Population screening for HFE-associated haemochromatosis: should we have to pay for our genes?

Haemochromatosis associated with mutations in the HFE gene is the most common inherited disorder in Caucasian populations. Early diagnosis and treatment allows for normal life expectancy whereas there is considerable morbidity and early mortality in those patients diagnosed late or untreated. Unfortunately, the development of symptoms and signs in haemochromatosis is usually associated with significant iron overload. For this reason, many clinicians and geneticists have advocated population screening. The recent identification of the HFE gene and the availability of a simple DNA-based diagnostic test have led to international debate as to the most cost-effective means of population screening for HFE-associated haemochromatosis. The present paper summarizes the evidence in favour of population screening and analyses the relative advantages of genotypic (DNA test) versus phenotypic (transferrin saturation) testing.

Host selection and utilisation of Sonchus oleraceus (Asteraceae) by Helicoverpa armigera (Lepidoptera : Noctuidae): A genetic analysis

The cotton bollworm (Helicoverpa armigera) prefers the common sowthistle (Sonchus oleraceus L.) to cotton (Gossypium hirsutum L.), sorghum (Sorghum bicolor L.) and maize (Zea mays L.) for oviposition in the field in Australia. Using the common sowthistle and cotton as host plants, we carried out this study to evaluate genetic variation in both oviposition preference and larval growth and genetic correlation between maternal preference and larval performance. There was a significant genetic component of phenotypic variation in both characters, and the heritability of oviposition preference was estimated as 0.602. Helicoverpa armigera larvae survived slightly better and grew significantly faster on common sowthistle than on cotton, but genetic correlation between maternal preference and larval growth performance was not detectable. Instead, larval growth performance on the two hosts changed with families, which renders the interaction between family and host plant significant. As a result, the genetic correlation between mean values of larval growth across the two host species was not different from zero. These results are discussed in the context of the relationship between H. armigera and the common sowthistle and the polyphagous behaviour of this insect in general.

Power of the joint segregation analysis method for testing mixed major-gene and polygene inheritance models of quantitative traits

Understanding the genetic architecture of quantitative traits can greatly assist the design of strategies for their manipulation in plant-breeding programs. For a number of traits, genetic variation can be the result of segregation of a few major genes and many polygenes (minor genes). The joint segregation analysis (JSA) is a maximum-likelihood approach for fitting segregation models through the simultaneous use of phenotypic information from multiple generations. Our objective in this paper was to use computer simulation to quantify the power of the JSA method for testing the mixed-inheritance model for quantitative traits when it was applied to the six basic generations: both parents (P-1 and P-2), F-1, F-2, and both backcross generations (B-1 and B-2) derived from crossing the F-1 to each parent. A total of 1968 genetic model-experiment scenarios were considered in the simulation study to quantify the power of the method. Factors that interacted to influence the power of the JSA method to correctly detect genetic models were: (1) whether there were one or two major genes in combination with polygenes, (2) the heritability of the major genes and polygenes, (3) the level of dispersion of the major genes and polygenes between the two parents, and (4) the number of individuals examined in each generation (population size). The greatest levels of power were observed for the genetic models defined with simple inheritance; e.g., the power was greater than 90% for the one major gene model, regardless of the population size and major-gene heritability. Lower levels of power were observed for the genetic models with complex inheritance (major genes and polygenes), low heritability, small population sizes and a large dispersion of favourable genes among the two parents; e.g., the power was less than 5% for the two major-gene model with a heritability value of 0.3 and population sizes of 100 individuals. The JSA methodology was then applied to a previously studied sorghum data-set to investigate the genetic control of the putative drought resistance-trait osmotic adjustment in three crosses. The previous study concluded that there were two major genes segregating for osmotic adjustment in the three crosses. Application of the JSA method resulted in a change in the proposed genetic model. The presence of the two major genes was confirmed with the addition of an unspecified number of polygenes.

Some vocabulary and grammar for the analysis of multi-environment trials, as applied to the analysis of FPB and PPB trials

For the improvement of genetic material suitable for on farm use under low-input conditions, participatory and formal plant breeding strategies are frequently presented as competing options. A common frame of reference to phrase mechanisms and purposes related to breeding strategies will facilitate clearer descriptions of similarities and differences between participatory plant breeding and formal plant breeding. In this paper an attempt is made to develop such a common framework by means of a statistically inspired language that acknowledges the importance of both on farm trials and research centre trials as sources of information for on farm genetic improvement. Key concepts are the genetic correlation between environments, and the heterogeneity of phenotypic and genetic variance over environments. Classic selection response theory is taken as the starting point for the comparison of selection trials (on farm and research centre) with respect to the expected genetic improvement in a target environment (low-input farms). The variance-covariance parameters that form the input for selection response comparisons traditionally come from a mixed model fit to multi-environment trial data. In this paper we propose a recently developed class of mixed models, namely multiplicative mixed models, also called factor-analytic models, for modelling genetic variances and covariances (correlations). Mixed multiplicative models allow genetic variances and covariances to be dependent on quantitative descriptors of the environment, and confer a high flexibility in the choice of variance-covariance structure, without requiring the estimation of a prohibitively high number of parameters. As a result detailed considerations regarding selection response comparisons are facilitated. ne statistical machinery involved is illustrated on an example data set consisting of barley trials from the International Center for Agricultural Research in the Dry Areas (ICARDA). Analysis of the example data showed that participatory plant breeding and formal plant breeding are better interpreted as providing complementary rather than competing information.

Lucerne biology and genetic improvement - an analysis of past activities and future goals in Australia

Breeding methodologies for cultivated lucerne (Medicago sativa L.), an autotetraploid, have changed little over the last 50 years, with reliance on polycross methods and recurrent phenotypic selection. There has been, however, an increase in our understanding of lucerne biology, in particular the genetic relationships between members of the M. sativa complex, as deduced by DNA analysis. Also, the differences in breeding behaviour and vigour of diploids versus autotetraploids, and the underlying genetic causes, are discussed in relation to lucerne improvement. Medicago falcata, a member of the M. sativa complex, has contributed substantially to lucerne improvement in North America, and its diverse genetics would appear to have been under-utilised in Australian programs over the last two decades, despite the reduced need for tolerance to freezing injury in Australian environments. Breeding of lucerne in Australia only commenced on a large scale in 1977, driven by an urgent need to introgress aphid resistance into adapted backgrounds. The release in the early 1980s of lucernes with multiple pest and disease resistance (aphids, Phytophthora, Colletotrichum) had a significant effect on increasing lucerne productivity and persistence in eastern Australia, with yield increases under high disease pressure of up to 300% being recorded over the predominant Australian cultivar, up to 1977, Hunter River. Since that period, irrigated lucerne yields have plateaued, highlighting the need to identify breeding objectives, technologies, and the germplasm that will create new opportunities for increasing performance. This review discusses major goals for lucerne improvement programs in Australia, and provides indications of the germplasm sources and technologies that are likely to deliver the desired outcomes.

Identification of causal relationships among traits related to drought resistance in Stylosanthes scabra using QTL analysis

Previous studies have shown that a negative relationship exists between transpiration efficiency (TE) and carbon isotope discrimination (Delta) and between TE and specific leaf area (SLA) in Stylosanthes scabra, A glasshouse experiment was conducted to confirm these relationships in an F-2 population and to study the causal nature of these relationships through quantitative trait loci (QTL) analysis, One hundred and twenty F-2 genotypes from a cross between two genotypes within S. scabra were used. Three replications for each genotype were maintained through vegetative propagation, Water stress was imposed by maintaining plants at 40% of field capacity for about 45 d. To facilitate QTL analysis, a genetic linkage map consisting of 151 RAPD markers was developed, Results from this study show that Delta was significantly and negatively correlated with TE and biomass production. Similarly, SLA showed significant negative correlation with TE and biomass production, Most of the QTL for TE and Delta were present on linkage groups 5 and 11. Similarly, QTL for SLA, transpiration and biomass productivity traits were clustered on linkage groups 13 and 24, One unlinked marker was also associated with these traits, There were several markers coincident between different traits, At all the coincident QTL, the direction of QTL effects was consistent with phenotypic data, At the coincident markers between TE and Delta, high alleles of TE were associated with low alleles of Delta. Similarly, low alleles of SLA were associated with high alleles of biomass productivity traits and transpiration. At the coincident markers between trans-4-hydroxy-N-methyl proline (MHP) and relative water content (RWC), low alleles of MHP were associated with high alleles of RWC, This study suggests the causal nature of the relationship between TE and Delta. Phenotypic data and QTL, data show that SLA was more closely associated with biomass production than with TE, This study also shows that a cause-effect relationship may exist between SLA and biomass production.

Modulation of the adrenocortical stress response in marine turtles (Cheloniidae): evidence for a hormonal tactic maximizing maternal reproductive investment

The relationships between reproductive condition, level of reproductive investment and adrenocortical modulation to capture stress in marine turtles form the basis of this study. When subjected to either capture or ecological stressors, nesting marine turtles have demonstrated adrenocortical responses that are both small in magnitude, and slow in responsiveness. These observations were further investigated to determine whether this minimal stress response was a physiological strategy to maximize reproductive investment in adult green Chelonia mydas and hawksbill Eretmochelys imbricata turtles. Female green and hawksbill turtles exhibited a decrease in adrenocortical responsiveness with progressive reproductive condition. Breeding turtles exhibited most suppression of their adrenocortical response to capture compared to both non-breeding and pre-breeding female counterparts. Nesting green turtles maintained a suppressed adrenocortical response to capture throughout the nesting season despite decreased reproductive investment. In contrast, male green and hawksbill turtles were less able to modulate their corticosterone (B) response to acute capture stress. During breeding, male turtles possessed significantly greater adrenocortical responses to capture than females. These results could indicate that the large reproductive investment necessary for female marine turtle reproduction might underlie the marked decrease in adrenocortical responsiveness. This hormonal mechanism could function as one strategy by which female marine turtles maximize their current reproductive event, even though under certain situations this mechanism could entail costs to female survival.

Chk2 activation dependence on Nbs1 after DNA damage

The checkpoint kinase Chk2 has a key role in delaying cell cycle progression in response to DNA damage. Upon activation by low-dose ionizing radiation (IR), which occurs in an ataxia telangiectasia mutated (ATM)dependent manner, Chk2 can phosphorylate the mitosis-inducing phosphatase Cdc25C on an inhibitory site, blocking entry into mitosis, and p53 on a regulatory site, causing G, arrest. Here we show that the ATM-dependent activation of Chk2 by gamma- radiation requires Nbs1, the gene product involved in the Nijmegen breakage syndrome (NBS), a disorder that shares with AT a variety of phenotypic defects including chromosome fragility, radiosensitivity, and radioresistant DNA synthesis. Thus, whereas in normal cells Chk2 undergoes a time-dependent increased phosphorylation and induction of catalytic activity against Cdc25C, in NBS cells null for Nbs1 protein, Chk2 phosphorylation and activation are both defective. Importantly, these defects in NBS cells can be complemented by reintroduction of wild-type Nbs1, but neither by a carboxy-terminal deletion mutant of Nbs1 at amino acid 590, unable to form a complex with and to transport Mre11 and Rad50 in the nucleus, nor by an Nbs1 mutated at Ser343 (S343A), the ATM phosphorylation site. Chk2 nuclear expression is unaffected in NBS cells, hence excluding a mislocalization as the cause of failed Chk2 activation in Nbs1-null cells, interestingly, the impaired Chk2 function in NBS cells correlates with the inability, unlike normal cells, to stop entry into mitosis immediately after irradiation, a checkpoint abnormality that can be corrected by introduction of the wild-type but not the S343A mutant form of Nbs1, Altogether, these findings underscore the crucial role of a functional Nbs1 complex in Chk2 activation and suggest that checkpoint defects in NBS cells may result from the inability to activate Chk2.

Canopy carbon and oxygen isotope composition of 9-year-old hoop pine families in relation to seedling carbon isotope composition, growth, field growth performance, and canopy nitrogen concentration

Carbon isotope composition (delta C-13), oxygen isotope composition (delta O-18), and nitrogen concentration (N-mass) of branchlet tissue at two canopy positions were assessed for glasshouse seedlings and 9-year-old hoop pine (Araucaria cunninghamii Ait. ex D. Don) trees from 22 open-pollinated families grown in 5 blocks of a progeny test at a water-limited and nitrogen-deficient site in southeastern Queensland, Australia. Significant variations in canopy delta C-13, delta O-18, and N-mass existed among the 9-year-old hoop pine families, with a heritability estimate of 0.72 for branchlet delta C-13 from the upper inner canopy position. There was significant variation in canopy delta C-13 of glasshouse seedlings between canopy positions and among the families, with a heritability estimate of 0.66. The canopy delta C-13 was positively related to canopy N-mass only for the upper outer crown in the field (R = 0.62, p < 0.001). Phenotypic correlations existed between tree height and canopy delta C-13 (R = 0.37-0.41, p < 0.001). Strong correlations were found between family canopy delta C-13 at this site and those at a wetter site and between field canopy delta C-13 and glasshouse seedling delta C-13. The mechanisms of the variation in canopy delta C-13 are discussed in relation to canopy photosynthetic capacity as reflected in the N-mass and stomatal conductance as indexed by canopy delta O-18.

Role of cytokine gene polymorphisms in acute rejection and renal impairment after liver transplantation

Although immunosuppressive regimens are effective, rejection occurs in up to 50% of patients after orthotopic liver transplantation (OLT), and there is concern about side effects from long-term therapy. Knowledge of clinical and immunogenetic variables may allow tailoring of immunosuppressive therapy to patients according to their potential risks. We studied the association between transforming growth factor-beta, interleukin-10, and tumor necrosis factor alpha (TNF-alpha) gene polymorphisms and graft rejection and renal impairment in 121 white liver transplant recipients. Clinical variables were collected retrospectively, and creatinine clearance was estimated using the formula of Cockcroft and Gault. Biallelic polymorphisms were detected using polymerase chain reaction-based methods. Thirty-seven of 121 patients (30.6%) developed at least 1 episode of rejection. Multivariate analysis showed that Child-Pugh score (P =.001), immune-mediated liver disease (P =.018), normal pre-OLT creatinine clearance (P =.037), and fewer HLA class 1 mismatches (P =.038) were independently associated with rejection, Renal impairment occurred in 80% of patients and was moderate or severe in 39%, Clinical variables independently associated with renal impairment were female sex (P =.001), pre-OLT renal dysfunction (P =.0001), and a diagnosis of viral hepatitis (P =.0008), There was a significant difference in the frequency of TNF-alpha -308 alleles among the primary liver diseases. After adjustment for potential confounders and a Bonferroni correction, the association between the TNF-alpha -308 polymorphism and graft rejection approached significance (P =.06). Recipient cytokine genotypes do not have a major independent role in graft rejection or renal impairment after OLT, Additional studies of immunogenetic factors require analysis of large numbers of patients with appropriate phenotypic information to avoid population stratification, which may lead to inappropriate conclusions.

Stenotherms at sub-zero temperatures: thermal dependence of swimming performance in Antarctic fish

We examined the burst swimming performance of two Antarctic fishes, Trematomus bernacchii and T. centronotus, at five temperatures between -1 degreesC and 10 degreesC. As Antarctic fishes are considered one of the most cold specialised and stenothermal of all ectotherms, we predicted they would possess a narrow thermal performance breadth for burst swimming and a correlative decrease in performance at high temperatures. Burst swimming was assessed by videotaping swimming sequences with a 50-Hz video camera and analysing the sequences frame-by-frame to determine maximum velocity, the distance moved throughout the initial 200 ms, and the time taken to reach maximum velocity. In contrast to our prediction, we found both species possessed a wide thermal performance breadth for burst swimming. Although maximum swimming velocity for both T. bernacchii and T. centronotus was significantly highest at 6 degreesC, maximum velocity at ah other test temperatures was less than 20% lower. Thus, it appears that specialisation to a highly stable and cold environment is not necessarily associated with a narrow thermal performance breadth for burst swimming in Antarctic fish. We also examined the ability of the Antarctic fish Pagothenia borchgrevinki to acclimate their burst-swimming performance to different temperatures. We exposed P, borchgrevinki to either -1 degreesC or 4 degreesC for 4 weeks and tested their burst-swimming performance at four temperatures between -1 degreesC and 10 degreesC. Burst-swimming performance of Pagothenia borchgrevinki was unaffected by exposure to either -1 degreesC or 4 degreesC for 4 weeks. Maximum swimming velocity of both acclimation groups was thermally independent over the total temperature range of -1 degreesC to 10 degreesC. Therefore, the loss of any capacity to restructure the phenotype and an inability to thermally acclimate swimming performance appears to be associated with inhabiting a highly stable thermal environment.

A phylogeny for the genus Isoodon and a range extension for I-obesulus peninsulae based on mtDNA control region and morphology

Short-nosed bandicoots, Isoodon, have undergone marked range contractions since European colonisation of Australia and are currently divided into many subspecies, the validity of which is debated. Discriminant function analysis of morphology and a phylogeny of Isoodon based on mtDNA control region sequences indicate a clear split between two of the three recognised species, I. macrourus and I. obesulus/auratus. However, while all previously recognised taxa within the I. obesulus/auratus group are morphologically distinct, I. auratus and I. obesulus are not phylogenetically distinct for mtDNA. The genetic divergence between I. obesulus and I. auratus (2.6%) is similar to that found among geographic isolates of the former (I. o. obesulus and I. o. peninsulae: 2.7%). Further, the divergence between geographically close populations of two different species (I. o. obesulus from Western Australia and I. a. barrowensis: 1.2%) is smaller than that among subspecies within I. auratus (I. a. barrowensis and I. auratus from northern Western Australia: 1.7%). A newly discovered population of Isoodon in the Lamb Range, far north Queensland, sympatric with a population of I. m. torosus, is shown to represent a range extension of I. o. peninsulae (350 km). It seems plausible that what is currently considered as two species, I. obesulus and I. auratus, was once one continuous species now represented by isolated populations that have diverged morphologically as a consequence of adaptation to the diverse environments that occur throughout their range. The taxonomy of these populations is discussed in relation to their morphological distinctiveness and genetic similarity.

Determination of breeding strategies for beef cattle bull breeders selling bulls into two competing markets on a non-linear price grid

Computer simulation was used to suggest potential selection strategies for beef cattle breeders with different mixes of clients between two potential markets. The traditional market paid on the basis of carcass weight (CWT), while a new market considered marbling grade in addition to CWT as a basis for payment. Both markets instituted discounts for CWT in excess of 340 kg and light carcasses below 300 kg. Herds were simulated for each price category on the carcass weight grid for the new market. This enabled the establishment of phenotypic relationships among the traits examined [CWT, percent intramuscular fat (IMF), carcass value in the traditional market, carcass value in the new market, and the expected proportion of progeny in elite price cells in the new market pricing grid]. The appropriateness of breeding goals was assessed on the basis of client satisfaction. Satisfaction was determined by the equitable distribution of available stock between markets combined with the assessment of the utility of the animal within the market to which it was assigned. The best goal for breeders with predominantly traditional clients was a CWT in excess of 330 kg, while that for breeders with predominantly new market clients was a CWT of between 310 and 329 kg and with a marbling grade of AAA in the Ontario carcass pricing system. For breeders who wished to satisfy both new and traditional clients, the optimal CWT was 310-329 kg and the optimal marbling grade was AA-AAA. This combination resulted in satisfaction levels of greater than 75% among clients, regardless of the distribution of the clients between the traditional and new marketplaces.

Habitat complexity, spatial interference, and "minimum risk distribution": a framework for population stability

In the past century, the debate over whether or not density-dependent factors regulate populations has generally focused on changes in mean population density, ignoring the spatial variance around the mean as unimportant noise. In an attempt to provide a different framework for understanding population dynamics based on individual fitness, this paper discusses the crucial role of spatial variability itself on the stability of insect populations. The advantages of this method are the following: (1) it is founded on evolutionary principles rather than post hoc assumptions; (2) it erects hypotheses that can be tested; and (3) it links disparate ecological schools, including spatial dynamics, behavioral ecology, preference-performance, and plant apparency into an overall framework. At the core of this framework, habitat complexity governs insect spatial variance. which in turn determines population stability. First, the minimum risk distribution (MRD) is defined as the spatial distribution of individuals that results in the minimum number of premature deaths in a population given the distribution of mortality risk in the habitat (and, therefore, leading to maximized population growth). The greater the divergence of actual spatial patterns of individuals from the MRD, the greater the reduction of population growth and size from high, unstable levels. Then, based on extensive data from 29 populations of the processionary caterpillar, Ochrogaster lunifer, four steps are used to test the effect of habitat interference on population growth rates. (1) The costs (increasing the risk of scramble competition) and benefits (decreasing the risk of inverse density-dependent predation) of egg and larval aggregation are quantified. (2) These costs and benefits, along with the distribution of resources, are used to construct the MRD for each habitat. (3) The MRD is used as a benchmark against which the actual spatial pattern of individuals is compared. The degree of divergence of the actual spatial pattern from the MRD is quantified for each of the 29 habitats. (4) Finally, indices of habitat complexity are used to provide highly accurate predictions of spatial divergence from the MRD, showing that habitat interference reduces population growth rates from high, unstable levels. The reason for the divergence appears to be that high levels of background vegetation (vegetation other than host plants) interfere with female host-searching behavior. This leads to a spatial distribution of egg batches with high mortality risk, and therefore lower population growth. Knowledge of the MRD in other species should be a highly effective means of predicting trends in population dynamics. Species with high divergence between their actual spatial distribution and their MRD may display relatively stable dynamics at low population levels. In contrast, species with low divergence should experience high levels of intragenerational population growth leading to frequent habitat-wide outbreaks and unstable dynamics in the long term. Six hypotheses, erected under the framework of spatial interference, are discussed, and future tests are suggested.

SOX18 directly interacts with MEF2C in endothelial cells

Recently, we demonstrated that mutations in the Sry-related HMG box gene Sox18 underlie vascular and hair follicle defects in the mouse allelic mutants ragged (Ra) and RaJ. Ra mice display numerous anomalies in the homozygote including, oedema, peritoneal secretions, and are almost completely naked. Sox18 and the MADS box transcription factor, Mef2C, are expressed in developing endothelial cells. Null mutants in Sox18 and Mef2c display overlapping phenotypic abnormalities, hence, we investigated the relationship between these two DNA binding proteins. We report here the direct interaction between MEF2C and SOX18 proteins, and establish that these proteins are coexpressed in vivo in endothelial cell nuclei. MEF2C expression potentiates SOX18-mediated transcription in vivo and regulates the function of the SOX18 activation domain. Interestingly, MEF2C fails to interact or co-activate transcription with the Ra or RaJ mutant SOX18 proteins. These results suggest that MEF2C and SOX18 may be important partners directing the transcriptional regulation of vascular development. (C) 2001 Academic Press.