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Biomedical subjects

R L Fernando

Publications and source records attributed to R L Fernando.

At least 19 recordsLinked to original sources
PubMed2006

Prospecting for pig single nucleotide polymorphisms in the human genome: have we struck gold?

Gene-to-gene variation in the frequency of single nucleotide polymorphisms (SNPs) has been observed in humans, mice, rats, primates and pigs, but a relationship across species in this variation has not been described. Here, the frequency of porcine coding SNPs (cSNPs) identified by in silico methods, and the frequency of murine cSNPs, were compared with the frequency of human cSNPs across homologous genes. From 150,000 porcine expressed sequence tag (EST) sequences, a total of 452 SNP-containing sequence clusters were found, totalling 1394 putative SNPs. All the clustered porcine EST annotations and SNP data have been made publicly available at http://sputnik.btk.fi/project?name=swine. Human and murine cSNPs were identified from dbSNP and were characterized as either validated or total number of cSNPs (validated plus non-validated) for comparison purposes. The correlation between in silico pig cSNP and validated human cSNP densities was found to be 0.77 (p < 0.00001) for a set of 25 homologous genes, while a correlation of 0.48 (p < 0.0005) was found for a primarily random sample of 50 homologous human and mouse genes. This is the first evidence of conserved gene-to-gene variability in cSNP frequency across species and indicates that site-directed screening of porcine genes that are homologous to cSNP-rich human genes may rapidly advance cSNP discovery in pigs.

Animals↗
PubMed2006

Pregnancy rate and first-service conception rate in Angus heifers.

The objective of this project was to determine the genetic control of conception rate, or pregnancy percentage in Angus beef heifers. Producers from 6 herds in 5 states provided 3,144 heifer records that included breeding dates, breeding contemporary groups, service sires, and pregnancy check information. Two hundred fourteen sires of the heifers were represented; with 104 sires having less than 5 progeny, and 14 sires having greater than 50 progeny. These data were combined with performance and pedigree information, including actual and adjusted birth weights, weaning weights, and yearling weights, from the American Angus Association database. Heifer pregnancy rate varied from 75 to 95% between herds, and from 65 to 100% between sires, with an overall pregnancy rate of 93%, measured as the percentage of heifers pregnant at pregnancy check after the breeding season. Pregnancy was analyzed as a threshold trait with an underlying continuous distribution. A generalized linear animal model, using a relationship matrix, was fitted. This model included the fixed effects of contemporary group, age of dam, and first AI service sire, and the covariates of heifer age at the beginning of breeding, adjusted birth weight, adjusted weaning weight, and adjusted yearling weight. The relationship matrix included 4 generations of pedigree. The heritability of pregnancy and first-service conception rates on the underlying scale was 0.13 +/- 0.07 and 0.03 +/- 0.03, respectively. Estimated breeding values for pregnancy rate on the observed scale ranged from -0.02 to 0.05 for sires of heifers. Including growth traits with pregnancy rate as 2-trait analyses did not change the heritability of pregnancy rate. As expected for a reproductive trait, the heritability of pregnancy rate was low. Because of its low heritability, genetic improvement in fertility by selection on heifer pregnancy rate would be expected to be slow.

Animals↗
PubMed2005

Optimal haplotype structure for linkage disequilibrium-based fine mapping of quantitative trait loci using identity by descent.

A linkage disequilibrium-based method for fine mapping quantitative trait loci (QTL) has been described that uses similarity between individuals' marker haplotypes to determine if QTL alleles are identical by descent (IBD) to model covariances among individuals' QTL alleles for a mixed linear model. Mapping accuracy with this method was found to be sensitive to the number of linked markers that was included in the haplotype when fitting the model at a putative position of the QTL. The objective of this study was to determine the optimal haplotype structure for this IBD-based method for fine mapping a QTL in a previously identified QTL region. Haplotypes consisting of 1, 2, 4, 6, or all 10 available markers were fit as a "sliding window" across the QTL region under ideal and nonideal simulated population conditions. It was found that using haplotypes of 4 or 6 markers as a sliding "window" resulted in the greatest mapping accuracy under nearly all conditions, although the true IBD state at a putative QTL position was most accurately predicted by IBD probabilities obtained using all markers. Using 4 or 6 markers resulted in greater discrimination of IBD probabilities between positions while maintaining sufficient accuracy of IBD probabilities to detect the QTL. Fitting IBD probabilities on the basis of a single marker resulted in the worst mapping accuracy under all conditions because it resulted in poor accuracy of IBD probabilities. In conclusion, for fine mapping using IBD methods, marker information must be used in a manner that results in sensitivity of IBD probabilities to the putative position of the QTL while maintaining sufficient accuracy of IBD probabilities to detect the QTL. Contrary to expectation, use of haplotypes of 4-6 markers to derive IBD probabilities, rather than all available markers, best fits these criteria. Thus for populations similar to those simulated here, optimal mapping accuracy for this IBD-based fine-mapping method is obtained with a haplotype structure including a subset of all available markers.

Crosses, Genetic↗
PubMed2004

Nitric oxide production by human peritoneal mesothelial cells.

Nitric oxide (NO) has multiple actions, ranging from immunomodulation to regulation of vascular tone and capillary flow. Thus NO generation within the peritoneum could potentially affect peritoneal transport by increasing capillary vasodilatation, and regulate the response to bacterial invasion. Peritoneal mesothelial cells have a common embryological derivation with endothelial cells. As mesothelial cells are the predominant cell type lining the peritoneal cavity, they could potentially be a major source of locally produced nitric oxide. Nitric oxide was measured using the Griess reaction, as total nitrite and nitrate, in fresh unused and spent dialysate effluent (SPDE) from both healthy peritoneal dialysis patients, and during episodes of bacterial peritonitis. Whereas fresh CAPD dialysate was nitrite free (5 +/- 0.1 microM), SPDE from a standard 4 h day time exchange contained 10.2 +/- 0.6 microM/L/h, and that from the overnight dwell 9.1 +/- 0.7 microM/L/h. During an episode of peritonitis, dialysate nitrite and nitrate increased significantly from 9.0 +/- 1.0 microM/L/h, when not infected to 17.5 +/- 2.4, from the first CAPD bag drained at presentation, and 15.2 +/- 1.8 for the second and 16.0 +/- 2.5 for the third exchange (p<0.01). By the following day nitrite levels had returned to baseline, 7.0 +/- 1.0 microM/L/h. Human peritoneal mesothelial cells (HPMC) were cultured and found to produce nitric oxide (261 nmol/mg cell protein), which increased in a dose dependent manner with the addition of spent uninfected CAPD dialysate. The addition of L-arginine, a NO substrate resulted in a 10% increase in nitric oxide production, whereas the addition of the blocker L-NMMA produced a 10% reduction. RNA for inducible nitric oxide synthase (iNOS) was sought using northern blotting technique following combination stimulation with lipopolysaccharide and cytokines (IL-1beta, TNFalpha and gamma-INF, and/or spent dialysate from patients with bacterial peritonitis). However, we could not demonstrate RNA production for iNOS. Peritoneal mesothelial cells may be an important source of locally generated nitric oxide within the peritoneal cavity under basal conditions, but as they do not contain iNOS, the markedly increased NO production observed with episodes of acute bacterial peritonitis is more likely due to a combination of increased NO production by peritoneal macrophages and endothelial cells.

Adolescent↗
PubMed2004

Controlling the proportion of false positives in multiple dependent tests.

Genome scan mapping experiments involve multiple tests of significance. Thus, controlling the error rate in such experiments is important. Simple extension of classical concepts results in attempts to control the genomewise error rate (GWER), i.e., the probability of even a single false positive among all tests. This results in very stringent comparisonwise error rates (CWER) and, consequently, low experimental power. We here present an approach based on controlling the proportion of false positives (PFP) among all positive test results. The CWER needed to attain a desired PFP level does not depend on the correlation among the tests or on the number of tests as in other approaches. To estimate the PFP it is necessary to estimate the proportion of true null hypotheses. Here we show how this can be estimated directly from experimental results. The PFP approach is similar to the false discovery rate (FDR) and positive false discovery rate (pFDR) approaches. For a fixed CWER, we have estimated PFP, FDR, pFDR, and GWER through simulation under a variety of models to illustrate practical and philosophical similarities and differences among the methods.

Chromosome Mapping↗
PubMed2004

Comparing linkage disequilibrium-based methods for fine mapping quantitative trait loci.

Recently, a method for fine mapping quantitative trait loci (QTL) using linkage disequilibrium was proposed to map QTL by modeling covariance between individuals, due to identical-by-descent (IBD) QTL alleles, on the basis of the similarity of their marker haplotypes under an assumed population history. In the work presented here, the advantage of using marker haplotype information for fine mapping QTL was studied by comparing the IBD-based method with 10 markers to regression on a single marker, a pair of markers, or a two-locus haplotype under alternative population histories. When 10 markers were genotyped, the IBD-based method estimated the position of the QTL more accurately than did single-marker regression in all populations. When 20 markers were genotyped for regression, as single-marker methods do not require knowledge of haplotypes, the mapping accuracy of regression in all populations was similar to or greater than that of the IBD-based method using 10 markers. Thus for populations similar to those simulated here, the IBD-based method is comparable to single-marker regression analysis for fine mapping QTL.

Alleles↗
PubMed2002

Technical note: determining peeling order using sparse matrix algorithms.

To study the effect of individual genes by segregation or linkage analyses, the likelihood of the model needs to be evaluated. The likelihood can be computed efficiently using the Elston-Stewart algorithm. This algorithm involves summing over the unobserved genotypes in the pedigree, which is called peeling. An important aspect of this algorithm is to determine the order of peeling to maximize efficiency. This paper shows how determining peeling order is related to a problem in solving systems of symmetric sparse linear equations. It also shows how algorithms developed to efficiently solve those systems, can be used to determine the optimal order of peeling in the Elston-Stewart algorithm.

Algorithms↗
PubMed2001

Quantitative trait locus analysis in crosses between outbred lines with dominance and inbreeding.

We provide a theoretical framework for quantitative trait locus (QTL) analysis of a crossed population where parental lines may be outbred and dominance as well as inbreeding are allowed for. It can be applied to any pedigree. A biallelic QTL is assumed, and the QTL allele frequencies can be different in each breed. The genetic covariance between any two individuals is expressed as a nonlinear function of the probability of up to 15 possible identity modes and of the additive and dominance effects, together with the allelic frequencies in each of the two parental breeds. The probabilities of each identity mode are obtained at the desired genome positions using a Monte Carlo Markov chain method. Unbiased estimates of the actual genetic parameters are recovered in a simulated F(2) cross and in a six-generation complex pedigree under a variety of genetic models (allele fixed or segregating in the parental populations and additive or dominance action). Results from analyzing an F(2) cross between Meishan and Large White pigs are also presented.

Alleles↗
PubMed1999

Calcineurin inhibitors enhance low-density lipoprotein oxidation in transplant patients.

BACKGROUND: Our objective was to assess the pro-oxidant status of neoral and tacrolimus in renal transplant patients and monitor the protection provided by vitamin C and vitamin E in normalizing low density lipoprotein (LDL) oxidation lag time of tacrolimus-treated patients. METHODS: Plasma LDL was isolated by density gradient ultracentrifugation from renal transplant patients receiving neoral, tacrolimus and tacrolimus with vitamin C and vitamin E. Oxidation was initiated by the addition of CuCl2 at 37 degrees C and monitored at 234 nm over 480 minutes and oxidation lag time was computed. Total antioxidant capacity of serum was measured using the enhanced chemiluminescent method. RESULTS: LDL from tacrolimus-treated patients had significantly lower oxidation lag time and serum antioxidant activity in comparison with neoral-treated patients, and this was particularly significant during the first four months after transplantation. Vitamin C and E supplementation in tacrolimus treated patients provided protection against oxidation and normalized their oxidation lag time. CONCLUSION: Calcineurin-inhibiting drugs, CsA and tacrolimus, have pro-oxidant activity and they increase the susceptibility of LDL to oxidation. Neoral formulation is fortified with DL-alpha tocopherol and therefore provides protection against oxidation. The present study clearly demonstrates the benefit of giving vitamin C and E supplements to patients taking tacrolimus and this seems to be particularly important during the early period after transplantation.

Adult↗
PubMed1998

Differential ability of cells to promote oxidation of low density lipoproteins in vitro.

Atherosclerosis and focal segmental glomerulosclerosis share some common histological features and it is speculated that they result from similar pathobiological mechanisms. There is strong evidence that oxidation of low density lipoprotein (LDL) may be an initiating event in atherogenesis and that oxidised LDL may also be involved in the glomerulosclerotic process. In vitro studies have demonstrated that cells present in the arterial intima and kidney-derived cells promote LDL oxidation. The aim of this study was to compare LDL oxidation by kidney-derived human mesangial cells and proximal tubular cells, with human umbilical vein endothelial cells and the human monocyte cell line THP-1. We used the thiobarbituric acid assay and agarose gel electrophoresis to measure the extent of LDL oxidation. Our results demonstrate that all of the cell types used had the ability to oxidise LDL significantly more than cell-free controls and that endothelial cells induced the highest degree of oxidative modification of LDL under our experimental conditions.

Arteriosclerosis↗
PubMed1998

Genetic evaluation by best linear unbiased prediction using marker and trait information in a multibreed population.

Genetic evaluation by best linear unbiased prediction (BLUP) requires modeling genetic means, variances, and covariances. This paper presents theory to model means, variances, and covariances in a multibreed population, given marker and breed information, in the presence of gametic disequilibrium between the marker locus (ML) and linked quantitative trait locus (MQTL). Theory and algorithms are presented to construct the matrix of conditional covariances between relatives (Gv) for the MQTL effects in a multibreed population and to obtain the inverse of Gv efficiently. Theory presented here accounts for heterogeneity of variances among pure breeds and for segregation variances between pure breeds. A numerical example was used to illustrate how the theory and algorithms can be used for genetic evaluation by BLUP using marker and trait information in a multibreed population.

Genetic Linkage↗
PubMed1998

Detection and utilization of single genes without DNA assays.

Quantitative traits are often assumed to be controlled by a large number of loci that each have a small effect. Under this assumption, the distribution of genotypic and phenotypic values can be adequately modeled by a multivariate normal distribution. Thus, most genetic analyses are based on mixed linear models. Evidence is accumulating, however, for the presence of loci that have large effects on traits of economic importance. If the genotypes for such loci can be observed without error, then--conditional on these observed genotypes--genotypic and phenotypic values follow a multivariate normal distribution, and data from very large pedigrees can be analyzed using a mixed linear model that includes the genotypic effects for these loci as fixed effects. However, when the major genotype is not observed, the genotypic and phenotypic values follow a mixture of multivariate normal distributions, and analyses based on fitting a mixed linear model may not be optimum, especially for populations undergoing selection and nonrandom mating. Several approaches are discussed for the genetic analysis of data when the major genotypes are not known.

Algorithms↗
PubMed1997

Genetic evaluation by BLUP in two-breed terminal crossbreeding systems under dominance.

To obtain estimates of breeding values by BLUP using Henderson's mixed-model equations, it is necessary to invert the covariance matrix for each random effect in the model. In a model in which the genotypic value is included as a random effect (genotypic model), it is necessary to invert the genotypic covariance matrix. Under additive inheritance, the inverse of the genotypic covariance matrix can be computed efficiently. Under dominance inheritance, however, an efficient method to invert the genotypic covariance matrix has not yet been developed, especially for crossbred populations. Thus, the use of a genotypic model for BLUP is not suitable for genetic evaluation in large, crossbred populations. We present an equivalent model in which the genotypic effect is partitioned into additive and dominance effects. With this equivalent model, methods used for within-breed genetic evaluation by BLUP can be used for a two-breed terminal cross under dominance.

Alleles↗
PubMed1997

Dominance models with method R for stature of Holsteins.

Estimates of variance components were obtained with method R for several additive and dominance models. The data included 301,960 records for first parity and 280,040 records for later parities of Holsteins. The single-record model included effects of management, regression on inbreeding percentage, age at calving, stage of lactation, and additive and dominance effects. The repeatability model included these effects in addition to permanent environment. For the single-record model, estimates were 46% of the total variance for additive variance, 12% of total variance for dominance variance, and -0.06 for the regression coefficient on inbreeding. In the repeatability model, the variance for permanent environment was estimated at 5%; other estimates were similar. When the dominance effect was eliminated, the estimate of the variance for permanent environment increased to 17% for the repeatability model. Elimination of stage of lactation increased regression on inbreeding to 0.09 and the estimate of dominance variance to 17% in the single-record model. The same change increased the estimate of additive variance to 64% for the repeatability model. Elimination of regression on inbreeding or stage of lactation had a small effect on the estimates. The presence or absence of the dominance effect had little influence on additive variance. In the absence of dominance, the estimate of the permanent environment effect included the dominance effect. Estimates of variances with method R are very sensitive to age adjustments. With the adjustments, the estimates of the dominance and additive variances are consistent.

Aging↗
PubMed1996

Do glomerular atherosclerosis and lipid-mediated tubulo-interstitial disease cause progressive renal failure in man?

The nephrotic syndrome presents the kidney with a new environment in which blood vessels, glomerular structures and tubules are exposed over substantial periods of time to lipoproteins. LDL has charge affinity with glomerular basement membrane glycosaminoglycans, so potentially increases or maintains albumin loss. This in turn stimulates LDL synthesis. HDL is small enough to be passed by the glomerular filter in substantial amounts and has been found to stimulate endothelin-1 production by human proximal tubular cells in culture. LDL also inhibits nitric oxide vasodilatory responses, an action which when added to that of endothelin-1 may result in decreased renal tissue oxygenation. Taken together, these aspects of the nephrotic syndrome broaden conventional definitions of atherosclerosis and offer a number of targets for therapy in progressive renal disease.

Arteriosclerosis↗
PubMed1996

Influence of slaughter weight on growth and carcass characteristics, commercial cutting and curing yields, and meat quality of barrows and gilts from two genotypes.

Pigs representing two crossbred genotypes, a breeding company hybrid (BCH) and a three breed cross (Hampshire x [Yorkshire x Duroc]) (HYD) were evaluated at five slaughter weights (SLW): 100, 115, 130, 145, and 160 kg. A total of 160 pigs were grown in like-sex (barrows [B] or gilts [G]), like-genotype groups, with four pigs/group, from 60 kg live weight. A corn-soybean meal-based diet was available on an ad libitum basis (15.8% crude protein, 3,300 kcal/kg ME). One-half of the pigs from each group (80 pigs) were slaughtered for carcass and meat quality evaluation. Genotype BCH grew faster, had lower backfat depths in the loin and lumbar regions, and a smaller loin eye area than HYD, but both groups had a similar gain:feed ratio. Few consistent genotype differences in cutting and curing yields and meat quality were observed. Differences between sexes for growth and carcass traits were generally in agreement with previous research; however, the magnitude of the differences was small. There were few nonlinear regressions involving SLW and limited differences between genotypes or sexes in the slopes of the linear regressions. Increases in SLW were associated with increases in feed intake, backfat depth and loin' eye area, and minimal changes in growth rate or gain:feed. Percentage of loin increased and ham, shoulder, and spare rib percentages decreased with slaughter weight. The weight of trimmed, boneless cuts increased with slaughter weight, but percentage trimmed, boneless cuts was reduced. Curing yields for belly increased with slaughter weight. Changes in meat quality with increasing slaughter weight were relatively small. Longissimus lumborum fat content increased and moisture content decreased with slaughter weight. These results suggest that modern genotypes can be slaughtered at live weights up to 160 kg with limited impact on growth performance, commercial meat yields, or meat quality characteristics.

Abattoirs↗
PubMed1995

Multilocus analysis for gene-centromere mapping using first polar bodies and secondary oocytes.

Polar body and oocyte typing is a new technique for gene-centromere mapping and for generating female linkage maps. A maximum likelihood approach is presented for ordering multiple markers relative to the centromere and for estimating recombination frequencies between markers and between the centromere and marker loci. Three marker-centromere orders are possible for each pair of markers: two orders when the centromere flanks the two markers and one order when the centromere is flanked by the two markers. For each possible order, the likelihood was expressed as a function of recombination frequencies for two adjacent intervals. LOD score for recombination frequency between markers or between the centromere and a marker locus was derived based on the likelihood for each gene-centromere order. The methods developed herein provide a general solution to the problem of multilocus gene-centromere mapping that involves all theoretical crossover possibilities, including four-strand double crossovers.

Animals↗