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J K Kelly

Publications and source records attributed to J K Kelly.

At least 19 recordsLinked to original sources
PubMed2001

Deleterious mutations and genetic variation for flower size in Mimulus guttatus.

Mimulus guttatus is a wildflower that exhibits substantial genetic variation in flower size. Here, we test the hypothesis that this variation is caused by deleterious mutations maintained through mutation-selection balance. The deleterious-mutation model predicts that rare, partially recessive alleles will be the primary source of variation. We test this prediction by measuring the change in the mean flower size (deltaM) and the directional dominance of flower size (deltaB) within a selection experiment. If variation is due to rare (partially) recessive alleles, deltaB/deltaM is expected to be positive and exceed one. However, we obtain negative values for deltaB/deltaM from three independent selection lines. This result is statistically inconsistent with the deleterious-mutation model.

Alleles↗
PubMed2000

Predicting response to selection on a quantitative trait: a comparison between models for mixed-mating populations.

Two different theoretical frameworks have been developed to predict response to selection in a mixed mating population (in which reproduction occurs by a mixture of outcrossing and self-fertilization). The genotypic covariance model (GCM) and the structured linear model (SLM) rely on the same assumptions regarding quantitative trait inheritance, but use different genetic summary statistics. Here, we demonstrate the algebraic relationships between the various genetic metrics used in each theory. This is accomplished by reformulating the GCM in terms of the Wright-Kempthorne equation. We use stochastic simulations to investigate the relative accuracy of each theory for a range of selfing rates. The SLM is generally more accurate than the GCM, the most pronounced differences emerging in simulations with inbreeding depression for fitness. In fact, with strong inbreeding depression and high selfing rates, evolution can occur opposite the direction predicted by the GCM. The simulations also indicate that direct application of random mating models to partially selfing populations can produce very inaccurate predictions if quantitative trait loci exhibit dominance.

Animals↗
PubMed2000

Molecular evolution near a two-locus balanced polymorphism.

Balancing selection at one locus can increase the amount of selectively neutral variation within neighboring genomic regions. Discrete phenotypic polymorphisms studied in natural populations are frequently determined by sets of interacting genes instead of alternative alleles at single loci. We extend coalescent theory to investigate balancing selection on combinations of linked genes. We find that variation at neutral sites is increased across a much larger genomic region relative to the single-locus models: the entire region lying between the two loci in balanced combination is affected to some degree. Epistatic selection maintains these high levels of neutral variation because it directly opposes the homogenizing effect of recombination. The results of the theory are discussed in relation to published gene sequence data, primarily from Drosophila.

Alleles↗
PubMed2000

Assessment of carotid artery invasion in patients with head and neck cancer.

PURPOSE: Define radiological and histological features in which patients with head and neck cancer would benefit from a carotid artery resection. Resection of the carotid artery has been advocated for local control of advanced squamous cell carcinoma of the head and neck. To provide appropriate preoperative counseling and optimize the utilization of resources, the criteria for patient selection has to be defined. METHODS: Thirty-four patients underwent carotid artery resection based on the clinical impression of tumor fixation. Eighteen and 28 patients were evaluated using computed tomography (CT) and histological analysis, respectively. The distance between the tumor cells and external elastic lamina was measured. CT scans were examined to determine the circumference of tumor attachment around the carotid artery. RESULTS: Clinical assessment predicted tumor within 1.8 mm of the carotid artery in 68% of cases. The overall survival for patients with tumor greater than 1.8 mm (N = 9) was better than that of patients with less (N = 19) than 1.8 mm (33.3% vs. 5.3%; median 24 versus 9 mo, P = .0899). Three of six patients (50%) with less than 180 degrees circumference tumor attachment had tumor within 1.8 mm from the external elastic lamina. Eight of twelve patients (67%) with tumors encompassing more than 180 degrees of the artery wall had tumor within 1.8 mm from the external elastic lamina. The overall survival rates for patients with tumor attachment greater and less than 180 degrees were 8.3% and 33%, respectively. DISCUSSION: Tumor invasion into the carotid artery was the strongest predictor of outcome. Clinical assessment was as predictive as CT for tumor invasion. If tumor involvement of the carotid artery is less than 180 degrees, peeling the tumor is an alternative to carotid artery resection.

Actuarial Analysis↗
PubMed1999

An experimental method for evaluating the contribution of deleterious mutations to quantitative trait variation.

Unconditionally deleterious mutations could be an important source of variation in quantitative traits. Deleterious mutations should be rare (segregating at low frequency in the population) and at least partially recessive. In this paper, I suggest that the contribution of rare, partially recessive alleles to quantitative trait variation can be assessed by comparing the relative magnitudes of two genetic variance components: the covariance of additive and homozygous dominance effects (Cad) and the additive genetic variance (Va). If genetic variation is due to rare recessives, then the ratio of Cad to Va should be equal to or greater than 1. In contrast, Cad/Va should be close to zero or even negative if variation is caused by alleles at intermediate frequencies. The ratio of Cad to Va can be estimated from phenotypic comparisons between inbred and outbred relatives, but such estimates are likely to be highly imprecise. Selection experiments provide an alternative estimator for Cad/Va, one with favourable statistical properties. When combined with other biometrical analyses, the ratio test can provide an incisive test of the deleterious mutation model.

Genetic Variation↗
PubMed1997

A test of neutrality based on interlocus associations.

The evolutionary processes governing variability within genomic regions of low recombination have been the focus of many studies. Here, I investigate the statistical properties of a measure of interlocus genetic associations under the assumption that mutations are selectively neutral and sites are completely linked. This measure, denoted ZnS, is based on the squared correlation of allelic identity at pairs of polymorphic sites. Upper bounds for ZnS are determined by simulations. Various deviations from the neutral model, including several different forms of natural selection, will inflate the value of ZnS relative to its neutral theory expectations. Larger than expected values of ZnS are observed in genetic samples from the yellow-ac-scute and Adh regions of Drosophila melanogaster.

Alcohol Dehydrogenase↗
PubMed1996

Replication rate and evolution in the human immunodeficiency virus.

Population genetic and virological methods yield estimates for the mean replication rate of the Human Immunodeficiency Virus type 1 (HIV-1) that differ by six fold. I present a simple model that can reconcile the estimates obtained from each method by considering the role of intra-host population structure on viral dynamics. The model shows how latently infected cells, which may produce only a small fraction of infective viruses, can nonetheless have an important influence on estimates of mean replication rate. This contribution of latently infected cells is most important when considering the evolution of HIV and the clinical consequences of viral evolution.

Biological Evolution↗
PubMed1996

Speciation by reinforcement: a model derived from studies of Drosophila.

Reinforcement is an increase in premating reproductive isolation between taxa resulting from selection against hybrids. We present a model of reinforcement with a novel type of selection on female mating behavior. Previous models of reinforcement have focused on the divergence of female mating preferences between nascent species. We suggest that an increase in the level of female mating discrimination can yield reinforcement without further divergence of either male characters or female preferences. This model indicates that selection on mating discrimination is a viable mechanism for reinforcement and may allow speciation under less stringent conditions than selection on female preference. This model also incorporates empirical results from genetic studies of hybrid fitness determination in Drosophila species. We find that the details of inheritance, which include sex-linked transmission, sex-limited fertility reduction, and X-autosome epistasis, have important effects on the likelihood of reinforcement. In particular, X-autosome epistasis for hybrid fitness determination facilitates reinforcement when hybrid fertility reduction occurs in males, but hinders the process when it occurs in females. HALDANE's rule indicates that hybrid sterility will generally evolve in males prior to females within nascent species. Thus, HALDANE's rule and X-autosome epistasis provide conditions that are surprisingly favorable for reinforcement in Drosophila.

Animals↗
PubMed1995

Cyclosporin A toxicity: MRI appearance of the brain.

Neurotoxicity is a recognized complication with the use of Cyclosporin A (CSA) in bone marrow and organ transplantation patients. Most common symptoms are seizures and altered mental status which are usually transient. We report three cases of transient neurotoxic episodes in patients receiving CSA after a bone marrow transplant. There were reversible low-attenuation changes on CT and bright T2-weighted signal changes on MRI in the cortex and/or white matter of the cerebral hemispheres. All three patients, when given lower maintenance doses of CSA, were free of recurrent neurotoxic effects.

Adolescent↗
PubMed1995

The nucleotide sequence, structure, and preliminary studies on the transcriptional regulation of the bovine alpha skeletal actin gene.

The promoters of mammalian striated muscle actin gene contain binding sites for a number of transcription factors. Examples are the CArG boxes, which bind a protein identical to or related to serum response factor (SRF), E boxes, which bind myogenic determination factors such as MyoD and myogenin, and -CCGCCC- motifs, which bind the transcription factor Sp1. To date, the only mammalian sequences isolated and analyzed are from rodent and human. We have now isolated and sequenced the bovine gene encoding alpha skeletal actin, including almost 3 kb of 5'-flanking region. When compared to the human and rodent genes (the only ones previously cloned and for which 5'-flanking sequences to only approximately -750 are known), there was the expected conservation in the coding region. A comparison of the promoter regions indicated that the bovine gene has three CArG boxes in the 5'-flanking region in positions identical to those in other species. The bovine proximal promoter is unique from those of human and rodent in that it has only one E box in the vicinity of the TATA box, near -350, whereas the other mammals have three. Far upstream sequences reveal clusters of E boxes near -2,500 and -1,500. A minimal promoter element, to -297, which has no E boxes, is sufficient to activate transcription in myotubes derived from rat L6 and mouse C2C12 myoblasts.

Actins↗
PubMed1995

Progressive type of focal nodular hyperplasia characterized by multiple tumors and recurrence.

Focal nodular hyperplasia (FNH) is usually a stable lesion that does not enlarge when studied for long periods of time; recurrence after resection has not been reported. We present a patient with a solitary FNH lesion that enlarged, was resected, and then recurred. A second resection was performed because of abdominal pain and disclosed multiple lesions, two of which were acutely infarcted. Thirty-two months later there was ultrasound evidence of further recurrence. Histology of the lesions showed the usual appearance of FNH with ducts and ductules in the central stalk regions but also some areas with minimal ductular differentiation and scanty connective tissue. Because of the clinical and histological appearance, the lesions in this patient were distinct from the usual type of FNH and merit the name "focal nodular hyperplasia, progressive type."

Adult↗
PubMed1994

The effect of scale dependent processes on kin selection: mating and density regulation.

Kin selection models describe fitness determining interactions that occur within small clusters of individuals often referred to as trait groups (Wilson, 1975). Because each individual influences not only its own fitness, but also the fitness of other members of the trait group, kin selection has both inter- and intra-group components (Hamilton, 1975; Wade, 1980). The importance of intergroup selection depends on the magnitude of inter-group differences in fertility and on the amount of genetic variation among trait groups. Migration and density regulation are likely to be important determinants of productivity and variation. Existing models integrate density regulation and migration structure into kin selection theory by applying carrying capacities or migration rates to trait groups. This requires that dispersal and density regulation both operate at the spatial scale of trait groups and excludes many cases of biological interest. I present a model that allows interaction, density regulation, and dispersion to operate over distinct spatial scales. The results of existing models can be retrieved as special cases of the general framework developed here. This model indicates that the appropriate scale for studying kin selection is determined by the spatial area over which the population is regulated. In effect, only a fraction of the total inter-trait group variance is available to intergroup selection. Processes that generate genetic variation over spatial scales larger than the "regulation scale" cannot aid the evolution of altruism. The analysis of a specific mating/migration model indicates how the various components of variation are determined by biological parameters such as migration rate. These results have important implications for the study of relatedness in natural populations.

Animals↗
PubMed1994

An application of population genetic theory to synonymous gene sequence evolution in the human immunodeficiency virus (HIV).

A population genetic model is developed and then applied to the synonymous gene sequence variation observed in samples of the Human Immunodeficiency Virus Type 1 (HIV-1). The samples, which were taken from several previous studies, contain sequences of the envelope glycoprotein gene (gp 120) of HIV-1. This analysis suggests that the viral population within an infected patient at any specific time is likely to be composed of close relatives. The viruses in a sample are likely to share a recent common ancestor probably due to consistent positive selection for non-synonymous mutations coupled with low recombination in this region of the genome. There is no substantial difference in synonymous evolutionary rate between samples of sequences obtained from Peripheral Blood Mononucleate Cells (PBMCs) and samples taken from blood plasma. This is likely to be due to the high rate of migration between these 2 HIV subpopulations. The mutation rate for the genetic region examined is estimated at 9.20 x 10(-4) per site per month. Under the assumptions of the estimation procedure, this estimate can be bounded between 8.50 and 9.91 x 10(-4) with 95% confidence. When coupled with direct estimates of mutation rate, the rate of synonymous evolution suggests that the mean number of generations per month for HIV-1 in vivo is between 1 and 4.

Base Sequence↗
PubMed1993

Hepatic and gastric cytoprotective effects of long-term prostaglandin E1 administration in cirrhotic rats.

BACKGROUND: Acute administration of prostaglandin E (PGE) may be cytoprotective for hepatocytes in acute hepatitis and for gastric mucosa in cirrhotic rats. We examined the effects of long-term PGE treatment on liver and stomach in cirrhotic rats. METHODS: Cirrhosis was induced by bile duct ligation. Controls had a sham operation. Half the rats received a PGE1 analogue, misoprostol (PGE1) (10 micrograms orally, daily) on days 1-29 postsurgery, and the others received vehicle only. On day 31, all rats underwent ex vivo gastric chamber procedures. Liver chemistry, portal pressures, and hepatic and gastric tissue levels of prostaglandin E2, leukotriene B4, myeloperoxidase, and collagen were determined. RESULTS: PGE1-treated cirrhotic rats had less hepatosplenomegaly, lower serum alanine aminotransferase levels, and portal pressures and higher arterial pressure than vehicle-treated cirrhotic rats. Hepatic and gastric leukotriene B4, myeloperoxidase and collagen levels were significantly lower in the PGE1-treated compared with vehicle-treated cirrhotic rats. Vehicle-treated cirrhotic rats had greater spontaneous and ethanol-induced gastric damage and failed to show a gastric hyperemic response to ethanol, whereas PGE1-pretreated rats did. PGE1 did not significantly affect sham-operated rats. CONCLUSIONS: Long-term PGE1 administration was cytoprotective for both the liver and gastric mucosa in cirrhotic rats. Clinical trials of PGE in human cirrhosis or portal hypertensive gastropathy may be warranted.

Alprostadil↗
PubMed1992

Kin selection in density regulated populations.

The process of kin selection has both intra- and inter-group components (Hamilton, 1975, in: Biosocial Anthropology Wade, 1980). Group advantageous characteristics can evolve when inter-group differences in fertility are sufficiently great to overcome any within-group disadvantage of the trait. The potential magnitude of inter-group differences in fertility is determined largely by the way a population is regulated. Inter-group differences decrease as the spatial scale over which a population is regulated becomes increasingly localized. The present paper extends previous work by Boyd (1982, Anim. Behav. 30, 972-982) on the quantitative relation between kin selection and density regulation. A simple genetic model is employed to examine the conditions under which the interaction of local density regulation and kin selection can maintain a stable polymorphism. The ecological factors determining the spatial and temporal scale of density regulation are discussed. Finally, the results are applied to two biological cases in which local density regulation may be influencing the direction of phenotypic plasticity in group advantageous characters.

Animals↗
PubMed1992

Carcinoid tumors and inflammatory bowel disease.

Three cases are described in which carcinoid tumors arose in previously established inflammatory bowel disease: two were in the ileum in cases of Crohn's disease, and one was in the rectum in a case of ulcerative colitis. Review of this association in the literature suggests that it may be more than fortuitous.

Adult↗