Biomedical subjects

W G Hill

Publications and source records attributed to W G Hill.

At least 19 recordsLinked to original sources

PubMed2006

Genetic parameters for a heavy female turkey line: impact of simultaneous selection for body weight and total egg number.

1. The objective of this study was to investigate the strength of the genetic association between growth and reproduction traits in turkeys selected for body weight, conformation and egg production. 2. Two distinct populations but derived from the same heavy turkey female line and situated in different locations (UK and USA), were used to estimate genetic parameters using multivariate REML for the following traits: body weight at 14 (BW14), 19 (BW19) and 24 (BW24) weeks of age and total egg number (EGG). 3. A Box-Cox transformation was applied to egg production data to reduce the impact of non-normality. 4. The heritability estimates for each trait for the UK and USA populations, respectively, were: BW14 0.37 and 0.48; BW19 0.34 and 0.43; BW24 0.28 and 0.43; EGG 0.22 and 0.34. 5. The genetic correlation between the body weight at all ages and the total egg production was strongly negative, reaching a value of -0.75 for the UK and -0.55 for the USA population. 6. The comparison of our results with published estimates in turkeys suggests that the genetic correlation may get stronger in magnitude following selection for increased body weight. 7. This could arise from fixation during selection of genes favouring larger weights but with minimal effect on egg production, leaving the segregating genetic variation dominated by pleiotropic loci with antagonistic effects on the traits. 8. Thus, in order to avoid continued selection for body weight reducing egg production to a point where natural selection offsets selection gains, alternative selection strategies should be considered.

Animals↗

PubMed2004

Allelic association patterns for a dense SNP map.

A dense set of 5,000 SNPs on a 10-Mb region of human chromosome 20 has been typed on samples of African Americans, East Asians, and United Kingdom Caucasians. There are departures from Hardy-Weinberg equilibrium beyond the level at which markers are often discarded because of possible genotyping errors. The observation that markers showing such departures are often close together on the chromosome confirms the result that Hardy-Weinberg tests at two loci are correlated to an extent that depends on the linkage disequilibrium between those two markers. Linkage disequilibrium can be described by the composite linkage disequilibrium coefficient, the parameter that determines the behavior of case-control allelic tests of association. A useful preliminary investigation of datasets of this type is provided by counting the numbers of distinct multi-locus genotypes in windows of a few markers.

Black or African American↗

PubMed2004

Moment estimation of population diversity and genetic distance from data on recessive markers.

A moment-based method for estimating a measure of population diversity, theta or Wright's FST, is given for dominant markers such as amplified fragment length polymorphisms (AFLPs) or RAPDs in noninbred populations. Basic assumptions are that there is random mating, Hardy-Weinberg equilibrium, linkage equilibrium, no mutation from common ancestor and equally distant populations. It is based on the variances between and within populations of genotype frequencies, whereas previously moment methods for dominant markers have been indirect in that they have been based on first estimating allele frequencies and then using the variances of those frequencies. The use of genotype frequencies directly appears to be more robust. Approximate sampling errors of the estimates are given. Methods are extended to estimate genetic distances and their sampling errors. The AFLP data from samples of breeds of pig are used for illustration.

Analysis of Variance↗

PubMed2004

Genotype and diet effects on energy balance in the first three lactations of dairy cows.

Dairy cows make strategic use of body energy to support early lactation and replenish this lost energy later in lactation, thereby creating body energy profiles that vary both within lactation and across lactations. The interaction between genotype and diet energy content is interesting from a management viewpoint and from a cow survival viewpoint. In this study, we modeled energy balance over 3 lactations using a multivariate random regression model, for cows from the Langhill Dairy Cattle Research Centre. This herd has been selected for maximum production or to remain at the UK national average for production (control group) and has been fed 2 diets of different energy density (high or low concentrate). Cows in the various groups differed in body condition score and the way they lost and regained body lipid. Cows selected for maximum production on a low-concentrate diet lost the greatest amount of body lipid (0.54 condition score units) after 3 lactations. Cows selected for maximum production lost more than control cows on either diet, indicating that selection mainly for yield has predisposed cows to utilize body energy to support lactation on diets spanning the range used here. Cows selected for maximum production were heavier at first calving than control cows but lost more weight and regained more weight so that at the end of each lactation, cows in the 2 groups did not differ significantly in weight. Cows use body lipid to support lactation over 3 lactations and the profile of that use varies according to genotype and diet.

Animals↗

PubMed2003

Genetic evaluations of dairy bulls for daughter energy balance profiles using linear type scores and body condition score analyzed using random regression.

The difference in body lipid between the start and end of lactation represents the body energy lost (or gained) in support of maintaining lactation including the nonproduction components of lactation. This source of energy is ignored in current genetic evaluations for production for dairy sires. The depletion and accretion of body tissue creates a pattern of body energy content over time that is, in part, under genetic control. Using random regression and field data, we modeled changes in body condition score (BCS) and liveweight, predicted from linear type traits, on first parity cows to produce daily breeding values of their sires for energy balance. These curves show that sires differ in the way their daughters lose and regain body energy throughout lactation. For all sires, the overall mean maximum daughter body energy loss was 1499 MJ (SD = 144 MJ) and occurred at d 99 (SD = 12.8 d) of lactation and the mean total daughter body energy loss at d 305 of lactation was 779 MJ (SD = 224 MJ). In this study, the profiles of body energy loss indicate that daughters of most sires lost body energy before d 150 and then recovered body energy, whereas the daughters of a few sires continued to lose body energy through to the end of lactation. Some sires with high merit for production may have daughters with body tissue mobilization profiles associated with poorer health and fertility leading to higher costs. A method of accounting for this cost could be to correct yield for body tissue mobilization. Deducting kilograms of milk from the breeding value for milk for each sire, equivalent in energy content to the body energy lost, resulted in a correlation of 0.98 between the ranking of sires for milk kilograms before and after adjustment. However, some sires changed rank bylarge amounts, the largest being +355 positions. Breeding values for energy balance can be calculated from single observations of BCS and linear type traits on daughters of a sire; data that can routinely be collected in national conformation assessment schemes.

Animals↗

PubMed2002

Estimating F-statistics.

A moment estimator of, the coancestry coefficient for alleles within a population, was described by Weir & Cockerham in 1984 (100) and is still widely cited. The estimate is used by population geneticists to characterize population structure, by ecologists to estimate migration rates, by animal breeders to describe genetic variation, and by forensic scientists to quantify the strength of matching DNA profiles. This review extends the work of Weir & Cockerham by allowing different levels of coancestry for different populations, and by allowing non-zero coancestries between pairs of populations. All estimates are relative to the average value of theta between pairs of populations. Moment estimates for within- and between-population theta values are likely to have large sampling variances, although these may be reduced by combining information over loci. Variances also decrease with the numbers of alleles at a locus, and with the numbers of populations sampled. This review also extends the work of Weir & Cockerham by employing maximum likelihood methods under the assumption that allele frequencies follow the normal distribution over populations. For the case of equal theta values within populations and zero theta values between populations, the maximum likelihood estimate is the same as that given by Robertson & Hill in 1984 (70). The review concludes by relating functions of theta values to times of population divergence under a pure drift model.

Genetics, Population↗

PubMed2002

On the use of double haploids for detecting QTL in outbred populations.

The power to detect quantitative trait loci (QTL) using the double haploid (DH), full-sib (FS) and hierarchical (HI) designs implemented in outbred fish populations was assessed for interval mapping using deterministic methods. The predictions were tested using simulation. The DH design was most efficient for the range of designs and parameters considered and was most beneficial when the FS design was not very powerful. The difference between the design was largest for a low amount of residual genetic variation. Accounting for an increase of the environmental variance due to the genetic constitution of the double haploid progeny changed the magnitude of the power, but the ranking of the designs remained the same. As large full sib family sizes can be obtained in fish, the practical value of HI designs as a strategy for increasing the power of QTL mapping experiments is limited when compared with the FS design. Overall, the results suggested that the DH design could be a very useful tool for QTL mapping in fish, and of particular importance when the effect of the QTL is low and the residual genetic variation from other chromosomes can be controlled by using multiple markers.

Animals↗

PubMed2001

Inbred lines of mice derived from long-term growth selected lines: unique resources for mapping growth genes.

Lines of mice selected for many generations for high or low growth in several laboratories around the world have been collected, and from these, inbred lines are being developed by recurrent full-sib mating in Edinburgh. There are seven high selected lines and four low lines (each low line is from the same base population as one of the high lines), and the histories of each are summarized. Mean body weight of males at 70 days of age in the Edinburgh laboratory in the heaviest inbred line (77 g) is 4.8-fold higher than in the lightest line (16 g), and 1.9-fold higher than in the least extreme high line (41 g). Litter size, food intake, and fat content also differ substantially. These inbred extreme selected lines are a uniquely valuable resource for QTL or gene mapping, candidate gene identification, and elucidation of epistatic effects.

Animals↗

PubMed2001

Thermoregulatory responses of two mouse Mus musculus strains selectively bred for high and low food intake.

We examined the thermoregulatory responses of male and female mice Mus musculus that had been divergently selected on voluntary food intake, corrected for body mass, to produce a high-intake and a low-intake strain. Resting metabolic rate was determined by indirect calorimetry (at 30 degrees C, 25 degrees C, 15 degrees C and 5 degrees C). Body temperature responses were measured in a separate group of mice in a parallel protocol. High-intake mice had significantly elevated body masses compared to low-intake mice in both sexes. Lower critical temperature in both strains appeared to be around 28 degrees C. At 30 degrees C there was a significant strain effect on resting metabolic rate, with high strain mice having greater metabolism than low strain mice. Sex and body mass were not significant main effects on resting metabolic rate and there were no significant interactions. Body temperature measured at 30 degrees C, 25 degrees C, 15 degrees C and 5 degrees C differed significantly between sexes (females higher) and there was a significant sexxbody mass interaction effect, but there was no difference between strains. Thermal conductance was significantly related to strain and sex, mice from the high strain and males having greater thermal conductances than mice from the low strain and females. Artificial selection has resulted in high-intake mice having greater body masses and greater thermal conductances, which together account for up to 45% of the elevated daily energy demands that underpin the increase in food intake. The greater levels of food intake were also associated with higher resting metabolic rates at 30 degrees C.

Animals↗

PubMed2001

Novel Plasmodium falciparum clones and rising clone multiplicities are associated with the increase in malaria morbidity in Ghanaian children during the transition into the high transmission season.

A survey of Plasmodium falciparum infection and clone multiplicity in Ghanaian children was carried out to study the effect of the onset of the malaria transmission season on disease incidence. Fortnightly blood samples were collected from 40 children living in the rural town of Dodowa, between February and August 1998. P. falciparum parasite densities were calculated and PCR genotyping was carried out using the polymorphic MSP-1 and MSP-2 genes as target loci for the estimation of the number of parasite clones in each sample. The average clone number was estimated using maximum likelihood techniques and the minimum number of clones per patient was analysed for the effects of age, sex, season, minimum number of clones per child, level of parasitaemia and parasite genotype. The statistical analysis indicated that the more clones a child carried, the more likely they were to have a clinical malaria episode. This was true after adjusting for age and season effects and for the measured circulating parasitaemia. The probability of clinical disease also increased if the MSP-1 MAD 20 and the MSP-2 FC 27 alleles were present. This longitudinal analysis thus indicates that the probability of a Ghanaian child having a symptomatic malaria episode is positively associated with both increasing numbers and novel types of P. falciparum clones.

Animals↗

PubMed2001

Water permeability of asymmetric planar lipid bilayers: leaflets of different composition offer independent and additive resistances to permeation.

To understand how plasma membranes may limit water flux, we have modeled the apical membrane of MDCK type 1 cells. Previous experiments demonstrated that liposomes designed to mimic the inner and outer leaflet of this membrane exhibited 18-fold lower water permeation for outer leaflet lipids than inner leaflet lipids (Hill, W.G., and M.L. Zeidel. 2000. J. Biol. Chem. 275:30176-30185), confirming that the outer leaflet is the primary barrier to permeation. If leaflets in a bilayer resist permeation independently, the following equation estimates single leaflet permeabilities: 1/P(AB) = 1/P(A) + 1/P(B) (Eq. l), where P(AB) is the permeability of a bilayer composed of leaflets A and B, P(A) is the permeability of leaflet A, and P(B) is the permeability of leaflet B. Using for the MDCK leaflet-specific liposomes gives an estimated value for the osmotic water permeability (P(f)) of 4.6 x 10(-4) cm/s (at 25 degrees C) that correlated well with experimentally measured values in intact cells. We have now constructed both symmetric and asymmetric planar lipid bilayers that model the MDCK apical membrane. Water permeability across these bilayers was monitored in the immediate membrane vicinity using a Na+-sensitive scanning microelectrode and an osmotic gradient induced by addition of urea. The near-membrane concentration distribution of solute was used to calculate the velocity of water flow (Pohl, P., S.M. Saparov, and Y.N. Antonenko. 1997. Biophys. J. 72:1711-1718). At 36 degrees C, P(f) was 3.44 +/- 0.35 x 10(-3) cm/s for symmetrical inner leaflet membranes and 3.40 +/- 0.34 x 10(-4) cm/s for symmetrical exofacial membranes. From, the estimated permeability of an asymmetric membrane is 6.2 x 10(-4) cm/s. Water permeability measured for the asymmetric planar bilayer was 6.7 +/- 0.7 x 10(-4) cm/s, which is within 10% of the calculated value. Direct experimental measurement of P(f) for an asymmetric planar membrane confirms that leaflets in a bilayer offer independent and additive resistances to water permeation and validates the use of.

Animals↗

PubMed2001

Resting metabolic rate and morphology in mice (Mus musculus) selected for high and low food intake.

We investigated the relationship between resting metabolic rate (RMR) and various morphological parameters in non-breeding mice, selected for high and low food intake corrected for body mass. RMR was measured at 30 degrees C, and mice were subsequently killed and dissected into 19 body components. High-food-intake mice had significantly greater body masses and a significantly elevated RMR compared with the low-intake mice. Data pooled across strains indicated that body mass, sex and strain together explained over 56 % of the observed variation in RMR. The effects of strain and sex on RMR and tissue morphology were removed, and three separate statistical analyses to investigate the relationship between RMR and organ morphology were performed: (i) employing individual regression analysis with each tissue component as a separate predictor against RMR; (ii) individual regression analysis with residual organ mass against residual RMR (i.e. with strain, sex and body mass effects removed); and (iii) pooling of some organ masses into functional groupings to reduce the number of predictors. Liver mass was the most significant morphological trait linked to differences in RMR. Small intestine length was significantly greater in the high-intake line; however, no difference was observed between strains in the dry mass of this organ, and there was no evidence to associate variability in the mass of the alimentary tract with variability in RMR. The effects of strain on RMR independent of the effect on body mass were consistent with the anticipated effect from the strain differences in the size of the liver.

Animals↗

PubMed2000

Reconstituting the barrier properties of a water-tight epithelial membrane by design of leaflet-specific liposomes.

To define aspects of lipid composition and bilayer asymmetry critical to barrier function, we examined the permeabilities of liposomes that model individual leaflets of the apical membrane of a barrier epithelium, Madin-Darby canine kidney type 1 cells. Using published lipid compositions we prepared exofacial liposomes containing phosphatidylcholine, sphingomyelin, glycosphingolipids, and cholesterol; and cytoplasmic liposomes containing phosphatidylethanolamine, phosphatidylserine, and cholesterol. The osmotic permeability of cytoplasmic liposomes to water (P(f)), solutes, and NH(3) was 18-90-fold higher than for the exofacial liposomes (P(f(ex)) = 2.4 +/- 0.4 x 10(-4) cm/s, P(f(cy)) = 4.4 +/- 0.3 x 10(-3) cm/s; P(glycerol(ex)) = 2.5 +/- 0.3 x 10(-8) cm/s, P(glycerol(cy)) = 2.2 +/- 0.02 x 10(-6) cm/s; P(NH3(ex)) = 0. 13 +/- 0.4 x 10(-4) cm/s, P(NH3(cy)) = 7.9 +/- 1.0 x 10(-3) cm/s). By contrast, the apparent proton permeability of exofacial liposomes was 4-fold higher than cytoplasmic liposomes (P(H+(ex)) = 1.1 +/- 0. 1 x 10(-2) cm/s, P(H+(cy)) = 2.7 +/- 0.6 x 10(-3) cm/s). By adding single leaflet permeabilities, we calculated a theoretical P(f) for a Madin-Darby canine kidney apical membrane of 4.6 x 10(-4) cm/s, which compares favorably with experimentally determined values. In exofacial liposomes lacking glycosphingolipids or sphingomyelin, permeabilities were 2-7-fold higher, indicating that both species play a role in barrier function. Removal of cholesterol resulted in 40-280-fold increases in permeability. We conclude: 1) that we have reconstituted the biophysical properties of a barrier membrane, 2) that the barrier resides in the exofacial leaflet, 3) that both sphingomyelin and glycosphingolipids play a role in reducing membrane permeability but that there is an absolute requirement for cholesterol to mediate this effect, 4) that these results further validate the hypothesis that each leaflet offers an independent resistance to permeation, and 5) that proton permeation was enhanced by sphingolipid/cholesterol interactions.

Acetamides↗

PubMed2000

Population dynamics of Plasmodium falciparum in an unstable malaria area of eastern Sudan.

The Plasmodium falciparum population in Asar village, eastern Sudan, where malaria transmission is markedly seasonal, was monitored monthly over a period of 15 months. A cohort of infected patients was treated and then followed monthly throughout the dry season until the next transmission season. Parasitaemia detected by microscopy among the cohort reduced dramatically following treatment, but remained sporadic during the dry season, and reappeared following the onset of the next wet season. However between 40 and 50% of the cohort retained a persisting parasitaemia detectable by PCR throughout the dry season. These parasites were genetically complex, consisting of multiple clones with a large repertoire of alleles of the studied genes. While the number of clones per host dropped significantly following treatment of acute cases during the transmission season, drug treated people nevertheless maintained an average of one clone throughout the dry season. Allele frequencies of MSP-1, MSP-2 and GLURP showed slight, statistically insignificant, fluctuations between the dry and wet seasons. A higher frequency of inbreeding was estimated among the parasites that survived the dry season compared to the wet season.

Alleles↗

PubMed2000

Estimating variance components in natural populations using inferred relationships.

Until recently, the estimation of the heritability of a trait has required knowledge of the pedigree within a population. In natural populations such knowledge is often unknown. Two techniques have been developed which use marker information to estimate heritabilities without reference to the exact nature of the relationships: a regression-based estimator that regresses phenotypic similarity for a pair of individuals against an estimate of their relationship and a likelihood-based estimator that maximizes the probability of the genotypic and phenotypic data given a known population structure. Computer simulation was used to compare the behaviour of these estimators. Bias in estimates of heritability decreased with increasing marker information, decreasing simulated heritability, increasing relatedness and increasing sample size. The techniques displayed reasonable tolerance to the percentage of missing data. The regression-based technique shows least average bias, but largest variance over simulations. Likelihood-based techniques show larger average bias, but smaller variances over estimates. A modified form of the likelihood technique, requiring fewer initial assumptions about population parameters, is presented. The modified form shows less bias in its estimates of heritability than the likelihood technique originally proposed.

Analysis of Variance↗

PubMed2000

Marker-assisted selection to increase effective population size by reducing Mendelian segregation variance.

Using both the genetic drift and inbreeding approaches, we derive more general equations for effective size (N(e)) of a diploid species under random mating. These equations show explicitly that inbreeding or genetic drift comes from two sources, the variation in the number of offspring from each parent and the variation in contribution between these parents' own paternally and maternally derived genes to their offspring. The first source can be easily and effectively controlled by choosing an equal number of offspring from each family, while the second can be manipulated by using information on genetic markers to reduce the variance due to Mendelian segregation. Marker-assisted selection (MAS) methods to increase N(e) for the whole genome with single or multiple marker loci per chromosome, different numbers of males, and females are developed and implemented in stochastic simulations. The analytical and simulation results show that, although in principle N(e) can be increased indefinitely, the efficiency of MAS is restricted in practice by the amount of marker information, the genome size, and the number of marker-genotyped offspring per family. The assumptions made in developing the theory and methods and the applications of MAS in conservation are discussed.

Chromosome Mapping↗

PubMed2000

Estimating quantitative genetic parameters using sibships reconstructed from marker data.

Previous techniques for estimating quantitative genetic parameters, such as heritability in populations where exact relationships are unknown but are instead inferred from marker genotypes, have used data from individuals on a pairwise level only. At this level, families are weighted according to the number of pairs within which each family appears, hence by size rather than information content, and information from multiple relationships is lost. Estimates of parameters are therefore not the most efficient achievable. Here, Markov chain Monte Carlo techniques have been used to partition the population into complete sibships, including, if known, prior knowledge of the distribution of family sizes. These pedigrees have then been used with restricted maximum likelihood under an animal model to estimate quantitative genetic parameters. Simulations to compare the properties of parameter estimates with those of existing techniques indicate that the use of sibship reconstruction is superior to earlier methods, having lower mean square errors and showing nonsignificant downward bias. In addition, sibship reconstruction allows the estimation of population allele frequencies that account for the relationships within the sample, so prior knowledge of allele frequencies need not be assumed. Extensions to these techniques allow reconstruction of half sibships when some or all of the maternal genotypes are known.

Algorithms↗

PubMed2000

Forskolin-induced apical membrane insertion of virally expressed, epitope-tagged CFTR in polarized MDCK cells.

Channel gating of the cystic fibrosis transmembrane conductance regulator (CFTR) is activated in response to cAMP stimulation. In addition, CFTR activation may also involve rapid insertion of a subapical pool of CFTR into the plasma membrane (PM). However, this issue has been controversial, in part because of the difficulty in distinguishing cell surface vs. intracellular CFTR. Recently, a fully functional, epitope-tagged form of CFTR (M2-901/CFTR) that can be detected immunologically in nonpermeabilized cells was characterized (Howard M, Duvall MD, Devor DC, Dong J-Y, Henze K, and Frizzell RA. Am J Physiol Cell Physiol 269: C1565-C1576, 1995; and Schultz BD, Takahashi A, Liu C, Frizzell RA, and Howard M. Am J Physiol Cell Physiol 273: C2080-C2089, 1997). We have developed replication-defective recombinant adenoviruses that express M2-901/CFTR and used them to probe cell surface CFTR in forskolin (FSK)-stimulated polarized Madin-Darby canine kidney (MDCK) cells. Virally expressed M2-901/CFTR was functional and was readily detected on the apical surface of FSK-stimulated polarized MDCK cells. Interestingly, at low multiplicity of infection, we observed FSK-stimulated insertion of M2901/CFTR into the apical PM, whereas at higher M2-901/CFTR expression levels, no increase in surface expression was detected using indirect immunofluorescence. Immunoelectron microscopy of unstimulated and FSK-stimulated cells confirmed the M2-901/CFTR redistribution to the PM upon FSK stimulation and demonstrates that the apically inserted M2-901/CFTR originates from a population of subapical vesicles. Our observations may reconcile previous conflicting reports regarding the effect of cAMP stimulation on CFTR trafficking.

Adenoviridae↗