Enlarging a training set for genomic selction by imputation of un-genotyped animals in populations of varying genetic architecture

Background: The most common application of imputation is to infer genotypes of a high-density panel of markers on animals that are genotyped for a low-density panel. However, the increase in accuracy of genomic predictions resulting from an increase in the number of markers tends to reach a plateau beyond a certain density. Another application of imputation is to increase the size of the training set with un-genotyped animals. This strategy can be particularly successful when a set of closely related individuals are genotyped. ----- Methods: Imputation on completely un-genotyped dams was performed using known genotypes from the sire of each dam, one offspring and the offspring’s sire. Two methods were applied based on either allele or haplotype frequencies to infer genotypes at ambiguous loci. Results of these methods and of two available software packages were compared. Quality of imputation under different population structures was assessed. The impact of using imputed dams to enlarge training sets on the accuracy of genomic predictions was evaluated for different populations, heritabilities and sizes of training sets. ----- Results: Imputation accuracy ranged from 0.52 to 0.93 depending on the population structure and the method used. The method that used allele frequencies performed better than the method based on haplotype frequencies. Accuracy of imputation was higher for populations with higher levels of linkage disequilibrium and with larger proportions of markers with more extreme allele frequencies. Inclusion of imputed dams in the training set increased the accuracy of genomic predictions. Gains in accuracy ranged from close to zero to 37.14%, depending on the simulated scenario. Generally, the larger the accuracy already obtained with the genotyped training set, the lower the increase in accuracy achieved by adding imputed dams. ----- Conclusions: Whenever a reference population resembling the family configuration considered here is available, imputation can be used to achieve an extra increase in accuracy of genomic predictions by enlarging the training set with completely un-genotyped dams. This strategy was shown to be particularly useful for populations with lower levels of linkage disequilibrium, for genomic selection on traits with low heritability, and for species or breeds for which the size of the reference population is limited.

Effects of fungicide dose and mixtures on selection for triazole resistance in Mycosphaerella graminicola under field conditions

The effects of varying doses of fungicides, alone or in mixtures, on selection for triazole resistance were examined under field conditions. Two experiments were conducted using the triazole fungicide fluquinconazole with the strobilurin fungicide azoxystrobin as a mixture partner. Inoculated wheat plots with a known ratio of more sensitive to less sensitive isolates of the leaf blotch fungus Mycosphaerella graminicola were sprayed with fungicide and sampled once symptoms had appeared. Selection for fluquinconazole resistance increased in proportion to the dose, up to one-half of the full dose (the maximum tested) in both experiments. At the higher doses of fluquinconazole, the addition of azoxystrobin was associated with a decrease in selection (nonsignificant in the first experiment) for triazole resistance. Control by low doses of fluquinconazole was increased by mixture with azoxystrobin, but at higher doses mixture with azoxystrobin sometimes decreased control, so that reduced selection was obtained at the cost of some reduction in control. The effects on resistance are not necessarily general consequences of mixing fungicides, and suggest that the properties of any specific mixture may need to be demonstrated experimentally. Selection was inversely related to control in the unmixed treatments in both experiments, but the relationship was weaker in the mixtures with azoxystrobin.

Half-sib progenies evaluation in velvet grass

O capim-lanudo (Holcus lanatus L.) possui grande potencial de utilização como pastagem de inverno nas regiões subtropicais, devido a seu bom estabelecimento, persistência, produção, resistência ao frio, palatabilidade e capacidade de afilhamento. O objetivo deste trabalho foi estimar a variabilidade genética e a herdabilidade de caracteres agronômicos e identificar progênies superiores. Foram avaliadas 60 progênies de meios-irmãos, para altura (NH) e diâmetro da planta na fase vegetativa, duração do ciclo vegetativo (ciclo), altura final (FH) e número de afilhos. Houve diferença entre progênies para todos os caracteres. As estimativas de herdabilidade foram de 38%, 32%, 92%, 57% e 64% para NH, diâmetro, ciclo, FH e afilhos, respectivamente. O maior ganho genético estimado foi de 30,77 % para o número de afilhos. Existe variabilidade para todos os caracteres e são esperados ganhos na seleção entre progênies.

Estimates of genetic correlations between days to calving and reproductive and weight traits in Nelore cattle

Data comprising 53,181 calving records were analyzed to estimate the genetic correlation between days to calving (DC), and days to first calving (DFC), and the following traits: scrotal circumference (SC), age at first calving (AFC), and weight adjusted for 550 d of age (W550) in a Nelore herd. (Co)variance components were estimated using the REML method fitting bivariate animal models. The fixed effects considered for DC were contemporary group, month of last calving, and age at breeding season (linear and quadratic effects). Contemporary groups were composed by herd, year, season, and management group at birth; herd and management group at weaning; herd, season, and management group at mating; and sex of calf and mating type (multiple sires, single sire, or AI). In DFC analysis, the same fixed effects were considered excluding the month of last calving. For DC, a repeatability animal model was applied. Noncalvers were not considered in analyses because an attempt to include them, attributing a penalty, did not improve the identification of genetic differences between animals. Heritability estimates ranged from 0.04 to 0.06 for DC, from 0.06 to 0.13 for DFC, from 0.42 to 0.44 for SC, from 0.06 to 0.08 for AFC, and was 0.30 for W550. The genetic correlation estimated between DC and SC was low and negative (-0.10), between DC and AFC was high and positive (0.76), and between DC and W550 was almost null (0.07). Similar results were found for genetic correlation estimates between DFC and SC (-0.14), AFC (0.94), and W550 (-0.02). The genetic correlation estimates indicate that the use of DC in the selection of beef cattle may promote favorable correlated responses to age at first mating and, consequently, higher gains in sexual precocity can be expected.

Genetic parameters and relationships between growth traits and scrotal circumference measured at different ages in Nellore cattle

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Classic and molecular cytogenetic analyses reveal chromosomal gains and losses correlated with survival in head and neck cancer patients

Purpose: Genetic biomarkers of head and neck tumors could be useful for distinguishing among patients with similar clinical and histopathologic characteristics but having differential probabilities of survival. The purpose of this study was to investigate chromosomal alterations in head and neck carcinomas and to correlate the results with clinical and epidentiologic variables.Experimental Design: Cytogenetic analysis of short-term cultures from 64 primary untreated head and neck squamous cell carcinomas was used to determine the overall pattern of chromosome aberrations. A representative subset of tumors was analyzed in detail by spectral karyotyping and/or confirmatory fluorescence in situ hybridization analysis.Results: Recurrent losses of chromosomes Y (26 cases) and 19 (14 cases), and gains of chromosomes 22 (23 cases), 8 and 20 (11 cases each) were observed. The most frequent structural aberration was del(22)(q13.1) followed by rearrangements involving 6q and 12p. The presence of specific cytogenetic aberrations was found to correlate significantly with an unfavorable outcome. There was a significant association between survival and gains in chromosomes 10 (P = 0.008) and 20 (P = 0.002) and losses of chromosomes 15 (P = 0.005) and 22 (P = 0.021). Univariate analysis indicated that acquisition of monosomy 17 was a significant (P = 0.0012) factor for patients with a previous family history of cancer.Conclusions: the significant associations found in this study emphasize that alterations of distinct regions of the genome may be genetic biomarkers for a poor prognosis. Losses of chromosomes 17 and 22 can be associated with a family history of cancer.

Estimation of variance components and prediction of breeding values in rubber tree breeding using the REML/BLUP procedure

The present paper deals with estimation of variance components, prediction of breeding values and selection in a population of rubber tree [Hevea brasiliensis (Willd. ex Adr. de Juss.) Müell.-Arg.] from Rio Branco, State of Acre, Brazil. The REML/BLUP (restricted maximum likelihood/best linear unbiased prediction) procedure was applied. For this purpose, 37 rubber tree families were obtained and assessed in a randomized complete block design, with three unbalanced replications. The field trial was carried out at the Experimental Station of UNESP, located in Selvíria, State of Mato Grosso do Sul, Brazil. The quantitative traits evaluated were: girth (G), bark thickness (BT), number of latex vessel rings (NR), and plant height (PH). Given the unbalanced condition of the progeny test, the REML/BLUP procedure was used for estimation. The narrow-sense individual heritability estimates were 0.43 for G, 0.18 for BT, 0.01 for NR, and 0.51 for PH. Two selection strategies were adopted: one short-term (ST - selection intensity of 8.85%) and the other long-term (LT - selection intensity of 26.56%). For G, the estimated genetic gains in relation to the population average were 26.80% and 17.94%, respectively, according to the ST and LT strategies. The effective population sizes were 22.35 and 46.03, respectively. The LT and ST strategies maintained 45.80% and 28.24%, respectively, of the original genetic diversity represented in the progeny test. So, it can be inferred that this population has potential for both breeding and ex situ genetic conservation as a supplier of genetic material for advanced rubber tree breeding programs. Copyright by the Brazilian Society of Genetics.

Genetic correlations between mature cow weight and productive and reproductive traits in Nellore cattle

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Genetic parameters for test-day milk yield, 305-day milk yield, and lactation length in Guzerat cows

Milk production in tropical environments requires the use of crossbreeding systems including breeds well adapted to harsh conditions, but with lower productivities when compared to specialized breeds. Besides the genetic improvement for milk production, lactation lengths also need to be studied for most of these breeds. Accordingly, genetic parameters were estimated for 305-day cumulative milk yield (MY305), test-day milk yield (TDMY), and lactation length (LL) using information from the first lactations of 2816 Guzerat cows selected for milk production in 28 herds in Brazil. Contemporary groups were defined as herd, year and season of the test for TDMY, and as herd, year and season of calving for MY305 and LL. Variance components were estimated with the restricted maximum likelihood method under a multi-trait animal model. Heritabilities estimated for TDMY ranged from 0.16 to 0.24, and were 0.24 and 0.12 for MY305 and LL, respectively. Genetic correlations were high and positive, ranging from 0.51 to 0.99 among TDMY records, from 0.81 to 0.98 between each TDMY and MY305, and from 0.71 to 0.94 between each TDMY and LL. Genetic parameters obtained in this study indicated the possibility of using test-day records for the prediction of breeding values for milk yield in this population of the Guzerat breed. The use of TDMY as selection criteria would result in indirect gains in MY305 and LL. However, the highest response to selection for MY305 would be obtained by direct selection for this trait. © 2012 Elsevier B.V.

Productivity, stability and adaptability in open pollination progenies of Eucalyptus urophylla ST Blake

Prediction of genetic gains within breeding programs is not always compatible with those observed in practice. One reason for this inconsistency is the lack of knowledge of genotype-environment interaction (GxE). The aim of this study was to estimate genetic variation, evaluate the GxE, investigate the genetic correlation between pairs of environments and for the set, and to study the productivity, stability and adaptability at 2 years of age for diameter at breast height (DBH) in five progenies trials of Eucalyptus urophylla, used in a randomized complete block design, with the number of progenies ranging from 138 to 167, four to eight blocks and five to six plants per plot. Estimates of variance components and genetic parameters were obtained using the REML/BLUP method. For analysis of productivity, stability and adaptability, the HMRPGV method was used. The highest DBH growth was observed in Anhembi (10.52 cm) and Uberaba (10.20 cm). Estimates considered high were obtained for the coefficient of individual additive genetic variation (>13.3%) and average heritability among progenies (>0.40), indicating the possibility of obtaining genetic gains by selection among progenies. The coefficient of determination of the GxE was 1.7%, a fact that led to a high value of genotypic correlation between the performance of the progenies and environments (78.1%), indicating that the interaction is simple. The first six progenies showed a coincidence of 100% in the order of stability (HMGV), adaptability (RPGV) and productivity (HMRPGV), being 13% higher than the overall mean of five experiments (9.21 cm). When ordering the progenies, the selection of the 20 best in growth led to an increase in gain ranging of from 10.4 to 70%. Anhembi is the ideal place to have a breeding population which will be good in the other places as well.

Estimates of life expectancy gains from reducing/eliminating major causes of death in the USA: An update analysis for population in 2001--2008

Evaluation of the impact of a disease on life expectancy is an important part of public health. Potential gains in life expectancy (PGLE) that can properly take into account the competing risks are an effective indicator for measuring the impact of the multiple causes of death. This study aimed to measure the PGLEs from reducing/eliminating the major causes of death in the USA from 2001 to 2008. To calculate the PGLEs due to the elimination of specific causes of death, the age-specific mortality rates for heart disease, malignant neoplasms, Alzheimer disease, kidney diseases and HIV/AIDS and life table constructing data were obtained from the National Center for Health Statistics, and the multiple decremental life tables were constructed. The PGLEs by elimination of heart disease, malignant neoplasms or HIV/AIDS continued decreasing from 2001 to 2008, but the PGLE by elimination of Alzheimer's disease or kidney diseases revealed increased trends. The PGLEs (by years) for all race, male, female, white, white male, white female, black, black male and black female at birth by complete elimination of heart disease 2001–2008 were 0.336–0.299, 0.327–0.301, 0.344–0.295, 0.360–0.315, 0.349–0.317, 0.371–0.316,0.278–0.251, 0.272–0.255, and 0.282–0.246 respectively. Similarly, the PGLEs (by years) for all race, male, female, white, white male, white female, black, black male and black female at birth by complete elimination of malignant neoplasms, Alzheimer's disease, kidney disease or HIV/AIDS 2001–2008 were also uncovered, respectively. Most diseases affect specific population, such as, HIV/AIDS tends to have a greater impact on people of working age, heart disease and malignant neoplasms have a greater impact on people over 65 years of age, but Alzheimer's disease and kidney diseases have a greater impact on people over 75 years of age. To measure the impact of these diseases on life expectancy in people of working age, partial multiple decremental life tables were constructed and the PGLEs were computed by partial or complete elimination of various causes of death during the working years. Thus, the results of the study outlined a picture of how each single disease could affect the life expectancy in age-, race-, or sex-specific population in USA. Therefore, the findings would not only assist to evaluate current public health improvements, but also provide useful information for future research and disease control programs.^

Chromosomal aberrations in PARP−/− mice: Genome stabilization in immortalized cells by reintroduction of poly(ADP-ribose) polymerase cDNA

Depletion of poly(ADP-ribose) polymerase (PARP) increases the frequency of recombination, gene amplification, sister chromatid exchanges, and micronuclei formation in cells exposed to genotoxic agents, implicating PARP in the maintenance of genomic stability. Flow cytometric analysis now has revealed an unstable tetraploid population in immortalized fibroblasts derived from PARP−/− mice. Comparative genomic hybridization detected partial chromosomal gains in 4C5-ter, 5F-ter, and 14A1-C1 in PARP−/−mice and immortalized PARP−/−fibroblasts. Neither the chromosomal gains nor the tetraploid population were apparent in PARP−/− cells stably transfected with PARP cDNA [PARP−/−(+PARP)], indicating negative selection of cells with these genetic aberrations after reintroduction of PARP cDNA. Although the tumor suppressor p53 was not detectable in PARP−/− cells, p53 expression was partially restored in PARP−/− (+PARP) cells. Loss of 14D3-ter that encompasses the tumor suppressor gene Rb-1 in PARP−/− mice was associated with a reduction in retinoblastoma(Rb) expression; increased expression of the oncogene Jun was correlated with a gain in 4C5-ter that harbors this oncogene. These results further implicate PARP in the maintenance of genomic stability and suggest that altered expression of p53, Rb, and Jun, as well as undoubtedly many other proteins may be a result of genomic instability associated with PARP deficiency.

Factors in the selection of patients for conditional release from their first psychiatric hospitalization

Objective: This study examined a sample of patients in Victoria, Australia, to identify factors in selection for conditional release from an initial hospitalization that occurred within 30 days of entry into the mental health system. Methods: Data were from the Victorian Psychiatric Case Register. All patients first hospitalized and conditionally released between 1990 and 2000 were identified (N = 8,879), and three comparison groups were created. Two groups were hospitalized within 30 days of entering the system: those who were given conditional release and those who were not. A third group was conditionally released from a hospitalization that occurred after or extended beyond 30 days after system entry. Logistic regression identified characteristics that distinguished the first group. Ordinary least-squares regression was used to evaluate the contribution of conditional release early in treatment to reducing inpatient episodes, inpatient days, days per episode, and inpatient days per 30 days in the system. Results: Conditional release early in treatment was used for 11 percent of the sample, or more than a third of those who were eligible for this intervention. Factors significantly associated with selection for early conditional release were those related to a better prognosis ( initial hospitalization at a later age and having greater than an 11th grade education), a lower likelihood of a diagnosis of dementia or schizophrenia, involuntary status at first inpatient admission, and greater community involvement ( being employed and being married). When the analyses controlled for these factors, use of conditional release early in treatment was significantly associated with a reduction in use of subsequent inpatient care.

Applied evolution: An integrated approach to studying life history traits in response to drug selection

The use of chemical control measures to reduce the impact of parasite and pest species has frequently resulted in the development of resistance. Thus, resistance management has become a key concern in human and veterinary medicine, and in agricultural production. Although it is known that factors such as gene flow between susceptible and resistant populations, drug type, application methods, and costs of resistance can affect the rate of resistance evolution, less is known about the impacts of density-dependent eco-evolutionary processes that could be altered by drug-induced mortality. The overall aim of this thesis was to take an experimental evolution approach to assess how life history traits respond to drug selection, using a free-living dioecious worm (Caenorhabditis remanei) as a model. In Chapter 2, I defined the relationship between C. remanei survival and Ivermectin dose over a range of concentrations, in order to control the intensity of selection used in the selection experiment described in Chapter 4. The dose-response data were also used to appraise curve-fitting methods, using Akaike Information Criterion (AIC) model selection to compare a series of nonlinear models. The type of model fitted to the dose response data had a significant effect on the estimates of LD50 and LD99, suggesting that failure to fit an appropriate model could give misleading estimates of resistance status. In addition, simulated data were used to establish that a potential cost of resistance could be predicted by comparing survival at the upper asymptote of dose-response curves for resistant and susceptible populations, even when differences were as low as 4%. This approach to dose-response modeling ensures that the maximum amount of useful information relating to resistance is gathered in one study. In Chapter 3, I asked how simulations could be used to inform important design choices used in selection experiments. Specifically, I focused on the effects of both within- and between-line variation on estimated power, when detecting small, medium and large effect sizes. Using mixed-effect models on simulated data, I demonstrated that commonly used designs with realistic levels of variation could be underpowered for substantial effect sizes. Thus, use of simulation-based power analysis provides an effective way to avoid under or overpowering a study designs incorporating variation due to random effects. In Chapter 4, I 3 investigated how Ivermectin dosage and changes in population density affect the rate of resistance evolution. I exposed replicate lines of C. remanei to two doses of Ivermectin (high and low) to assess relative survival of lines selected in drug-treated environments compared to untreated controls over 10 generations. Additionally, I maintained lines where mortality was imposed randomly to control for differences in density between drug treatments and to distinguish between the evolutionary consequences of drug treatment versus ecological processes affected by changes in density-dependent feedback. Intriguingly, both drug-selected and random-mortality lines showed an increase in survivorship when challenged with Ivermectin; the magnitude of this increase varied with the intensity of selection and life-history stage. The results suggest that interactions between density-dependent processes and life history may mediate evolved changes in susceptibility to control measures, which could result in misleading conclusions about the evolution of heritable resistance following drug treatment. In Chapter 5, I investigated whether the apparent changes in drug susceptibility found in Chapter 4 were related to evolved changes in life-history of C. remanei populations after selection in drug-treated and random-mortality environments. Rapid passage of lines in the drug-free environment had no effect on the measured life-history traits. In the drug-free environment, adult size and fecundity of drug-selected lines increased compared to the controls but drug selection did not affect lifespan. In the treated environment, drug-selected lines showed increased lifespan and fecundity relative to controls. Adult size of randomly culled lines responded in a similar way to drug-selected lines in the drug-free environment, but no change in fecundity or lifespan was observed in either environment. The results suggest that life histories of nematodes can respond to selection as a result of the application of control measures. Failure to take these responses into account when applying control measures could result in adverse outcomes, such as larger and more fecund parasites, as well as over-estimation of the development of genetically controlled resistance. In conclusion, my thesis shows that there may be a complex relationship between drug selection, density-dependent regulatory processes and life history of populations challenged with control measures. This relationship could have implications for how resistance is monitored and managed if life histories of parasitic species show such eco-evolutionary responses to drug application.

Transitioning students to work through authentic employment-based training in an Australian senior secondary VET program.

A common challenge among OECD countries has been the development of education and training pathways that accommodate student needs and interests at the upper secondary level (OECD, 2000). The introduction of trade-focussed Australian Technical Colleges (ATCs) has met with mixed response. The ATCs aim to create a supported transition from school to work through dual pathway programs enabling students to follow a trade career while completing their upper secondary studies. There has been little explicit examination of the effectiveness of such senior secondary school arrangements. Using one such Australian Technical College as a case-study, this paper investigates the perceptions of the employers and students who were associated with the college. Using mixed-methods consisting of quantitative perception surveys and focus interviews, the results of this study show that students and employers are very satisfied with the College and illustrate that students have made significant gains in relating their learning to the workplace and everyday life.