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PubMed2002

Isochore chromosome maps of the human genome.

The human genome is a mosaic of isochores, which are long DNA segments (z.Gt;300 kbp) relatively homogeneous in G+C. Human isochores were first identified by density-gradient ultracentrifugation of bulk DNA, and differ in important features, e.g. genes are found predominantly in the GC-richest isochores. Here, we use a reliable segmentation method to partition the longest contigs in the human genome draft sequence into long homogeneous genome regions (LHGRs), thereby revealing the isochore structure of the human genome. The advantages of the isochore maps presented here are: (1) sequence heterogeneities at different scales are shown in the same plot; (2) pair-wise compositional differences between adjacent regions are all statistically significant; (3) isochore boundaries are accurately defined to single base pair resolution; and (4) both gradual and abrupt isochore boundaries are simultaneously revealed. Taking advantage of the wide sample of genome sequence analyzed, we investigate the correspondence between LHGRs and true human isochores revealed through DNA centrifugation. LHGRs show many of the typical isochore features, mainly size distribution, G+C range, and proportions of the isochore classes. The relative density of genes, Alu and long interspersed nuclear element repeats and the different types of single nucleotide polymorphisms on LHGRs also coincide with expectations in true isochores. Potential applications of isochore maps range from the improvement of gene-finding algorithms to the prediction of linkage disequilibrium levels in association studies between marker genes and complex traits. The coordinates for the LHGRs identified in all the contigs longer than 2 Mb in the human genome sequence are available at the online resource on isochore mapping: http://bioinfo2.ugr.es/isochores.

Alu Elements↗
PubMed2000

Common gene variants, mortality and extreme longevity in humans.

Genetic factors influence variation in human life span. The fast technological advancements in genome research and the methodology for statistical analysis of complex traits provided new tools to unravel these genetic influences. Most of the genetic epidemiology and quantitative genetics is focused on the dissection of the genetic component of specific diseases rather than of human life span. Nevertheless, common variants of 22 genes have been tested for their contribution to mortality in the general population and extreme longevity in one or more studies. These studies provide indications as to the nature of biological pathways that might play a role in human ageing. Perhaps even more important at this time is the fact that they give valuable insights in the strengths and weaknesses of current strategies to identify gene variants affecting human life span and point at more powerful approaches.

Apolipoproteins E↗
PubMed2003

Association between the HLA-DR alleles and longevity: a study in Sardinian population.

Human longevity may be correlated with optimal functioning of the immune system, suggesting that genetic determinants of longevity also resides in those polymorphisms for the immune system genes that regulate immune responses as histocompatibility (HLA) antigens. However, conflicting results have been obtained. Some well planned and designed association studies performed in Caucasians suggest that longevity is associated with positive selection of alleles (i.e. HLA-DR11) or haplotypes (i.e. HLA-B8,DR3) that confer resistance to infectious diseases, respectively, via peptide presentation or via antigen non-specific control of immune response. Association studies are subjected to a number of possible confounding factors, the homogeneity of the population in term of geographical origin among others. Because of the lack of large-scale heterogeneity, the Sardinians represent a suitable population for association studies addressed to dissect the complex traits as longevity. Thus, we have evaluated, by the amplification refractory mutation system/polymerase chain reaction, HLA-DR frequencies in 120 centenarians (79 women and 41 men) and 86 controls (53 women and 33 men) from Sardinia, to validate, in this very homogeneous population, the associations between HLA alleles or haplotypes and longevity observed in other Caucasoid populations. No significant differences were obtained by analysing the differences between Centenarians and controls except for HLA-DRB1*15 that was increased in centenarians. However, the significance was not maintained by multiplying P values for the number of alleles under study. Thus, in Sardinian centenarians, we were not able to confirm the findings observed in the well planned and designed studies performed in other Caucasoid populations. Besides, HLA HFE gene polymorphisms have been recently demonstrated to be associated with longevity in the Sicilian population but not in Danish one. On the whole these findings clearly show that HLA/longevity associations are population-specific, being heavily affected by the population-specific genetic and environmental history. So, in our opinion, HLA genes might be considered survival genes not longevity genes.

Aged↗
PubMed2003

Variants of kappa-opioid receptor gene and mRNA in alcohol-preferring and alcohol-avoiding mice.

Results of recent studies have indicated an association between voluntary alcohol intake and activities of kappa-opioid receptor systems in animal models. We assessed the possibility that genetic differences observed in alcohol preference among mouse strains are related to possible polymorphisms of the kappa-opioid receptor gene (Oprk1). We compared DNA sequences of the coding region and the promoter/regulatory region of Oprk1 among C57BL/6ByJ (B6, alcohol-preferring), BALB/cJ (alcohol-avoiding), CXBI (alcohol-avoiding), and six B6.C and B6.I Recombinant QTL Introgression (RQI) strains, which carry approximately 3% of the donor BALB/cJ genome in the background B6 genome and showed various alcohol preferences. Although there were no sequence differences in the coding region, BALB/cJ had a single nucleotide polymorphism (SNP) in the promoter region, which was not detected in other strains. The results indicate that the difference in alcohol preference between B6 and BALB/cJ is not correlated with polymorphisms of Oprk1. However, results of further studies comparing Oprk1 mRNA expression between B6 and BALB/cJ showed that Oprk1 expression is regulated differently in these strains. Also, DBA/2J mice (alcohol-avoiding) showed expression of Oprk1 mRNA subtypes (alternatively spliced) different from B6 and BALB/cJ mice. Search of the Celera Genomics database indicated that DBA/2J had several SNP sites in the promoter/regulatory regions, which might explain the different expression of Oprk1 mRNA subtypes in this strain. The strain-dependent variation in the expression of alternatively spliced genes can be a significant source of phenotypic variation of complex traits such as alcohol preference.

Alcohol Drinking↗
PubMed1998

Developmental effects on intersexual and intrasexual variation in growth and reproduction in a lizard with temperature-dependent sex determination.

The mechanisms that control growth and reproduction have received considerable attention by molecular and cellular endocrinologists, yet there has been relatively little effort to link these two aspects of physiology. On the other hand, evolutionary biologists have long commented on the relationship between growth and reproduction in many species, yet have generally neglected the mechanisms underlying such complex traits. An approach that integrates the multiple proximate levels promises to provide significant insight into the evolution of neuroendocrine control mechanisms. In this chapter, we take this approach in reviewing environmental influences on growth and reproduction in the leopard gecko, Eublepharis macularius. In this species, incubation temperature during embryonic development not only determines gonadal sex, but also underlies within-sex differences in growth, adult morphology, aggressiveness, reproductive physiology and behaviour, and brain organization. Thus, the leopard gecko is an excellent model to elucidate the developmental interactions among the environment and the endocrine and nervous systems that control growth and reproduction.

Animals↗
PubMed2003

Diminished renal kallikrein responses to mineralocorticoid stimulation in African Americans: determinants of an intermediate phenotype for hypertension.

BACKGROUND: Hypertension is a complex trait with an ill-defined genetic predisposition, in which renal mechanisms seem to be involved even at the early stages. Renal kallikrein excretion is diminished in patients with hypertension, and perhaps even in the early, prehypertensive phases of the syndrome. African Americans, a group at increased risk of developing hypertension, have especially diminished kallikrein expression, coupled with decreased renal excretion of K(+), a known stimulant of kallikrein expression, suggesting an environmental mechanism for their kallikrein deficit. We, therefore, tested whether short-term indirect (K(+)) or direct (fludrocortisone) stimulation of mineralocorticoid activity might be capable of restoring kallikrein excretion in African Americans. METHODS: Nineteen healthy normotensive young men (n = 10 white, n = 9 African Americans) were treated with the following sequence of four oral medications, each for 1 week: placebo, KCl (120 mEq/day), placebo, and the mineralocorticoid fludrocortisone (0.4 mg/day). At each stage, we measured vital signs, excretion of kallikrein, aldosterone and electrolytes, and serum renin. Results were evaluated by two-way, repeated measures ANOVA. RESULTS: African Americans had diminished urinary excretion of not only kallikrein (P =.007), but also K(+) (P <.001) and aldosterone (P =.015). Kallikrein responses to mineralocorticoid stimulation were substantially blunted in African Americans, whether achieved indirectly (by supplemental K(+); P =.019) or directly (by the exogenous mineralocorticoid fludrocortisone; P =.027), despite achievement of substantial increments in K(+) excretion after KCl (P =.002), and multiple other mineralocorticoid effects after fludrocortisone (P =.005). The kallikrein increment after KCl was best predicted by renin activity (P =.001) rather than ethnicity. Potassium chloride did not lower blood pressure (BP) in either group (P >.4). CONCLUSIONS: Restoration of K(+) and aldosterone secretion to levels found in whites does not normalize kallikrein excretion or lower BP in African Americans, at least in the short term. Nor does exogenous mineralocorticoid stimulation fully restore kallikrein expression in African Americans. Therefore, the diminution of kallikrein biosynthesis in African Americans seems to involve mechanisms at or distal to the aldosterone receptor, and perhaps at the level of the kallikrein gene itself.

Adult↗
PubMed1998

The inheritance of alcoholic liver disease.

Available evidence supports the concept that alcoholic liver disease (ALD) is a multifactorial disease with a heritable component. A number of polymorphic genes with small and additive effects will thus encode susceptibilty to this 'polygenic' disease. Molecular genetic studies of ALD are in their infancy, and methods available for the genetic dissection of complex traits are discussed. Some candidate genes have been identified, and studies have been undertaken to test for association between specific alleles and ALD susceptibility. There is evidence to support a role for alleles of two genes encoding enzymes involved in the oxidative metabolism of alcohol (acetaldehyde dehydrogenase2*2 and cytochrome P4502E1 c2 allele) in susceptibility to ALD. More recently, attention has focused on cytokines, and there are now data showing association of specific alleles of both tumour necrosis factor alpha and interleukin-10 with predisposition to ALD. These candidate genes need to be subjected to rigorous evaluation in different populations. Such research should help to define more precisely the molecular mechanisms underlying the development of ALD in a sub-population (< 20%) of alcoholics, thereby improving the hepatologist's ability to develop rational treatments.

Animals↗
PubMed2001

Ancient asymmetries in the evolution of flowers.

Dorsoventral asymmetry in flowers is thought to have evolved many times independently as a specialized adaptation to animal pollinators. To understand how such a complex trait could have arisen repeatedly, we have compared the expression of a gene controlling dorsoventral asymmetry in Antirrhinum with its counterpart in Arabidopsis, a distantly related species with radially symmetrical flowers. We found that the Arabidopsis gene is expressed asymmetrically in floral meristems, even though they are destined to form symmetrical flowers. This suggests that, although the flowers of the common ancestor were probably radially symmetrical, they may have had an incipient asymmetry, evident at the level of early gene activity, which could have been recruited many times during evolution to generate asymmetric flowers.

Arabidopsis↗
PubMed2001

Psychiatric genetics: a frightful chromosome.

A duplication of part of chromosome 15q, apparently inherited in a non-Mendelian fashion, has been found to be strongly associated with phobic disorders. This unusual genetic mechanism may partly explain the heritability of phobias and other complex traits.

Chromosome Aberrations↗
PubMed2003

Evolution: have wings come, gone and come again?

Can complex traits be re-evolved by lineages that have lost them? Phylogenetic study now suggests that wings may indeed have reappeared several times within the ancestrally wingless stick insects.

Animals↗
PubMed1997

Nociceptive and morphine antinociceptive sensitivity of 129 and C57BL/6 inbred mouse strains: implications for transgenic knock-out studies.

Gene-targeting studies of pain, using transgenic 'knock-out' mice possessing null mutations of pain-relevant genes, are becoming increasingly common. This approach is a potentially powerful tool for the molecular dissection of complex traits such as pain modulation, but is subject to several theoretical drawbacks. One problem arises from the fact that the genetic background of knock-out mice is virtually always a mixture of alleles from two different strains; commonly 129 and C57BL/6. A more general caveat to knock-out findings derives from the demonstration that null mutations interact with genetic background to produce phenotypic changes. The present study investigated basal' nociceptive sensitivity (on the 49 degrees C tail-immersion/withdrawal test) and sensitivity to morphine antinociception in 129 and C57BL/6 mice (129/J, 129/Sv-+(p)+(Tyr-c)+(Mgf-SIJ), and C57BL/6J substrains). C57BL/6 mice displayed almost two-fold greater initial sensitivity to thermal stimulation than 129 mice, and three-fold reduced sensitivity to morphine inhibition of that noxious stimulus. These findings suggest that gene targeting studies of pain are particularly subject to the aforementioned concerns, and that C57BL/6 mice represent a suboptimal background strain for such efforts.

Journal Article↗
PubMed2001

How evolutionary history shapes recognition mechanisms.

Evolutionary psychologists have emphasized the importance of natural selection in shaping cognitive functions, but historical contingency has not received direct study. This is crucial because in response to selection, complex traits tend to be fine-tuned or jury-rigged rather than totally reconstructed. We hypothesize that the neural and cognitive strategies an animal employs in signal recognition are influenced by the strategies used by its ancestors. The responses of female túngara frogs to ancestral calls and to calls of other closely related species are influenced by history. By training artificial neural networks with a series of calls that mimic the species' past history of call evolution or various control histories, we have shown that only networks that evolved through the mimetic history predict the response biases of túngara frogs.

Journal Article↗
PubMed2003

Comparison of GenFlex Tag array and Pyrosequencing in SNP genotyping.

With the completion of the Human Genome Project, over 2 million sequence-verified single nucleotide polymorphisms (SNPs) have been deposited in public databases. The challenge has shifted from SNP identification to high-throughput SNP genotyping. Although this has had little impact on molecular diagnostics, it provides the potential for future molecular diagnostics of complex traits to include SNP profiling. Accordingly, efficient, accurate, and flexible SNP genotyping are needed. In addition, the drive for low cost has pushed genotyping reactions toward multiplexing capability. We compared two SNP genotyping techniques: Affymetrix GenFlex Tag array and Pyrosequencing. The reference method was a well-established, solid-phase, single nucleotide extension reaction technique based on tritium detection. Fourteen SNPs were selected from the fine mapping project of a multiple sclerosis locus on chromosome 17q. Using all three techniques and the reference method, the SNPs were analyzed in 96 related individuals. Without extensive optimization, we successfully genotyped 11 of 14 SNPs with both GenFlex and Pyrosequencing. Our study suggests that the Pyrosequencing technique provides higher accuracy between the two systems which is most likely due to the single-stranded template in the extension reaction. Thus, Pyrosequencing has potential for diagnostic applications. Pyrosequencing, however, is not optimal for large SNP profiling analyses wherein multiplexing potential is an advantage.

Alleles↗
PubMed2000

Sib pair linkage and association studies between bone mineral density and the interleukin-6 gene locus.

A major determinant of the risk for osteoporosis in later life is bone mineral density (BMD) attained during early adulthood. Bone mineral density is a complex trait that, presumably, is influenced by multiple genes. Interleukin-6 (IL-6) is an attractive candidate gene for osteoporosis susceptibility, because it has effects on bone cells and has been implicated in the pathogenesis of osteoporosis. Furthermore, previous investigators have identified an association between a 3' UTR polymorphism of the IL-6 gene and BMD. In this study, we searched for linkage and association between this IL-6 gene polymorphism and peak BMD in a large population (812 individuals) of healthy premenopausal sibpairs. Although previous investigators identified only 6 IL-6 alleles, we identified 17 alleles by modifying electrophoretic conditions and evaluating a very large population. We found no evidence for either linkage or association between the IL-6 gene locus and BMD of the spine or hip in either Caucasians or African Americans.

Adult↗
PubMed2000

Lack of association between interleukin-1 receptor antagonist protein gene polymorphism and bone mineral density in Hungarian postmenopausal women.

The major determinant for risk of osteoporosis in later life is bone mineral density (BMD) attained during early adulthood. Bone mineral density is a complex trait that is presumably influenced by multiple genes. Interleukin-1 receptor antagonist protein (IL-1RN) is an attractive candidate gene for osteoporosis susceptibility, because IL-1RN completely inhibits the stimulatory effects of interleukin-1 (IL-1) on bone resorption in organ cultures and has been implicated in the pathogenesis of osteoporosis. In addition, the IL-1RN gene contains a variable-number tandem repeat polymorphism (VNTR) in intron 2 with three potential protein-binding sites. Recently, an association has been found between this polymorphism and postmenopausal bone loss in the spine. In this study, we use the previously described IL-1RN polymorphism to test for an association between this polymorphism and bone mineral density in our population of postmenopausal women. There was no correlation between alleles or genotypes and BMD in the 286 subjects. Dividing subjects into osteoporotic and healthy groups (osteoporotics and controls), we found no difference in the distribution of alleles or genotypes between groups. We found no association between IL-1RN alleles or genotypes and BMD either at the lumbar spine or the femoral neck within groups. Our data do not support the hypothesis that this IL-1RN gene VNTR polymorphism has an impact on bone mass in postmenopausal women.

Adult↗
PubMed2001

Correcting for multiple analyses in genomewide linkage studies.

The dissection of complex traits frequently calls for multiple analyses to be performed, including the use of both multiple phenotypes and genetic models. These multiple phenotypes and models are often not independent, and hence the necessary correction for the multiple testing is not straightforward. In this paper we offer a new approach to address the problem of how to correct for non-independent multiple analyses in genomewide linkage studies. We describe one method of how to determine the number of 'effectively independent' tests performed in a linkage study using simple linear regression techniques. Further we describe how to use such information to establish genomewide significance thresholds for infinitely dense genomewide maps.

Chromosome Mapping↗
PubMed2004

Focus on The 5-HT1A receptor: emerging role of a gene regulatory variant in psychopathology and pharmacogenetics.

While multiple lines of evidence implicate the 5-HT1A receptor in the pathophysiology of anxiety and depression as well as in the mechanism of action of anxiolytics/antidepressants, its relevance to the therapeutic effectiveness of these drugs has been a matter of considerable debate (for review see Griebel, 1995; Hensler, 2003; Hjorth et al., 2000; Lesch et al., 2003). In the current issue of the International Journal of Neuropsychopharmacology, however, both Serretti et al. (2004) and Lemonde et al. (2004) make a strong argument for contribution of a functional 5-HT1A receptor gene variant in the pharmacogenetics of antidepressant treatment with prototypic tricyclics and selective serotonin reuptake inhibitors (SSRIs). Furthermore, the third study in this series by Huang and associates (2004) reveals an association of allelic variation of 5-HT1A receptor expression in a wide spectrum of psychopathology including schizophrenia, substance abuse, and panic disorder. Not unexpectedly, the failure to detect a consistent effect of this gene variation on 5-HT1A receptor functionality in the mature brain as indicated by both receptor binding in post-mortem brain and in-vivo receptor responsivity further supports a critical role of the 5-HT1A receptor in engineering neurodevelopmental processes which may have the potential to set the stage for the brain's permissiveness for psychopathology in later life. The availability of an increasing number of functional gene variants within the serotonergic pathway together with integration of emerging concepts of developmental genetics of complex traits will provide the groundwork for the molecular dissection of syndromal dimensions and treatment response.

Alleles↗