The major murine systemic lupus erythematosus susceptibility locus, Sle1, is a cluster of functionally related genes

The major murine systemic lupus erythematosus (SLE) susceptibility locus Sle1 is syntenic to a chromosomal region linked with SLE susceptibility in multiple human studies. Congenic analyses have shown that Sle1 breaks tolerance to chromatin, a necessary step for full disease induction that can be suppressed by specific modifier loci. In the present study, our fine mapping analysis of the location of Sle1 has determined that three loci within this congenic interval, termed Sle1a, Sle1b, and Sle1c, can independently cause a loss of tolerance to chromatin. Each displays a distinctive profile of serological and cellular characteristics, with T and B cell functions being more affected by Sle1a and Sle1b, respectively. The epistatic interactions of Sle1 with other susceptibility loci to cause severe nephritis cannot be accounted, however, by these three loci alone, suggesting the existence of an additional locus, termed Sle1d. These findings indicate that the potent autoimmune phenotype caused by the Sle1 genomic interval reflects the combined impact of four, separate, susceptibility genes. This level of genetic complexity, combined with similar findings in other systems, supports the possibility that many complex trait loci reflect the impact of polymorphisms in linked clusters of genes with related functions.

Rapid, local adaptation of zooplankton behavior to changes in predation pressure in the absence of neutral genetic changes

Organisms producing resting stages provide unique opportunities for reconstructing the genetic history of natural populations. Diapausing seeds and eggs often are preserved in large numbers, representing entire populations captured in an evolutionary inert state for decades and even centuries. Starting from a natural resting egg bank of the waterflea Daphnia, we compare the evolutionary rates of change in an adaptive quantitative trait with those in selectively neutral DNA markers, thus effectively testing whether the observed genetic changes in the quantitative trait are driven by natural selection. The population studied experienced variable and well documented levels of fish predation over the past 30 years and shows correlated genetic changes in phototactic behavior, a predator-avoidance trait that is related to diel vertical migration. The changes mainly involve an increased plasticity response upon exposure to predator kairomone, the direction of the changes being in agreement with the hypothesis of adaptive evolution. Genetic differentiation through time was an order of magnitude higher for the studied behavioral trait than for neutral markers (DNA microsatellites), providing strong evidence that natural selection was the driving force behind the observed, rapid, evolutionary changes.

The μ opiate receptor as a candidate gene for pain: Polymorphisms, variations in expression, nociception, and opiate responses

There are differences between human individuals and between mouse strains in levels of μ opiate receptor (μOR) expression, responses to painful stimuli, and responses to opiate drugs. One of the best candidates for contributing to these differences is variation at the μOR gene locus. Support for this idea comes from analyses of the human and murine μOR genes. Assessments of individual differences in human μOR expression add further support. Studies with mice, including knockout-transgenic, quantitative trait locus, and strain-comparison studies, also strongly support the possibility that μOR gene alleles would be strong candidates for contributing to individual differences in human nociception and opiate drug responses. This paper reviews current analyses of the murine and human μOR genes, their important variants, and correlations between these variants and opiate influences on pain.

Genetic effects of kangaroo harvesting

There is concern that the commercial harvest of kangaroos (Macropus spp.) is affecting species fitness and evolutionary potential because the harvest selects for larger individuals, particularly males. This paper reviews the likely effect of selective harvesting on specific traits associated with fitness, including size, and on adaptive genotypes through generalised loss of gene diversity. Heritability for traits associated with fitness is low generally. The intensity of selection imposed by harvesting is low for several reasons: the geographic size of genetic populations is much larger than the harvest localities, which are therefore not closed but open with immigration acting to correct any change in allele frequencies through harvesting; the harvest targets kangaroos above a threshold weight that includes all adult males, not the largest males specifically; larger, older males may not confer significant fitness benefits on offspring; fitness traits are inherited through both sexes while males are targeted predominantly; populations are not at a selective equilibrium because food availability fluctuates, and the fittest is unlikely to be the largest. Comparisons of harvested and unharvested populations do not show any loss of gene diversity as a result of harvesting. The likelihood of a long-term genetic impact of kangaroo harvesting as currently practiced is negligible.

Novel Genetic Determinants of Diabetic Kidney Disease

Diabetic kidney disease (DKD) is a devastating diabetes complication, with known heritability not fully revealed by previous genetics studies. We performed the largest genome-wide association study of type 1 DKD to date, in a 13-cohort consortium of 15,590 individuals of European ancestry genotyped on the Illumina HumanCoreExome Beadchip, which allows exploration of coding variation in addition to genomic markers.

As prior work has shown that different characterizations of the DKD phenotype highlight distinct genetic associations, we investigated a spectrum of DKD definitions based on proteinuria and renal function criteria. Controls were DKD-free after a minimum of 15 years diabetes duration; cases had diabetes for at least 10 years prior to DKD diagnosis. We also performed a quantitative trait analysis of estimated glomerular filtration rate in all participants.

Our top finding was a missense mutation in COL4A3, rs55703767 (Asp326Tyr); the minor allele is common in Europeans (20%) and East Asians (13%) but not Africans (2%). This SNP had a genome-wide significant association with traditionally defined DKD (macroalbuminuria or end-stage renal disease [ESRD], (OR= 0.79, P=1.9×10-9), and a suggestive association with macroalbuminuria (OR= 0.79, P=1.6×10-6) and ESRD (OR= 0.79, P=4.5×10-5) individually. Though its PolyPhen score is 0.3 (benign), this SNP has been implicated as a splice site disruptor.

The COL4A3 gene encodes the alpha 3 subunit of Type IV collagen, the major structural component of basement membranes. Pathogenic mutations in COL4A3 have been identified in thin basement membrane nephropathy, familial focal segmental glomerulosclerosis, and Alport syndrome. A proxy (r2=0.6) for rs55703767 had no significant associations in the CKDGen consortium, suggesting its pathogenicity occurs solely in the setting of hyperglycemia.

By significantly increasing sample size we have discovered a novel locus underlying DKD risk, paving the way for better understanding of pathology, prevention, and treatment.

Molecular Typing, Virulence Traits and Antimicrobial Resistance of Diabetic Foot Staphylococci

Diabetes mellitus is a major chronic disease that continues to increase significantly. One of the most important and costly complications of diabetes are foot infections that may be colonized by pathogenic and antimicrobial resistant bacteria, harboring several virulence factors, that could impair its successful treatment. Staphylococcus aureus is one of the most prevalent isolate in diabetic foot infections, together with aerobes and anaerobes.

Banana agronomy – can unravelling the Musa genome help?

Unravelling the Musa genome allows genes and alleles linked to desired traits to be identified. Short stature and early flowering are desirable agronomic features of banana, as they are of bread wheat (Triticum aestivum). In wheat they were achieved through knowledge of the physiology and genetics of vernalization and photoperiod during development. Bananas and plantains have a facultative long-day response to photoperiod, as do wheat and wall cress (Arabidopsis thaliana). Using keyword searches of the genome of Musa acuminata 'Pahang' we found homologues of the genes of either T. aestivum or Arabidopsis that govern responses to vernalization and photoperiod. This knowledge needs to be interpreted in the context of plant development. Bananas have juvenile, mid-vegetative and reproductive phases of development. Leaf and bunch 'clocks' operate concurrently throughout the juvenile and mid-vegetative phases. In the mid-vegetative phase the plant becomes sensitive to photoperiod. Increased sensitivity to photoperiod reduces the overall pace of the bunch clock without affecting the leaf clock. Separation of the clocks changes the link between leaf number and time of flowering. The 'critical' quantitative trait for the time of flowering is the pace of the bunch clock up to bunch initiation. For bunch size it is the duration of the subsequent phase of female hand formation. Plants with either a short juvenile phase or a faster bunch clock in the mid-vegetative phase will produce fewer leaves and bunch early. In turn, independent manipulation of hand number per bunch and/or fruit per hand will provide manageable bunches with appropriate fruit size. Using published data we explore relationships between plant height, leaf number, bunch weight and hand number among bananas and plantains. Identifying and then manipulating the appropriate genes in Musa opens opportunities for earlier flowering, leading to plants with desirable agronomic qualities.

Characterization of the effect of nitrogen deficiency on above-ground plant phenotypes in relation to root complexity in maize

Nitrogen (N) is an essential plant nutrient in maize production, and if considering only natural sources, is often the limiting factor world-wide in terms of a plant’s grain yield. For this reason, many farmers around the world supplement available soil N with synthetic man-made forms. Years of over-application of N fertilizer have led to increased N in groundwater and streams due to leaching and run-off from agricultural sites. In the Midwest Corn Belt much of this excess N eventually makes its way to the Gulf of Mexico leading to eutrophication (increase of phytoplankton) and a hypoxic (reduced oxygen) dead zone. Growing concerns about these types of problems and desire for greater input use efficiency have led to demand for crops with improved N use efficiency (NUE) to allow reduced N fertilizer application rates and subsequently lower N pollution. It is well known that roots are responsible for N uptake by plants, but it is relatively unknown how root architecture affects this ability. This research was conducted to better understand the influence of root complexity (RC) in maize on a plant’s response to N stress as well as the influence of RC on other above-ground plant traits. Thirty-one above-ground plant traits were measured for 64 recombinant inbred lines (RILs) from the intermated B73 & Mo17 (IBM) population and their backcrosses (BCs) to either parent, B73 and Mo17, under normal (182 kg N ha-1) and N deficient (0 kg N ha-1) conditions. The RILs were selected based on results from an earlier experiment by Novais et al. (2011) which screened 232 RILs from the IBM to obtain their root complexity measurements. The 64 selected RILs were comprised of 31 of the lowest complexity RILs (RC1) and 33 of the highest complexity RILs (RC2) in terms of root architecture (characterized as fractal dimensions). The use of the parental BCs classifies the experiment as Design III, an experimental design developed by Comstock and Robinson (1952) which allows for estimation of dominance significance and level. Of the 31 traits measured, 12 were whole plant traits chosen due to their documented response to N stress. The other 19 traits were ear traits commonly measured for their influence on yield. Results showed that genotypes from RC1 and RC2 significantly differ for several above-ground phenotypes. We also observed a difference in the number and magnitude of N treatment responses between the two RC classes. Differences in phenotypic trait correlations and their change in response to N were also observed between the RC classes. RC did not seem to have a strong correlation with calculated NUE (ΔYield/ΔN). Quantitative genetic analysis utilizing the Design III experimental design revealed significant dominance effects acting on several traits as well as changes in significance and dominance level between N treatments. Several QTL were mapped for 26 of the 31 traits and significant N effects were observed across the majority of the genome for some N stress indicative traits (e.g. stay-green). This research and related projects are essential to a better understanding of plant N uptake and metabolism. Understanding these processes is a necessary step in the progress towards the goal of breeding for better NUE crops.

Some problems and errors in cytogenetic biodosimetry

Human radiosensitivity is a quantitative trait that is generally subject to binomial distribution. Individual radiosensitivity, however, may deviate significantly from the mean (by 2-3 standard deviations). Thus, the same dose of radiation may result in different levels of genotoxic damage (commonly measured as chromosome aberration rates) in different individuals. There is significant genetic component in individual radiosensitivity. It is related to carriership of variant alleles of various single-nucleotide polymorphisms (most of these in genes coding for proteins functioning in DNA damage identification and repair); carriership of different number of alleles producing cumulative effects; amplification of gene copies coding for proteins responsible for radioresistance, mobile genetic elements, and others. Among the other factors influencing individual radioresistance are: radioadaptive response; bystander effect; levels of endogenous substances with radioprotective and antimutagenic properties and environmental factors such as lifestyle and diet, physical activity, psychoemotional state, hormonal state, certain drugs, infections and others. These factors may have radioprotective or sensibilising effects. Apparently, there are too many factors that may significantly modulate the biological effects of ionising radiation. Thus, conventional methodologies for biodosimetry (specifically, cytogenetic methods) may produce significant errors if personal traits that may affect radioresistance are not accounted for.

Desenvolvimento de marcadores para a seleção assistida de ausência de sementes em videiras no programa de melhoramento da Embrapa Uva e Vinho.

desenvolvimento de novas cultivares de uvas sem sementes é uma das prioridades dos programas de melhoramento de uvas de mesa do mundo. Em trabalho anterior o nosso grupo detectou um QTL (quantitative trait locus) para ausência de sementes no cromossomo 18 no locus SDI (seed development inhibitor). Evidências adicionais demonstraram que o gene VvAGL11, localizado neste locus, possui papel fundamental na morfogênese de sementes em videira. O objetivo deste trabalho foi genotipar acessos apirêincos e pirênicos com nove marcadores do tipo SNP e INDEL únicos para o alelo associado a ausência de sementes em Vitis vinifera e verificar se a metodologia de genotipagem baseada em KASP? tem potencial de uso em seleção assistida.

Heritability and quantitative genetic divergence of serotiny, a fire-persistence plant trait.

BACKGROUND AND AIMS: Although it is well known that fire acts as a selective pressure shaping plant phenotypes, there are no quantitative estimates of the heritability of any trait related to plant persistence under recurrent fires, such as serotiny. In this study, the heritability of serotiny in Pinus halepensis is calculated, and an evaluation is made as to whether fire has left a selection signature on the level of serotiny among populations by comparing the genetic divergence of serotiny with the expected divergence of neutral molecular markers (QST-FST comparison). METHODS: A common garden of P. halepensis was used, located in inland Spain and composed of 145 open-pollinated families from 29 provenances covering the entire natural range of P. halepensis in the Iberian Peninsula and Balearic Islands. Narrow-sense heritability (h(2)) and quantitative genetic differentiation among populations for serotiny (QST) were estimated by means of an 'animal model' fitted by Bayesian inference. In order to determine whether genetic differentiation for serotiny is the result of differential natural selection, QST estimates for serotiny were compared with FST estimates obtained from allozyme data. Finally, a test was made of whether levels of serotiny in the different provenances were related to different fire regimes, using summer rainfall as a proxy for fire regime in each provenance. KEY RESULTS: Serotiny showed a significant narrow-sense heritability (h(2)) of 0·20 (credible interval 0·09-0·40). Quantitative genetic differentiation among provenances for serotiny (QST = 0·44) was significantly higher than expected under a neutral process (FST = 0·12), suggesting adaptive differentiation. A significant negative relationship was found between the serotiny level of trees in the common garden and summer rainfall of their provenance sites. CONCLUSIONS: Serotiny is a heritable trait in P. halepensis, and selection acts on it, giving rise to contrasting serotiny levels among populations depending on the fire regime, and supporting the role of fire in generating genetic divergence for adaptive traits.

Genetic associations in the detection of QTLs for wheat spike-related traits

The objective of this work was to assess the genetic diversity and population structure of wheat genotypes, to detect significant and stable genetic associations, as well as to evaluate the efficiency of statistical models to identify chromosome regions responsible for the expression of spike-related traits. Eight important spike characteristics were measured during five growing seasons in Serbia. A set of 30 microsatellite markers positioned near important agronomic loci was used to evaluate genetic diversity, resulting in a total of 349 alleles. The marker-trait associations were analyzed using the general linear and mixed linear models. The results obtained for number of allelic variants per locus (11.5), average polymorphic information content value (0.68), and average gene diversity (0.722) showed that the exceptional level of polymorphism in the genotypes is the main requirement for association studies. The population structure estimated by model-based clustering distributed the genotypes into six subpopulations according to log probability of data. Significant and stable associations were detected on chromosomes 1B, 2A, 2B, 2D, and 6D, which explained from 4.7 to 40.7% of total phenotypic variations. The general linear model identified a significantly larger number of marker-trait associations (192) than the mixed linear model (76). The mixed linear model identified nine markers associated to six traits.

Localisation de loci à trait quantitatif pour l'hypertension sur les chromosomes 17 et 16 du rat Dahl Salt-Sensitive

Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal.

Modelos alternativos para detecção de locos de características quantitativas (QTL) de carcaça e crescimento nos cromossomos 4, 5 e 7 de suínos

O conhecimento do genoma pode auxiliar na identificação de regiões cromossômicas e, eventualmente, de genes que controlam características quantitativas (QTLs) de importância econômica. em um experimento com 1.129 suínos resultantes do cruzamento entre machos da raça Meishan e fêmeas Large White e Landrace, foram analisadas as características gordura intramuscular (GIM), em %, e ganho dos 25 aos 90 kg de peso vivo (GP), em g/dia, em 298 animais F1 e 831 F2, e espessura de toucinho (ET), em mm, em 324 F1 e 805 F2. Os animais das gerações F1 e F2 foram tipificados com 29 marcadores microsatélites. Estudou-se a ligação entre os cromossomos 4, 6 e 7 com GIM, ET e GP. Análises de QTL utilizando-se metodologia Bayesiana foram aplicadas mediante três modelos genéticos: modelo poligênico infinitesimal (MPI); modelo poligênico finito (MPF), considerando-se três locos; e MPF combinado com MPI. O número de QTLs, suas respectivas posições nos três cromossomos e o efeito fenotípico foram estimados simultaneamente. Os sumários dos parâmetros estimados foram baseados nas distribuições marginais a posteriori, obtidas por meio do uso da Cadeia de Markov, algoritmos de Monte Carlo (MCMC). Foi possível evidenciar dois QTLs relacionados a GIM nos cromossomos 4 e 6 e dois a ET nos cromossomos 4 e 7. Somente quando se ajustou o MPI, foram observados QTLs no cromossomo 4 para ET e GIM. Não foi possível detectar QTLs para a característica GP com a aplicação dessa metodologia, o que pode ter resultado do uso de marcadores não informativos ou da ausência de QTLs segregando nos cromossomos 4, 6 e 7 desta população. Foi evidenciada a vantagem de se analisar dados experimentais ajustando diferentes modelos genéticos; essas análises ilustram a utilidade e ampla aplicabilidade do método Bayesiano.