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Allelic penetrance approach as a tool to model twolocus
Get PDFMany binary phenotypes do not follow a classical Mendelian
inheritance pattern. Interaction between genetic and environmental
factors is thought to contribute to the incomplete
penetrance phenomena often observed in these complex
binary traits. Several two-locus models for penetrance have
been proposed to aid the genetic dissection of binary traits.
Such models assume linear genetic effects of both loci in
different mathematical scales of penetrance, resembling the
analytical framework of quantitative traits. However, changes
in phenotypic scale are difficult to envisage in binary traits
and limited genetic interpretation is extractable from current
modeling of penetrance. To overcome this limitation, we
derived an allelic penetrance approach that partitioned
incomplete penetrance into the alleles controlling the
phenotype and into the genetic background and environmental
factors. We applied this approach to formulate
dominance and recessiveness in a single biallelic locus and
to model different genetic mechanisms for the joint action of
two biallelic loci. We fit the models to data on the
susceptibility of mice following infections with Listeria
monocytogenes and Plasmodium berghei. These models
gain in genetic interpretation, because they specify the
alleles that are responsible for the genetic (inter)action and
their genetic nature (dominant or recessive), and predict
genotypic combinations determining the phenotype. Further,
we show via computer simulations that the proposed models
produce penetrance patterns not captured by traditional twolocus
models. This approach provides a new analysis
framework for dissecting mechanisms of interlocus joint
action in binary traits using genetic crosses
Multiple domain insertions and losses in the evolution of the Rab prenylation complex
Get PDFBACKGROUND: Rab proteins are regulators of vesicular trafficking, requiring a lipid modification for proper function, prenylation of C-terminal cysteines. This is catalysed by a complex of a catalytic heterodimer (Rab Geranylgeranyl Transferase - RabGGTase) and an accessory protein (Rab Escort Protein. REP). Components of this complex display domain insertions relative to paralogous proteins. The function of these inserted domains is unclear. RESULTS: We profiled the domain architecture of the components of the Rab prenylation complex in evolution. We identified the orthologues of the components of the Rab prenylation machinery in 43 organisms, representing the crown eukaryotic groups. We characterize in detail the domain structure of all these components and the phylogenetic relationships between the individual domains. CONCLUSION: We found different domain insertions in different taxa, in alpha-subunits of RGGTase and REP. Our results suggest that there were multiple insertions, expansions and contractions in the evolution of this prenylation comple
Selection against males in Caenorhabditis elegans under two mutational treatments
Get PDFWithin populations with mixed mating systems, selfing is expected to be favoured over outcrossing unless a countervailing process such as severe inbreeding depression is present. In this study, we consider the relationship between the expression of deleterious alleles and the maintenance of outcrossing in the nematode species, Caenorhabditis elegans. This species is characterized by an androdioecious breeding system composed of males at low frequency and self-fertilizing hermaphrodites that can only outcross via males. Here, we find that experimentally increasing the mutational load in four different isogenic wild isolates using 10 generations of Ethylmethane sulphonate (EMS) and UV irradiation mutagenesis significantly diminishes the cost of males. Males are maintained at higher frequencies in mutagenized versus non-mutagenized populations. Nevertheless, males still tend to be driven to low frequencies within isolates that are known to be prone to lose males. Further, we determine the viability effects of a single round of mutagen exposure and find that, for EMS, outcrossing overcomes the almost completely recessive and nearly lethal effects generated. We briefly interpret our results in light of current evolutionary theory of outcrossing rates
Low frequency of CD4(+) CD25(+) Treg in SLE patients: a heritable trait associated with CTLA4 and TGF gene variants
Get PDFBackground: CD4(+)CD25(+) regulatory T cells play an essential role in maintaining immune homeostasis and preventing autoimmunity. Therefore, defects in Treg development, maintenance or function have been associated with several human autoimmune diseases including Systemic Lupus Erythematosus (SLE), a systemic autoimmune disease characterized by loss of tolerance to nuclear components and significantly more frequent in females
How many genes are needed to make a pollen tube? lessons from transcriptomics
Get PDFBackground Pollen is the male gametophyte of higher plants. Upon pollination, it germinates and develops into a fast-growing cytoplasmic extension, the pollen tube, which ultimately delivers the sperm into the ovary. The biological relevance of its role, and the uniqueness of this kind of cellular organization, have made pollen the focus of many approaches, and it stands today as one of the best-known models in plant cell biology. In contrast, the genetic background of its development has been until recently largely unknown. Some genes involved have been described and a few functional mutants have been characterized, but only to a limited extent and allowing only a limited understanding of the regulatory mechanisms. Yet, being a relatively simple organ (2 or 3 cells), pollen stands as an excellent target for molecular-biology-based approaches.
Recent studies on Arabidopsis thaliana have characterized the transcriptional profile of pollen grains and microgametogenesis in comparison to sporophytic tissues. They underline the unique characteristics of pollen, not only in terms of a strongly reduced set of genes being expressed, but also in terms of the functions of the proteins encoded and the pathways they are involved in. These approaches have expanded the number of genes with known expression in pollen from a few hundred to nearly eight thousand. While for the first time allowing systems and/or gene-family approaches, this information also expands dramatically the possibility of hypothesis-driven experimentation based on specific gene function predictions. Recent studies reveal this to be the case in, for example, transcriptional regulation, cell-cycle progression and gene-silencing mechanisms in mature polle
Mapping of quantitative trait loci using the skew-normal distribution
Get PDFThis deposit is in restrictedAccess (it can't be in open access to the public), and can only be accessed by two ways: either by requesting a legal copy from the author (the email contact present in this deposit) or by visiting the following link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2064950/In standard interval mapping (IM) of quantitative trait loci (QTL), the QTL effect is described by a normal mixture
model. When this assumption of normality is violated, the most commonly adopted strategy is to use the previous model after data
transformation. However, an appropriate transformation may not exist or may be difficult to find. Also this approach can raise
interpretation issues. An interesting alternative is to consider a skew-normal mixture model in standard IM, and the resulting
method is here denoted as skew-normal IM. This flexible model that includes the usual symmetric normal distribution as a special
case is important, allowing continuous variation from normality to non-normality. In this paper we briefly introduce the main
peculiarities of the skew-normal distribution. The maximum likelihood estimates of parameters of the skew-normal distribution
are obtained by the expectation-maximization (EM) algorithm. The proposed model is illustrated with real data from an intercross
experiment that shows a significant departure from the normality assumption. The performance of the skew-normal IM is assessed
via stochastic simulation. The results indicate that the skew-normal IM has higher power for QTL detection and better precision of
QTL location as compared to standard IM and nonparametric IM
The effect of spatial structure in adaptive evolution
Get PDFWe study the dynamics of adaptation in a spatially structured population. The model assumes local competition for replication, where each organism interacts only with its nearest neighbors and is inspired by experimental methods that can be used to study the process of adaptive evolution in microbes. In such experiments microbial populations are grown on petri dishes and allowed to adapt by serial passage. We compare the rate of adaptation in a structured population where the structure is maintained intact to those where movement of individuals can occur. We observe that the rate of adaptive evolution is higher and the mean effect of fixed beneficial mutations is lower in intact structures than in structures with mixing.The original version is available at www.springerlink.co
Clusters of cytokines determine malaria severity in Plasmodium falciparum - Infected patients from endemic areas of central India
Get PDFWe investigated the role of interferon (IFN)- gamma , interleukin (IL)-1 beta , IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, tumor necrosis factor (TNF)- alpha , and transforming growth factor (TGF)- beta in clinically well-defined groups of Plasmodium falciparum-infected patients manifesting mild malaria (MM), severe noncerebral malaria (SM), or cerebral malaria (CM) and in control subjects from Gondia, a malaria-endemic site in India, as well as in healthy subjects from non-malaria-endemic areas. Two-way coupled cluster analysis revealed 2 clusters of cytokines relevant to clinical subgroups of disease. The first cluster was composed of IFN- gamma , IL-2, IL-5, IL-6, and IL-12, the levels of which were significantly increased during infection but were predominant in patients with MM and allowed us to distinguish them from patients with SM or CM. The second cluster was composed of TGF- beta , TNF- alpha , IL-10, and IL-1 beta , the levels of which were highly correlated with each other in the different clinical groups of patients and significantly increased with disease severity, particularly in CM. Discriminant analyses allowed us to propose a minimal model. Levels of cytokines such as IL-5, IL-1 beta , IL-10, and IL-2 increase with infection. Levels of IL-12, IL-5, and IL-6 discriminate severe forms of malaria from MM. Finally, levels of IL-1 beta , IL-12, and IFN- gamma are relevant for the discrimination of CM from SM: high IL-1 beta levels are associated with CM, and high IL-12 and IFN- gamma levels are associated with S
Genetic variation for outcrossing among Caenorhabditis elegans isolates
Get PDFThe evolution of breeding systems results from the existence of genetic variation and selective forces favoring different outcrossing rates. In this study we determine the extent of genetic variation for characters directly related to outcrossing, such as male frequency, male mating ability, and male reproductive success, in several wild isolates of the nematode Caenorhabditis elegans. This species is characterized by an androdioecious breeding system in which males occur with hermaphrodites that can either self-fertilize or outcross with males. We find genetic variation for all characters measured, but also find that environmental variation is a large fraction of the total phenotypic variance. We further determine the existence of substantial genetic variation for population competitive performance in several laboratory environments. However, these measures are uncorrelated with outcrossing characters. The data presented here contribute to an understanding of male maintenance in natural populations through their role in outcrossing
Adaptive evolution in a spatially structured asexual population
Get PDFWe study the process of adaptation in a spatially structured asexual haploid population. The model assumes a local competition for replication, where each organism interacts only with its nearest neighbors. We observe that the substitution rate of beneficial mutations is smaller for a spatially structured population than that seen for populations without structure. The difference between structured and unstructured populations increases as the adaptive mutation rate increases. Furthermore, the substitution rate decreases as the number of neighbors for local competition is reduced. We have also studied the impact of structure on the distribution of adaptive mutations that fix during adaptation.The original version is available at www.springerlink.co