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PubMed1988

Genetic selection for mutations that reduce or abolish ribosomal recognition of the HIS4 translational initiator region.

A unique genetic selection was devised at the HIS4 locus to address the mechanism of translation initiation in Saccharomyces cerevisiae and to probe sequence requirements at the normal translational initiator region that might participate in ribosomal recognition of the AUG start codon. The first AUG codon at the 5' end of the HIS4 message serves as the start site for translation, and the -3 and +4 nucleotide positions flanking this AUG (AXXAUGG) correspond to a eucaryotic consensus start region. Despite this similarity, direct selection for mutations that reduce or abolish ribosomal recognition of this region does not provide any insight into the functional nature of flanking nucleotides. The only mutations identified that affected recognition of this region were alterations in the AUG start codon. Among 150 spontaneous isolates, 26 were shown to contain mutations in the AUG start codon, including all +1 changes (CUG, GUG, and UUG), all +3 changes (AUA, AUC, and AUU), and one +2 change (ACG). These seven mutations of the AUG start codon, as well as AAG and AGG constructed in vitro, were assayed for their ability to support HIS4 expression. No codon other than AUG is physiologically relevant to translation initiation at HIS4 as determined by growth tests and quantitated in his4-lacZ fusion strains. These data and analysis of other his4 alleles are consistent with a mechanism of initiation at HIS4 as proposed in the scanning model whereby the first AUG codon nearest the 5' end of the message serves as the start site for translation and points to the AUG codon in S. cerevisiae as an important component for ribosomal recognition of the initiator region.

Alleles↗
PubMed1987

Failure of genetically selected miniature swine to model NIDDM.

Ten young adult miniature swine from a line reported to be genetically selected for glucose intolerance and eight normal controls were obtained from Colorado State University. They were consecutively exposed to 4 mo of a high-fiber, low-fat standard swine diet; 4 mo of a high-sucrose, high-fat, low-fiber diabetogenic diet; and 4 mo of excess diabetogenic diet for obesification. Results of oral glucose tolerance and intravenous insulin tolerance tests conducted at the end of each regimen were compared. Hyperglycemia was not observed in any animals after any manipulation. Insulin sensitivity was also not influenced by diet. We conclude that F7 low-K miniature swine from this colony fail to model human non-insulin-dependent diabetes.

Animals↗
PubMed1984

An inverse relationship between heparin content and antibody response in genetically selected mice. Sex effect and evidence of a polygenic control for skin heparin concentration.

The heparin content of genetically selected mice with high and low antibody response to bacterial antigens is reported. An inverse relationship between antibody titres and concentration of heparin was observed for both male and female mice. The lower-antibody-responder line contains twice as much heparin as the higher-responder ones. Furthermore, the female mice also contained twice as much heparin as the male mice. Genetic analysis of the parental and interline hybrids has shown a partial dominance for the character 'heparin content' in favour of the high-heparin phenotype and this character appears to be subjected to polygenic control. The possible biological role of heparin and/or mast cells in the surveillance of the organism against some pathogens is discussed in the light of these and other findings.

Animals↗
PubMed1990

Phagocytic functions of pulmonary alveolar macrophages in genetically selected lean and obese swine and the effects of exogenous linolenic acid upon cell function.

Alveolar macrophages from genetically selected obese and lean swine were compared for in vitro phagocytic capabilities, using Fc (gamma)- and C3-mediated phagocytosis. Cells from obese pigs were significantly more effective at Fc (gamma)-mediated phagocytosis than those from lean pigs, both for percentage of total cells phagocytosing (P less than 0.044) and for the average number of opsonized sheep erythrocytes (SRBC) ingested per phagocyte (P less than 0.045). A seasonal interaction was noted for average number of SRBC ingested per phagocyte: the relative difference in macrophage responses between obese and lean groups became significantly more pronounced during winter and spring months (P less than 0.080). Macrophages from obese pigs also exhibited higher phagocytic activities at C3-mediated phagocytosis than did cells from lean pigs, but these differences were significant only for average number of SRBC ingested per phagocyte (P less than 0.080). Exogenous linolenic acid was added to selected cultures undergoing Fc (gamma)-mediated phagocytosis. Addition of the fatty acid frequently caused enhanced phagocytosis. Macrophages from obese pigs were stimulated by fatty acid treatment more frequently than cells from lean pigs (P less than 0.05). Relatively greater enhancement was also seen in cells from obese pigs, when compared with those from lean swine (P less than 0.025). These results suggest that genetically transferred factors are of primary importance in alveolar macrophage phagocytic responses and that linolenic acid can induce increased phagocytic activity by porcine alveolar macrophages in vitro.

Analysis of Variance↗
PubMed1997

Commercial approaches to genetic selection for growth and feed conversion in domestic poultry.

Tremendous genetic progress has been observed historically for growth and feed conversion through the efforts of the primary breeding companies. However, significant between-strain variation still exists due to differences in selection emphasis and selection techniques practiced by these organizations. This paper provides an overview of methods currently employed in commercial poultry breeding with reference to factors complicating program design and future challenges facing the industry. Mass selection for body weight has resulted in a significant reduction in the number of days required to grow bird to market weight with indirect improvements in feed conversion. Direct selection for feed conversion is accomplished through part record testing of males that have been preselected for body weight, conformation, and defect traits. Data are commonly subjected to complex statistical analysis both to correct feed conversion for variation in body weight and to improve the accuracy of breeding value estimates. Feed conversion breeding values of male sibs are sometimes used for the selection of female candidates as well. Selection for growth rate and efficiency has resulted in negative complications, such as ascites, reduced reproductive performance, skeletal abnormalities, and increased carcass fatness. Some of these factors may be partially ameliorated through modified selection practices. If not addressed by the breeding industry, the disruption of physiological homeostasis might ultimately represent economic and genetic barriers to further progress in improving growth and efficiency. Modern techniques in molecular genetics, utilized in conjunction with traditional quantitative genetic approaches, will provide additional opportunities to circumvent these physiological complications associated with genetic selection for growth and feed efficiency.

Animals↗
PubMed1983

Variation in the potassium needs of chickens selected genetically for variation in blood uric acid concentrations.

Two strains of sex-linked dwarf chickens that have been selected genetically for divergence in plasma uric acid concentrations were found to differ in their requirements for potassium. The rates of growth of chicks from both strains were similar when nutritionally adequate levels of potassium were provided. However, the growth of chicks having normal plasma uric acid concentrations was significantly poorer than that of hyperuricemic chicks when the chicks received potassium-deficient diets, and the retention of dietary potassium was less in the former group. There were no consistent strain differences in response to sodium deficiency. Because the two strains previously were found to differ in the renal tubular transport of uric acid, the strain difference in potassium requirement may reflect an association of potassium with uric acid excretion.

Animals↗
PubMedDate not supplied

Differential effects of pre- and/or post-natal d-amphetamine on avoidance response in genetically selected lines of rats.

Effects of pre- and post-natal d-amphetamine on avoidance response were investigated in genetically selected lines of rats. Pregnant animals of the Roman high- and low avoidance (RHA and RLA) lines were administered daily either 3 mg/kg d-amphetamine or physiological saline from day 7 to 20 of gestation. Either-way avoidance learning was studied in prenatally treated offspring over four days of training and subsequently under the effects of four dosages of d-amphetamine. Prenatal intervention with d-amphetamine contributed significantly to avoidance learning over four days of training. A significant genetic line X prenatal treatment X dose response interaction was found in one-way and two-way responses. Results were discussed in terms of inverted-U arousal function, and it is proposed that the prenatal amphetamine intervention may affect baseline levels of physiological arousal. This effect may enhance or impair learning depending upon the nature of the response and the genetic line.

Animals↗
PubMed1983

In vitro viability of lymphoid cells from lines of mice genetically selected for high or low responsiveness to phytohemagglutinin.

The kinetics of viability of lymph node and spleen cells of mice genetically selected for "high" or "low" in vitro lymphocyte responsiveness to PHA were studied in PHA or PPD-stimulated short-term cultures. Lo/PHA cells were found to be less viable than Hi/PHA cells in unstimulated control cultures. PHA improved the viability of Lo/PHA cells while inducing proliferation of Hi/PHA cells with the appearance of more and larger lymphoblasts in the latter. PPD only improved the viability of spleen cell cultures, more so for the Hi/PHA line. The interline difference in thymidine uptake was smaller after PPD than after PHA stimulation. Modifications of culture conditions designed to decrease the interline difference in cell viability lessened but did not abolish the separation between the two lines for the PHA response as measured by thymidine uptake.

Animals↗
PubMed2000

Effects of voluntary activity and genetic selection on muscle metabolic capacities in house mice Mus domesticus.

Selective breeding is an important tool in behavioral genetics and evolutionary physiology, but it has rarely been applied to the study of exercise physiology. We are using artificial selection for increased wheel-running behavior to study the correlated evolution of locomotor activity and physiological determinants of exercise capacity in house mice. We studied enzyme activities and their response to voluntary wheel running in mixed hindlimb muscles of mice from generation 14, at which time individuals from selected lines ran more than twice as many revolutions per day as those from control (unselected) lines. Beginning at weaning and for 8 wk, we housed mice from each of four replicate selected lines and four replicate control lines with access to wheels that were free to rotate (wheel-access group) or locked (sedentary group). Among sedentary animals, mice from selected lines did not exhibit a general increase in aerobic capacities: no mitochondrial [except pyruvate dehydrogenase (PDH)] or glycolytic enzyme activity was significantly (P < 0.05) higher than in control mice. Sedentary mice from the selected lines exhibited a trend for higher muscle aerobic capacities, as indicated by higher levels of mitochondrial (cytochrome-c oxidase, carnitine palmitoyltransferase, citrate synthase, and PDH) and glycolytic (hexokinase and phosphofructokinase) enzymes, with concomitant lower anaerobic capacities, as indicated by lactate dehydrogenase (especially in male mice). Consistent with previous studies of endurance training in rats via voluntary wheel running or forced treadmill exercise, cytochrome-c oxidase, citrate synthase, and carnitine palmitoyltransferase activity increased in the wheel-access groups for both genders; hexokinase also increased in both genders. Some enzymes showed gender-specific responses: PDH and lactate dehydrogenase increased in wheel-access male but not female mice, and glycogen phosphorylase decreased in female but not in male mice. Two-way analysis of covariance revealed significant interactions between line type and activity group; for several enzymes, activities showed greater changes in mice from selected lines, presumably because such mice ran more revolutions per day and at greater velocities. Thus genetic selection for increased voluntary wheel running did not reduce the capability of muscle aerobic capacity to respond to training.

Animals↗
PubMed1985

Resistance to listeriosis in two lines of mice genetically selected for high and low antibody production.

Infection by the intracellular parasite Listeria monocytogenes was studied in two inbred lines of mice genetically selected for high and low antibody production against xenogeneic red blood cells. It was revealed that, during the early non-specific phase of infection, bacterial growth in tissues was significantly enhanced in high responder (HR) mice, as opposed to low responder (LR) mice. This is interpreted as the in vivo expression of a genetic impairment of the bactericidal activity of resident macrophages in this line of mice. After Day 2 of infection, the kinetics of bacterial growth in the spleen and the liver was almost identical in the two lines, indicating that mice from both lines generated efficient anti-Listeria immunity. This was confirmed by the fact that no interline difference could be detected in the expression of T-cell mediated immunity, as estimated by the production of protective T cells and delayed sensitivity T cells, and by the level of immunological memory. The genetic impairment in the bactericidal activity of resident macrophages resulted in a significant increase of anti-Listeria antibody production in HR mice and did not prevent T-dependent activation of effector macrophages mobilized in infectious sites. This explains that the overall resistance to listeriosis was similar in LR and HR mice, as shown by the LD50 values respectively estimated as 2.2 X 10(5) and 3.8 X 10(5) bacteria per mouse. This natural resistance was expressed at the same level as that of C57BL/6 mice.

Animals↗
PubMed1999

Two genetically selected strains of rats exhibit hypersensitivity or resistance to cocaine-induced fatal arrhythmias.

We identified for the first time two genetically selected strains of rats that differ markedly in sensitivity to cocaine-induced life-threatening cardiac arrhythmias and arrest. The two strains of rats, designated as Fast and Slow, were bred for sensitivity (Fast) or resistance (Slow) to electrically kindled seizures. Studies were performed on halothane-anesthetized, mechanically ventilated rats. Animals were given cocaine (3 or 4 mg/kg/min i.v.) until they died. Arrhythmias (atrioventricular conduction block) developed at much lower cumulative cocaine doses in Slow-kindling rats than in Fast-kindling rats (15 +/- 1 versus 42 +/- 3 mg/kg, p <.01). The lethal cocaine dose (the dose that caused cardiac arrest) was also markedly lower in Slow than in Fast strains (32 +/- 2 versus 62 +/- 6 mg/kg, p <.01). These differences between the two strains were not significantly altered by pretreatment of animals with either ganglionic blockers, hexamethonium (20 mg/kg i.v.) or chlorisondamine (5 mg/kg i.v.), or a nonselective beta adrenergic receptor blocker, propranolol (1 mg/kg i.v.). A nonselective alpha adrenergic receptor blocker, phentolamine (10 mg/kg i.v.), however, abolished the differences between the Fast and Slow strains in the doses of cocaine required to produced atrioventricular conduction block and cardiac arrest. The results provide the first evidence of genetically determined susceptibility or resistance to cocaine-induced cardiotoxicity. There appears to be a genetically determined difference in the alpha adrenergic receptor system between the two strains that is responsible for the differential sensitivity to cocaine-induced arrhythmias and cardiac arrest.

Animals↗
PubMed2025

CRISPR/Cas9-compatible plasmids enabling seven dominant genetic selection methods for the human fungal pathogen Cryptococcus neoformans.

Cryptococcus neoformans is the most common cause of human fungal meningitis and an important model system for studying fundamental eukaryotic biology. Genetic manipulation of this organism relies on three dominant drug resistance markers (nourseothricin acetyltransferase [NAT], neomycin phosphotransferase II [NEO], and hygromycin B phosphotransferase [HYG]) and the recyclable dominant prototrophic marker amdS. With ongoing technological advances that are expanding our ability to explore cryptococcal gene function, contemporary studies often require multiple genetic manipulations in the same strain. Additional dominant selection methods would maximize the utility of these tools by facilitating their combinatorial use. Here, we identify blasticidin S resistance via the blasticidin S deaminase (BSD) or blasticidin S resistance (BSR) markers as a novel dominant selection method for C. neoformans. We further validate phleomycin resistance via the bleomycin resistance gene (BLE) marker as an additional selection method, confirming a study that first established this marker 25 years ago (J. Hua, J. D. Meyer, and J. K. Lodge, Clin Diagn Lab Immunol 7:125-128, 2000, https://doi.org/10.1128/cdli.7.1.125-128.2000). To enable highly efficient CRISPR/Cas9-mediated genome modification, we incorporated these markers, as well as the newly established dominant prototrophic marker ptxD (M. Khongthongdam, T. Phetruen, and S. Chanarat, Microbiol Spectr 13:e01618-24, 2025, https://doi.org/10.1128/spectrum.01618-24), into a vector series that enables the construction of fused marker-sgRNA products via PCR. Altogether, this work expands the number of dominant genetic selection methods for C. neoformans to seven, including five drug selection regimes and two prototrophic methods. The vector series has been deposited at Addgene. IMPORTANCE Cryptococcus neoformans is the top-ranked World Health Organization priority fungal pathogen due to its widespread distribution and inadequate treatment options. Additionally, as a basidiomycete yeast occupying an underexplored branch of the fungal kingdom, this organism is a powerful system for deciphering core eukaryotic biology that is absent in classic model fungi. Defining functions for novel cryptococcal genes is a crucial priority, and the availability of additional genetic selection methods would facilitate these efforts. In this study, we establish blasticidin S resistance as a novel genetic selection method for C. neoformans, and we validate a previous report using phleomycin resistance as such. This work expands the number of reliable dominant selection methods to seven, providing flexibility for the introduction of sequential genetic modifications into single strains.

Cryptococcus neoformans↗
PubMed1996

Human immunodeficiency virus reverse transcriptase. Functional mutants obtained by random mutagenesis coupled with genetic selection in Escherichia coli.

We describe catalytically active mutants of HIV RT (human immunodeficiency virus reverse transcriptase) generated by random sequence mutagenesis and selected in Escherichia coli for ability to complement the temperature-sensitive phenotype of a DNA polymerase I (Pol Its) mutant. We targeted amino acids Asp-67 through Arg-78 in HIV RT, which form part of the beta3-beta4 flexible loop and harbor many of the currently known mutations that confer resistance to nucleoside analogs. DNA sequencing of 109 selected mutants that complement the Pol Its phenotype revealed substitutions at all 12 residues targeted, indicating that none of the wild-type amino acids is essential. However, single mutations were not observed at Trp-71, Arg-72, and Arg-78, consistent with evolutionary conservation of these residues among viral RTs and lack of variation at these positions among isolates from patients. The mutations we recovered included most of those associated with drug resistance as well as previously unidentified mutations. Purification and assay of 14 mutant proteins revealed correlation between their DNA-dependent DNA polymerize activity in vitro and ability to complement the Pol Its phenotype. Activity of several mutants was resistant to 3'-azidothymidine triphosphate. We conclude that random sequence mutagenesis coupled with positive genetic selection in E. coli yields large numbers of functional HIV RT mutants. Among these are less active variants which are unlikely to be isolated from HIV-infected individuals and which will be informative of the roles of individual amino acids in the catalytic functions of the enzyme.

Amino Acid Sequence↗
PubMed2003

Regulation of the resistance to nematode parasites of single- and twin-bearing Merino ewes through nutrition and genetic selection.

Periparturient Merino ewes obtained from lines of sheep that had been selected either for increased resistance to Haemonchus contortus (R) or at random (C) were supplemented, while grazing at pasture, with either nil or 250 g/day cottonseed meal (CSM) for the 6 weeks prior to or the 6 weeks after the start of parturition. Ewes from both supplement groups had lower (mean 66% reduction) faecal egg counts (FECs) during the postpartum period and this coincided with a period of maternal body weight loss. Factors which increased the rate of maternal body weight loss, such as pregnancy and lactation status, also increased FEC. Evidence is presented that the magnitude of the periparturient rise (PPR) in FEC in grazing ewes will be greatest during periods of maternal weight loss and at these times supplementation to increase metabolisable protein (MP) supply will be most effective in increasing resistance to nematode parasites. The resistance of R ewes to nematode parasites was greater than that of C ewes throughout the experiment and was sufficiently low such that anthelmintic treatment in a commercial environment may not have been required. Irrespective of actual FEC, ewes from all treatment combinations exhibited a PPR in FEC. Reduced FEC of R ewes resulted in reduced apparent pasture larval contamination after 18 weeks of continuous grazing but supplementation was ineffective in this regard. It is suggested that integrated parasite management (IPM) programs for periparturient ewes should make use of both protein supplementation and genetic selection to increase worm resistance and reduce dependency on anthelmintics for worm control.

Animal Nutritional Physiological Phenomena↗
PubMed1990

Use of regulated cell lysis in a lethal genetic selection in Escherichia coli: identification of the autoinducer-binding region of the LuxR protein from Vibrio fischeri ATCC 7744.

A lethal genetic selection utilizing the bacteriophage lambda lysis genes (S, R, RZ) has been developed and used in conjunction with a luminescence screen to allow the isolation and characterization of six missense mutations and two nonsense mutations in the luxR gene from Vibrio fischeri ATCC 7744. A transcriptional fusion of the lysis genes in operonR downstream of a truncated luxI gene allows control of cell lysis by the addition of synthetic autoinducer to the growth medium. The six missense mutations isolated resulted in changes in the LuxR protein of Asp at position 79 to Asn (hereafter designated as D79N), V82I, V109L, L118F, S123I, and H217Y. Variant LuxR proteins with amino acid changes of D79N, V82I, V82L, and H127Y were shown to require higher concentrations of autoinducer to elicit a certain amplitude response than is required by the wild-type protein. We believe that the clustering of a total of seven randomly generated missense mutations in a 49-amino-acid region of the LuxR primary sequence defines a critical portion of the LuxR protein. The observation that proteins with lesions in this region responded to elevated levels of autoinducer suggests that the autoinducer-binding site is constructed, at least in part, from several amino acid residues within the 79-to-127 region of the LuxR protein.

Amino Acid Sequence↗
PubMed1986

Pelvic development as affected by relaxin in three genetically selected frame sizes of beef heifers.

Purified porcine relaxin was administered into the cervical os on Day 278 of gestation to determine its effects on pelvic development in three genetically selected frame sizes of primiparous beef heifers. Heifers were categorized as small, medium and large frame based upon their genetic composition. Pelvic height, pelvic width and cervical dilatation were determined from Day 270 to 2 days postpartum. On Day 270, heifers were assigned at random to one of three treatments: vehicle control, n = 16; relaxin once (3,000 U), n = 14; and relaxin twice (2 times 3,000 U 12 h apart), n = 17. Each heifer-frame size was represented in each treatment. Relaxin caused marked increases in pelvic height and width, as well as in the rate of linear increase (cm/day) of these parameters (p less than 0.05). These linear increases in pelvic height were 510, 264 and 204%, and pelvic width, were 280, 213 and 204% of the respective pretreatment rates for small, medium and large heifers. The rate of linear increase in pelvic width was greater than pelvic height in all heifers, but maximal in small-frame heifers; relaxin attenuated these intrinsic differences. For small heifers, the rate of linear increase in pelvic width was 121 and 145% of increases for medium and large heifers, respectively, before treatment, and 160 and 200% after treatment. The rate of postpartum involution of pelvic width was -0.03, -0.36 and -0.50 cm/day and, for pelvic height, -0.02, -0.27 and -0.29 cm/day in small, medium and large heifers, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1979

Aortic glycopeptide sialic acid, hexose and hexosamine in a genetically selected (WC-2) strain of atherosclerosis-susceptible pigeon.

The aortic content of glycopeptide sialic acid, hexosamine and hexose was studied in a genetically selected strain of White Carneau pigeons (WC-2) with significantly more severe atherosclerosis than randomly bred White Carneau pigeons (RBWC). Pigeons were fed an atherogenic diet for 3 months and examined to determine differences in content of glycopeptide-sugars between WC-2 and RBWC, changes with the progression of atherosclerosis and the relationship of aortic cholesterol to glycopeptide-sugar content. In animals with mainly normal aorta (cholesterol content of 0.2-0.3 mg/cm2-aorta) sialic acid was significantly lower in WC-2 pigeons. The progression of atherosclerosis was associated with increased aortic glycopeptide sialic acid (r = 0.78; p less than 0.05) in WC-2 pigeons whereas an inverse relationship was suggested in RBWC pigeons. In WC-2, but not RBWC pigeons, significant positive relationships were seen for aortic glycopeptide hexosamine and aortic cholesterol and for aortic glycopeptide hexose and aortic cholesterol. The findings implicate a possible role of aortic glycoproteins in either the initiation or modulation of atherosclerosis of the WC-2 pigeon.

Animals↗