RXR form heterodimers with a number of other nuclear receptors, such as the vitamin D3 receptor (VDR) and are involved in several signaling pathways. In the skin, RARgamma and RXRalpha predominate, but RARalpha and RXRbeta are also expressed. To elucidate the role of RA in skin physiology, we produced mutant mouse lines null for RAR or RXR. On the one hand, null mutations for RARa or RXRbeta have no effect on the skin, whereas a RARgamma-null mutation induces alterations in the granular cell layer. On the other, genetic inactivation of RXRa leads to embryonic lethality before epidermal development. Consequently, to determine the role of RXRa in adult mice, studies were performed using conditional somatic mutagenesis (permitting inactivation of a given gene in a specific tissue and in a time-dependent manner). Using this novel genetic approach, mutant mice were obtained in which RXRalpha was not expressed in the skin. These mice developed hair follicle degeneration, then alopecia, similar to that observed in VDR-null mutants, suggesting that hair follicle homeostasis depends on RXRalpha/VDR heterodimers. A similar genetic approach applied to the RARgamma locus demonstrated that topical administration of RA on the skin activates RARgamma/RXR heterodimers in suprabasal cells, and induces expression of a paracrine growth factor (HB-EGF) in these cells which, in turn, stimulates the proliferation of basal cells.

Alopecia↗
PubMed2002

Genetic dissection of increased urinary albumin excretion in the munich wistar frömter rat.

An elevated urinary albumin excretion (UAE) is a risk factor for the development of chronic nephropathy and for cardiovascular mortality. The Munich Wistar Frömter (MWF) rat represents a genetic model that develops spontaneously mild hypertension and a 142-fold increased UAE compared with normal Lewis rats at 14 wk of age. The genetic basis of UAE in male MWF was analyzed in relation to BP by using a quantitative trait (QTL) mapping strategy. F1-hybrids generated from a cross between MWF and Lewis rats showed normal UAE rates similar to Lewis. A backcross strategy including 213 animals was therefore used. To account for age-of-onset effects, UAE was determined in young backcross animals at 8 wk and in adult animals at 14 and 24 wk of age, respectively. Total genome scan analysis identified three QTL with significant linkage to UAE and one QTL with suggestive linkage to UAE. These loci showed no linkage to BP, and BP explained only 2% of the total variance of UAE. Homozygosity for the MWF allele accounted for a similar mean increase in UAE in adult backcross animals at each UAE QTL. When single gene effects were analyzed, only one UAE QTL led to a significant increase in UAE. Early onset of albuminuria and a considerable increase of UAE in adult animals required homozygosity at three loci at least. This study demonstrates the polygenetic recessive determination of increased UAE by a set of genes that are unlinked to BP.

Albuminuria↗