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PubMed1999

Genetic dissection of Plasmodium falciparum blood infection levels and other complex traits related to human malaria infection.

There is accumulating evidence of host genetic control in malaria infection and, in humans, some genes have been associated with severe malaria. Nevertheless, other important genes controlling blood infection levels, malarial disease and immune responses are likely to be identified. In this paper, we focus on segregation and linkage analyses of blood infection levels in an urban population living in Burkina Faso. We found evidence of a complex genetic control and a linkage to chromosome 5q31-q33. The identification of genes controlling complex traits related to malaria infection should be helpful in understanding protective mechanisms and the relationship between infection, malaria attacks and severe malaria.

Age Factors↗
PubMed2000

Genetic dissection of the molecular pathogenesis of severe infection.

A fundamental question for the intensivist is why some individuals but not others succumb to life-threatening infection. A growing body of evidence indicates that both the risk of acquiring infection and the risk of developing severe complications are determined by host genetic factors. These include a number of single gene defects with devastating consequences, e. g. interferon-gamma receptor mutations that lead to fatal infections with ubiquitous mycobacteria, but such examples are relatively rare. Of greater importance for routine clinical practice is the potentially vast number of genetic variants with subtle effects on the regulation or function of specific immunological, physiological and metabolic mediators. Such polygenic traits do not obey simple patterns of familial segregation seen for monogenic disorders, and their clinical investigation is further complicated by the environmental variability of infectious exposure. Recent advances in this field have therefore largely stemmed from hospital-based case-controlled studies that have uncovered disease associations with specific DNA polymorphisms in candidate gene regions. For example, tumour necrosis factor polymorphisms have been associated with susceptibility to malaria and other infections; chemokine receptor polymorphisms with susceptibility to HIV; natural resistance-associated macrophage protein 1 with tuberculosis; and mannose binding lectin polymorphisms with meningococcal disease. A much greater number of genetic associations will emerge as the full extent of human genomic diversity becomes known. The challenge for clinical investigators is to generate an epidemiological framework for population- and family-based association studies, which is sufficiently robust to exclude population artifacts and sufficiently powerful to be able to dissect true disease-causing polymorphisms from linked genetic markers. In the long term this approach promises to identify host mediators that are critical for pathogenesis and immunity and to yield molecular insights into the complex processes of human gene regulation. This information is likely to be of considerable value in designing more effective approaches to the treatment and prevention of life-threatening infectious disease.

Communicable Diseases↗
PubMed1995

Biochemical and genetic dissection of mitotic chromosome condensation.

The molecular mechanisms responsible for mitotic chromosome condensation are unknown. Two independent approaches, biochemical studies in vertebrate cells and genetic analyses in yeasts, have converged recently, leading to the identification of a family of putative ATPases that play a fundamental role in this process. Further characterization of these proteins promises to uncover a highly dynamic aspect of mitotic chromosome architecture.

Adenosine Triphosphatases↗
PubMed2001

Genetic dissection of the olfactory bulbs of mice: QTLs on four chromosomes modulate bulb size.

Olfaction is influenced by a complex mix of environmental and genetic factors that modulate the production, migration, and maturation of cells in the olfactory bulbs. In this study we analyzed effects of sex, age, body weight, and brain weight on olfactory bulb size in sexually mature mice. We then used regression corrected values (residuals) to map quantitative trait loci (QTLs) that selectively modulate bulb weight. This biometric analysis has relied on an F2 intercross between C57BL/6J (B6) and DBA/2J (D2) inbred strains and a large sample of 35 BXD recombinant inbred (RI) strains. Bilateral bulb weight in adult mice ranges from 10 to 30 mg. Half of this remarkable variation can be predicted from differences in brain weight, sex, body weight, and age. A 100-mg difference in brain weight is associated with a 4.4-mg difference in bulb weight. Bulbs gain in weight by 0.2 mg/week--a 1% increase that continues until at least 300 days of age. Males tend to have slightly larger bulbs than females. By combining data from both related crosses (F2 and RI) we identified four QTLs with selective effects on bulb size (genomewide p < .05). Bulb4a is located on chromosome 4 (Chr 4) and Bulb6a is located on Chr 6. Alleles inherited from B6 at both of these loci increase bulb weight by 0.5-1.0 mg. Bulb11a is located on proximal Chr 11 and Bulb17a is located on the proximal part of Chr 17. In contrast to the first two QTLs, B6 alleles at these two loci decrease bulb weight by 0.5-1.0 mg. Collectively, the four loci account for 20% of the phenotypic variance in bulb weight.

Alleles↗
PubMed2003

Genetic dissection of hybrid incompatibilities between Drosophila simulans and D. mauritiana. I. Differential accumulation of hybrid male sterility effects on the X and autosomes.

The genetic basis of hybrid incompatibility in crosses between Drosophila mauritiana and D. simulans was investigated to gain insight into the evolutionary mechanisms of speciation. In this study, segments of the D. mauritiana third chromosome were introgressed into a D. simulans genetic background and tested as homozygotes for viability, male fertility, and female fertility. The entire third chromosome was covered with partially overlapping segments. Many segments were male sterile, while none were female sterile or lethal, confirming previous reports of the rapid evolution of hybrid male sterility (HMS). A statistical model was developed to quantify the HMS accumulation. In comparison with previous work on the X chromosome, we estimate that the X has approximately 2.5 times the density of HMS factors as the autosomes. We also estimate that the whole genome contains approximately 15 HMS "equivalents"-i.e., 15 times the minimum number of incompatibility factors necessary to cause complete sterility. Although some caveats for the quantitative estimate of a 2.5-fold density difference are described, this study supports the notion that the X chromosome plays a special role in the evolution of reproductive isolation. Possible mechanisms of a "large X" effect include selective fixation of new mutations that are recessive or partially recessive and the evolution of sex-ratio distortion systems.

Animals↗
PubMed1999

Genetic dissection of "OLETF," a rat model for non-insulin-dependent diabetes mellitus: quantitative trait locus analysis of (OLETF x BN) x OLETF.

To identify genetic determinants relevant to non-insulin-dependent diabetes mellitus (NIDDM), we performed a genome-wide analysis for quantitative trait loci (QTLs) using 359 backcross progeny of the Otsuka Long-Evans Tokushima Fatty (OLETF) rat. The OLETF strain is a well-studied animal model of obese NIDDM, with features of hyperinsulinemia, hyperglycemia, insulin resistance, and abundant abdominal fat. Our extensive genomic scanning with 218 markers revealed nine significant QTLs, including a strong determinant of obesity on chromosome 1 (Dmo1: LOD = 13.99, for body weight). Two highly significant QTLs for glucose homeostasis were found, one on chromosome 1 (Dmo4 LOD = 7.16, for postprandial glucose level) and the other on chromosome X (Dmo11/Odb1: LOD = 7.81, for postprandial glucose level). These data are comparable to results of our previous studies of the OLETF rat.

Adipose Tissue↗
PubMed2006

Genetic dissection of proteinuria in the Sabra rat.

The pathophysiology underlying proteinuria remains incompletely understood and warrants further research. We currently initiated the investigation of the genetic basis of proteinuria in the Sabra rat, a model of salt susceptibility that we showed previously to be also a model of spontaneous proteinuria that is unrelated to salt loading or development of hypertension. We applied the total genome scan strategy in 75 F2 male animals derived from a cross between SBH/y, which are prone to develop proteinuria, and SBN/y, which are relatively resistant to the development of proteinuria. Animals were subjected to uninephrectomy (UNx) to accelerate the development of proteinuria and were provided chow with a low salt content, thus avoiding the development of hypertension. Urinary protein excretion was monitored before UNx and monthly thereafter for 8 mo. The genotype of F2 was determined with microsatellite markers. The data were analyzed for cosegregation by ANOVA and for genetic linkage with a novel multifaceted statistical genetic paradigm. We detected three proteinuria-related quantitative trait loci (QTL) that were associated with the salt sensitivity (H) alleles from SBH/y: SUP2, SUP17, and SUP20 on rat chromosomes (Chr) 2, 17, and 20. We detected an additional QTL on Chr 3, SUP3, that was associated with the salt resistance (N) alleles from SBN/y. A temporal effect was noted: QTL SUP2 and SUP17 surfaced at months 7-8, QTL SUP20 at months 6-8, and QTL SUP3 at months 5-6. The QTL emerging from this study lead us a step closer to identifying the genes associated with and elucidating the pathophysiology of proteinuria.

Animals↗
PubMed2003

Genetic dissection of hybrid incompatibilities between Drosophila simulans and D. mauritiana. III. Heterogeneous accumulation of hybrid incompatibilities, degree of dominance, and implications for Haldane's rule.

The genetic basis of Haldane's rule was investigated through estimating the accumulation of hybrid incompatibilities between Drosophila simulans and D. mauritiana by means of introgression. The accumulation of hybrid male sterility (HMS) is at least 10 times greater than that of hybrid female sterility (HFS) or hybrid lethality (HL). The degree of dominance for HMS and HL in a pure D. simulans background is estimated as 0.23-0.29 and 0.33-0.39, respectively; that for HL in an F1 background is unlikely to be very small. Evidence obtained here was used to test the Turelli-Orr model of Haldane's rule. Composite causes, especially, faster-male evolution and recessive hybrid incompatibilities, underlie Haldane's rule in heterogametic male taxa such as Drosophila (XY male and XX female). However, if faster-male evolution is driven by sexual selection, it contradicts Haldane's rule for sterility in heterogametic-female taxa such as Lepidoptera (ZW female and ZZ male). The hypothesis of a faster-heterogametic-sex evolution seems to fit the current data best. This hypothesis states that gametogenesis in the heterogametic sex, instead of in males per se, evolves much faster than in the homogametic sex, in part because of sex-ratio selection. This hypothesis not only explains Haldane's rule in a simple way, but also suggests that genomic conflicts play a major role in evolution and speciation.

Animals↗
PubMed1998

Genetic dissection of retinal development.

Retinal development depends on complex interactions between products of thousands of genes and numerous cellular and environmental factors. We are using novel quantitative genetic methods to map and characterize genes that are responsible for the pervasive quantitative differences in the architecture of the eye and the retina. These genes, known as quantitative trait loci (QTLs), may also determine susceptibility to common eye diseases. To map QTLs that generate variation among normal individuals we have analyzed several traits in a wide variety of mice, including standard inbred strains, recombinant inbred strains, wild mice, F1 hybrids and intercross progeny. Here we review this approach and give three specific examples of how genes with well-defined functions in retinal development are being mapped and characterized.

Animals↗
PubMed2004

Genetic dissection of tumor angiogenesis: are PlGF and VEGFR-1 novel anti-cancer targets?

Many proliferative diseases, most typically cancer, are driven by uncontrolled blood vessel growth. Genetic studies have been very helpful in unraveling the cellular and molecular players in pathological blood vessel formation and have provided opportunities to reduce tumor growth and metastasis. The fact that tumor vessels and normal blood vessels have distinct properties may help in designing more specific--and therefore safer--anti-angiogenic strategies. Such strategies may interfere with angiogenesis at the cellular or molecular level. Possible molecular targets include angiogenic growth factors and their receptors, proteinases, coagulation factors, junctional/adhesion molecules and extracellular matrix (ECM) components. Some anti-angiogenic drugs, i.e., vascular endothelial growth factor (VEGF) antibodies and VEGF receptor-2 (VEGFR-2) inhibitors, have progressed into clinical cancer trials. While the results of these trials support the potential of anti-angiogenic therapy to treat cancer, they also demonstrate the need for more effective and safer alternatives. Targeting placental growth factor (PlGF) or VEGFR-1 may constitute such an alternative since animal studies have proven their pleiotropic working mechanism and attractive safety profile. Together, these insights may bring anti-angiogenic drugs closer from bench to bedside.

Angiogenesis Inducing Agents↗
PubMed2002

Gene-expression profiling and the genetic dissection of complex disease.

Several recent studies have highlighted how combining the powerful techniques of microarray analysis and congenic-strain analysis may greatly facilitate unravelling the genetic basis of susceptibility to common autoimmune diseases. In addition to providing pointers to the genetic variants themselves, the pathway(s) they control may also be highlighted, thereby identifying new targets for therapeutic intervention.

Animals↗
PubMed1997

Genetic dissection of sexual behavior in Drosophila melanogaster.

Mating of Drosophila melanogaster is a sterotypically patterned behavior consisting of a fixed sequence of actions that are primarily under genetic control. Mutations that disrupt specific aspects of mating activities offer a starting point for exploring the molecular machineries underlying sexual behavior. Several genes, identified as causing aberrant sexual behavior when mutated, have been isolated and cloned, providing molecular probes for expression and mosaic analyses that can be used in specifying the cells responsible for the behavior. This review presents current understandings of mating behavior obtained by such molecular and cellular approaches and provides an overview of future directions of research in behavioral genetics.

Animal Nutritional Physiological Phenomena↗
PubMed1997

Use of Arabidopsis for genetic dissection of plant defense responses.

Arabidopsis thaliana (Arabidopsis) is proving to be an ideal model system for studies of host defense responses to pathogen attack. The Arabidopsis genetic system is significantly more tractable than those of other plant species, and Arabidopsis exhibits all of the major kinds of defense responses described in other plants. A large number of virulent and avirulent bacterial, fungal, and viral pathogens of Arabidopsis have been collected. In the last few years, a large number of mutations have been identified in Arabidopsis that cause a wide variety of specific defense-related phenotypes. Analysis of these mutant phenotypes is beginning to give glimpses into the complex signal transduction pathways leading to the induction of the defense responses involved in protecting plants from pathogen infection.

Animals↗
PubMed2005

Genetic dissection of the signaling pathways that control gastric acid secretion.

Gastric acid secretion is regulated by endocrine, paracrine and neurocrine signals via at least three pathways, the gastrin-histamine pathway, the CCK-somatostatin pathway and the neural pathway. Genetically-engineered mice, subjected to targeted gene disruption (i.e., knockout mice), have been used to dissect the signaling pathways that are responsible for the complexity of the regulation of acid secretion in vivo. Both gastrin knockout and gastrin/CCK2 receptor knockout mice displayed greatly impaired acid secretion, presumably because of the loss of the gastrin-histamine pathway. Gastrin/CCK double-knockout mice had a relatively high percentage of active parietal cells with a maintained ability to respond with copious acid secretion to pylorus ligation-evoked vagal stimulation and to a histamine challenge. The low acid secretion in gastrin knockout mice and gastrin/CCK2 receptor knockout mice and the restoration of acid secretion in gastrin/CCK double-knockout mice suggest that CCK plays an important role as inhibitor of the parietal cells via the CCK-somatostatin pathway by stimulating the CCK1 receptor of the D cell. In the absence of both the gastrin-histamine and the CCK-somatostatin pathway (as in gastrin/CCK2 receptor double-knockout mice), the control of acid secretion is probably taken over by neural pathways, explaining the high acid output. The observations illustrate the complexity and plasticity of the acid regulatory mechanisms. It seems that one pathway may be suppressed or allowed to dominate over the others depending on the circumstances.

Animals↗
PubMed2004

Genetic dissection of diseases: design and methods.

The etiology of heritable diseases may be elucidated by localizing genes conferring susceptibility and by subsequent biological characterization of these genes. To localize genetic components for multifactorial traits, both hypothesis-driven candidate gene and hypothesis-free genome scan approaches have been applied. To date, only a handful of results have been reproduced in either a different cohort or model organisms. The integration of genetic approaches with high-throughput genomic techniques is very promising. Unfortunately, most genetic studies completely ignore strong nongenetic effects such as low education and poverty even though these factors are well-known to predict, for example, obesity. Thus, what are most needed in future research are statistical methods for discovering sets of susceptibility genes and environmental factors, as well as systematic verifications of the gene-environment-disease network.

Gene Expression Profiling↗