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Background This cross-sectional study aimed to determine the influence of genetic polymorphism in two renin-angiotensin system (RAS)-candidate genes on urinary trefoil family factor 3 (TFF3) levels in children with congenital anomalies of kidney and urinary tract (CAKUT). Methods The study included fifty children with CAKUT (PUV, VUR, and PUJO) and twenty age-matched controls. Urinary TFF3 levels were measured by enzyme-linked immunosorbent assay. Detection of genetic polymorphisms in two genes, i.e., I/D polymorphism (SNP at rs4340) in angiotensin-converting enzyme (ACE) and A/T polymorphism in the angiotensin II receptor type-2 (AT2R) due to point mutation at rs3736556 was performed by polymerase chain reaction. Progressive deterioration in kidney function was defined as fall in GFR to < 60 ml/min/1.73 m.sup.2 and/or progressive scarring. Results In our cohort, the genotypic distribution of patients and controls showed no difference. Progressive functional deterioration was significantly associated with the presence of D allele (p = 0.0004), A allele (p = 0.005), and both (p I/D > I/I; p A/T > TT; p < 0.0001). Also, children with both D/D and A/A allelic genotypes had significantly elevated urinary TFF3 compared to those having either of them. Conclusions The presence of D allele and/or A allele is significantly associated with progressive functional deterioration and elevated urinary TFF3 levels. These findings support the role of angiotensin II-AT2R-NF-[kappa]B interaction in progressive deterioration of kidney function and subsequent TFF3 expression in CAKUT. Graphical abstract, Author(s): Sachit Anand [sup.1] , Minu Bajpai [sup.1] , Tripti Khanna [sup.2] , Alok Kumar [sup.1] Author Affiliations: (1) grid.413618.9, 0000 0004 1767 6103, Department of Pediatric Surgery, All India [...]

Research on antecedents of organized attachment has focused on the quality of caregiving received during childhood. In recent years, research has begun to examine the influence of genetic factors on quality of infant attachment. However, no published studies report on the association between specific genetic factors and adult attachment. This study examined the link between the 5-HTTLPR promoter polymorphism of the serotonin transporter gene and adult unresolved attachment assessed with the Adult Attachment Interview. Genetic material and information on attachment-related loss or trauma were available for 86 participants. Multivariate regression analyses showed an association between the short 5-HTTLPR allele and increased risk for unresolved attachment. Temperament traits and psychological symptoms did not affect the association between 5-HTTLPR and unresolved attachment. The authors hypothesize that the increased susceptibility to unresolved attachment among carriers of the short allele of 5-HTTLPR is consistent with the role of serotonin in modulation of frontal--amygdala circuitry. The findings challenge current thinking by demonstrating significant genetic influences on a phenomenon previously thought to be largely environmentally driven. Keywords: unresolved attachment, serotonin, emotion regulation, 5-HTTLPR

Most microbes have complex life cycles with multiple modes of reproduction that differ in their effects on DNA sequence variation. Population genomic analyses can therefore be used to estimate the relative frequencies of these different modes in nature. The life cycle of the wild yeast Saccharomyces paradoxus is complex, including clonal reproduction, outcrossing, and two different modes of inbreeding. To quantify these different aspects we analyzed DNA sequence variation in the third chromosome among 20 isolates from two populations. Measures of mutational and recombinational diversity were used to make two independent estimates of the population size. In an obligately sexual population these values should be approximately equal. Instead there is a discrepancy of about three orders of magnitude between our two estimates of population size, indicating that S. paradoxus goes through a sexual cycle approximately once in every 1,000 asexual generations. Chromosome III also contains the mating type locus (MAT), which is the most outbred part in the entire genome, and by comparing recombinational diversity as a function of distance from MATwe estimate the frequency of matings to be [approximately equal to] 94% from within the same tetrad, 5% with a clonemate after switching the mating type, and 1% outcrossed. Our study illustrates the utility of population genomic data in quantifying life cycles. mating systems | inbreeding | sex | nucleotide polymorphism | linkage disequilibrium

Escherichia coil O157:H7, a toxin-producing food and waterborne bacterial pathogen, has been linked to large outbreaks of gastrointestinal illness for more than two decades. E. coil O157 causes a wide range of clinical illness that varies by outbreak, although factors that contribute to variation in disease severity are poorly understood. Several recent outbreaks involving O157 contamination of fresh produce (e.g., spinach) were associated with more severe disease, as defined by higher hemolytic uremic syndrome and hospitalization frequencies, suggesting that increased virulence has evolved. To test this hypothesis, we developed a system that detects SNPs in 96 loci and applied it to >500 E. coil 0157 clinical strains. Phylogenetic analyses identified 39 SNP genotypes that differ at 20% of SNP loci and are separated into nine distinct clades. Differences were observed between clades in the frequency and distribution of Shiga toxin genes and in the type of clinical disease reported. Patients with hemolytic uremic syndrome were significantly more likely to be infected with clade 8 strains, which have increased in frequency over the past 5 years. Genome sequencing of a spinach outbreak strain, a member of clade 8, also revealed substantial genomic differences. These findings suggest that an emergent subpopulation of the clade 8 lineage has acquired critical factors that contribute to more severe disease. The ability to detect and rapidly genotype 0157 strains belonging to such lineages is important and will have a significant impact on both disease diagnosis and treatment guidelines. pathogens| polymorphisms | population genetics

Objective: To investigate whether variable antidepressant response may be influenced by an interaction between the serotonin transporter promoter polymorphism (5-HTTLPR) and antidepressant concentration. Methods: Elderly subjects with depression treated withp [...]

The N-ribosyldihydronicotinamide (NRH):quinone oxidoreductase 2 (NQO2) gene encodes an enzyme that catalyzes activation of quinones. Blood DNA from 80 control individuals and 118 age-matched Parkinson's disease patients were analyzed for NQO2 gene promoter polymorphisms. The results revealed three allelic variants, designated 1-29, 1-16, and D. These results were confirmed in fibroblast cell lines. In patients with Parkinson's disease, there was a significant increase in the frequency of the D allele, but there was no difference in the frequency of the alleles in familial compared to sporadic Parkinson's disease. The D and 1-16 promoters direct higher NQO2 gene expression that results in higher enzyme activity. Overexpression of NQO2 in the catecholaminergic neuroblastoma SH-SY5Y cells resulted in increased production of reactive oxygen species when exposed to exogenous dopamine. The results suggest that the association of the D promoter with Parkinson's disease may be due to an increase in expression of the NQO2 gene. Key Words: NRH:quinone oxidoreductase 2--Promoter polymorphism--Parkinson's disease.

Lactation-associated bone loss has been reported in adolescent mothers. Polymorphisms in the vitamin D receptor (VDR) gene may contribute to differences in the physiologic skeletal response to lactation in these mothers. We evaluated the influence of VDR gene polymorphisms Apal, Bsml, and Taql on bone mass, bone and calcium-related hormones, and breast milk calcium of lactating adolescents with habitually low calcium intake. Total body bone mineral content (TBMC), total body bone mineral density (TBMD), lumbar spine BMD (LSBMD), serum hormones [intact parathyroid hormone (iPTH), 25-hydroxyvitamin D, insulin-like growth factor-I (IGF1), prolactin, and estradiol), and breast milk calcium were measured in 40 lactating Brazilian adolescents (15-18 y), and compared by VDR genotype subgroups after adjustment for calcium intake and postmenarcheal and lactational periods. TBMD and LSBMD Zscores were -0.55 [+ or -] 1.01 and -1.15 [+ or -] 1.48, respectively. LSBMD was higher (21%; P < 0.05) in adolescents with the aa genotype (n = 5) compared with those with the AA genotype (n = 7). TBMC and IGF1 were higher (23 and 50%, respectively; P < 0.05) in adolescents with tt (n = 4) than those with TT(n = 29) and Tt (n = 7) genotypes. Breast milk calcium and serum iPTH were higher (24 and 80%, respectively; P < 0.05) in adolescents with bb (n = 8) compared with those with BB (n = 21) genotype. These results indicate that bone mass and breast milk calcium are significantly associated with VDR genotypes in lactating Brazilian adolescents. Those with aa and tt genotypes had a better bone status and those with bb genotype had greater breast milk calcium.

This experiment was designed to test the effect of polymorphism in the cholesterol 7-[alpha] hydroxylase (CYP7) gene locus and dietary cholesterol (C) on cerebrum C in neonatal pigs fed sow's milk formulas. Thirty-six pigs (18 male and 18 female) genetically selected for high (HG) or low (LG) plasma total C were weaned at 24-36 h after birth and assigned in a 2 x 2 x 2 factorial arrangement of treatments with 2 diets (0 or 0.5% C), 2 sexes, and 2 genotypes (HG and LG). Individually housed pigs consumed diets ad libitum for 42 d. Open-field behavior was tested at wk 2 and 4. All pigs were killed at 42 d of age, the cerebrum was weighed, and C content and concentration measured. All data were analyzed by general linear model ANOVA. Cerebrum weight was greater in HG than LG pigs (P < 0.03) but was not affected by diet or sex. Pigs fed C tended to have a higher cerebrum C concentration than those deprived (P = 0.12). At 2 wk, LG pigs explored a novel open-field environment less often (P < 0.001) than did HG pigs. At 4 wk, some LG pigs explored the open field but fewer (P < 0.001) vs. HG pigs retreated back to the safe area. There were no genotype x diet, genotype x sex, or diet x sex interactions affecting cerebrum weight, or C content or concentration. Polymorphism in the CYP7 gene locus affected cerebrum weight and behavior and dietary C tended to increase cerebrum C concentration in neonatal pigs. These findings in neonatal pigs have considerable potential importance in human infant nutrition and behavioral development.

Dysregulation of brain serotonin (5-HT) neurotransmission is thought to underlie mental conditions as diverse as depression, anxiety disorders, bipolar disorder, autism, and schizophrenia. Despite treatment of these conditions with serotonergic drugs, the molecular mechanisms by which 5-HT is involved in the regulation of aberrant emotional behaviors are poorly understood. Here, we generated knockin mice expressing a mutant form of the brain 5-HT synthesis enzyme, tryptophan hydroxylase 2 (Tph2), This mutant is equivalent to a rare human variant (R441H) identified in few individuals with unipolar major depression. Expression of mutant Tph2 in mice results in markedly reduced ([approximately equal to] 80%) brain 5-HT production and leads to behavioral abnormalities in tests assessing 5-HT-mediated emotional states. This reduction in brain 5-HT levels is accompanied by activation of glycogen synthase kinase 3[beta] (GSK3[beta]), a signaling molecule modulated by many psychiatric therapeutic agents. Importantly, inactivation of GSK3[beta] in Tph2 knockin mice, using pharmacological or genetic approaches, alleviates the aberrant behaviors produced by 5-HT deficiency. These findings establish a critical role of Tph2 in the maintenance of brain serotonin homeostasis and identify GSK3[beta] signaling as an important pathway through which brain 5-HT deficiency induces abnormal behaviors. Targeting GSK3[beta] and related signaling events may afford therapeutic advantages for the management of certain 5-HT-related psychiatric conditions. GSK-3 | mood disorders | serotonin | Tph2 | functional polymorphism

Potatoes (Solanum tuberosum L.) and humans (Homo sapiens L.) are both outcrossing species. The phenotypic variation of both is controlled by environmental factors and by natural DNA polymorphisms between individuals. Therefore we adopt similar approaches as used in human population genetics, such as association mapping, to identify loci and their alleles that are causal for complex agronomic characters such as quantitative resistance to pathogens or tuber sugar content. Functional analysis of genes operating in resistance to pests and pathogens or n carbohydrate metabolism, either in potato itself or in other plants including the model species Arabidopsis thaliana (L.) Heynh., provides many functional candidates for these complex agronomic traits, n our approach functional candidate genes are tested for linkage to quantitative trait loci (QTL) for pathogen resistance or tuber quality traits, thereby selecting positional candidates (genes colocalizing with a QTL). DNA polymorphisms n or physically linked to positional candidate genes are then evaluated n populations of tetraploid potato genotypes and tested for association with phenotypes evaluated in the same populations. We have used the candidate gene approach to identify DNA-based markers that are diagnostic for quantitative resistance to late blight caused by Phytophthora infestans (Mont.) de Bary, to the root cyst nematode Globodera pallida (Stone), and for chip color in tetraploid potato cultivars and in advanced breeding clones.

In a randomized controlled trial we tested the role of genetic differences in explaining variability in intervention effects on child externalizing behavior. One hundred fifty-seven families with 1- to 3-year-old children screened for their relatively high levels of externalizing behavior participated in a study implementing Video-feedback Intervention to promote Positive Parenting and Sensitive Discipline (VIPP-SD), with six 1.5-hr intervention sessions focusing on maternal sensitivity and discipline. A moderating role of the dopamine D4 receptor (DRD4) variable-number tandem repeat (VNTR) exon III polymorphism was found: VIPP-SD proved to be effective in decreasing externalizing behavior in children with the DRD4 7-repeat allele, a polymorphism that is associated with motivational and reward mechanisms and Attention Deficit Hyperactivity Disorder (ADHD) in children. VIPP-SD effects were largest in children with the DRD4 7-repeat allele whose parents showed the largest increase in the use of positive discipline. The findings of this first experimental test of (measured) gene by (observed) environment interaction in human development indicate that children may be differentially susceptible to intervention effects depending on genetic differences. Keywords: intervention, dopamine, DRD4, externalizing behavior, toddlers, sensitive parenting

Subcortical dopamine D2 receptor (DRD2) signaling is implicated in cognitive processes and brain disorders, but the effect of DRD2 variants remains ambiguous. We measured allelic mRNA expression in postmortem human striatum and prefrontal cortex and then performed single nucleotide polymorphism (SNP) scans of the DRD2 locus. A previously uncharacterized promoter SNP (rs12364283) located in a conserved suppressor region was associated with enhanced DRD2 expression, whereas previously studied DRD2 variants failed to affect expression. Moreover, two frequent intronic SNPs (rs2283265 and rs1076560) decreased expression of DRD2 short splice variant (expressed mainly presynaptically) relative to DRD2 long (postsynaptic), a finding reproduced in vitro by using minigene constructs. Being in strong linkage disequilibrium with each other, both intronic SNPs (but not rs12364283) were also associated with greater activity of striatum and prefrontal cortex measured with fMRI during working memory and with reduced performance in working memory and attentional control tasks in healthy humans. Our results identify regulatory DRD2 polymorphisms that modify mRNA expression and splicing and working memory pathways. allelic expression imbalance | splice variant | promoter polymorphism | brain imaging

Two regulatory region polymorphisms in the prion gene of cattle have been reported to have an association with resistance to classical bovine spongiform encephalopathy (BSE). However, it is not known if this association also applies to other transmissible spongiform encephalopathies (TSE) in cattle. In this report, we compare the relationship between these 2 polymorphisms and resistance in cattle affected with naturally occurring atypical BSE as well as in cattle experimentally inoculated with either scrapie, chronic wasting disease, or transmissible mink encephalopathy. Our analysis revealed no association between genotype and resistance to atypical BSE or experimentally inoculated TSE. This indicates the promoter polymorphism correlation is specific to classical BSE and that atypical BSE and experimentally inoculated TSE are bypassing the site of influence of the polymorphisms. This genetic discrepancy demonstrates that atypical BSE progresses differently in the host relative to classical BSE. These results are consistent with the notion that atypical BSE originates spontaneously in cattle. Key words: atypical, bovine spongiform encephalopathy, genotype, prion

Adaptive evolution of animals depends on behaviors that are essential for their survival and reproduction. The olfactory system of Drosophila melanogaster has emerged as one of the best characterized olfactory systems, which in addition to a family of odorant receptors, contains an approximately equal number of odorant-binding proteins (OBPs), encoded by a multigene family of 51 genes. Despite their abundant expression, little is known about their role in chemosensation, largely due to the lack of available mutations in these genes. We capitalized on naturally occurring mutations (polymorphisms) to gain insights into their functions. We analyzed the sequences of 13 Obp genes in two chromosomal clusters in a population of wild-derived inbred lines, and asked whether polymorphisms in these genes are associated with variation in olfactory responsiveness. Four polymorphisms in 30bp genes exceeded the statistical permutation threshold for association with responsiveness to benzaldehyde, suggesting redundancy and/or combinatorial recognition by these OBPs of this odorant. Model predictions of alternative pre-mRNA secondary structures associated with polymorphic sites suggest that alterations in Obp mRNA structure could contribute to phenotypic variation in olfactory behavior.

Numerous loci in host organisms are involved in parasite recognition, such as major histocompatibility complex (MHC) genes in vertebrates or genes involved in gene-for-gene (GFG) relationships in plants. Diversity is commonly observed at such loci and at corresponding loci encoding antigenic molecules in parasites. Multilocus theoretical models of host-parasite coevolution predict that polymorphism is more likely than in single-locus interactions because recurrent coevolutionary cycles are sustained by indirect frequency-dependent selection as rare genotypes have a selective advantage. These cycles are stabilized by direct frequency-dependent selection, resulting from repeated reinfection of the same host by a parasite, a feature of most diseases. Here, it is shown that for realistically small costs of resistance and virulence, polycyclic disease and high autoinfection rates, stable polymorphism of all possible genotypes is obtained in parasite populations. Two types of epistatic interactions between loci tend to increase the parameter space in which stable polymorphism can occur with all possible host and parasite genotypes. In the parasite, the marginal cost of each additional virulence allele should increase, while in the host, the marginal cost of each additional resistance allele should decrease. It is therefore predicted that GFG polymorphism will be stable (and hence detectable) when there is partial complementation of avirulence genes in the parasite and of resistance genes in the host.

OBJECTIVE: To investigate the role of angiotensin-converting enzyme (ACE) gene polymorphism in patients with degenerative aortic valve calcification (AVC). PATIENTS AND METHODS: Our study consisted of 305 Turkish patients of [...]

The susceptibility to arsenic-induced diseases differs greatly between individuals, possibly due to interindividual variations in As metabolism that affect retention and distribution of toxic metabolites. To elucidate the role of [...]

A genome scan was conducted to seek evidence for polymorphic genes that influence cause of death in mice produced by a cross between CB6F1 females and C3D2F1 males. Loci on chromosomes 1 and 4 were found to modulate risk of lymphoma. A locus on chromosome 4 influenced risk of mammary adenocarcinoma among multiparous female mice, but had no significant effect in virgin females. A chromosome 4 locus was found to modulate risk of death from either hemangiosarcoma or fibrosarcoma. A suggestive linkage was noted (at p = .09) between a marker on chromosome 11 and hepatocellular carcinoma. Lastly, a locus on chromosome 6 was noted to influence the likelihood that pulmonary adenocarcinoma would be present at death. The collection of normal and neoplastic tissues from 1004 terminal necropsies. together with genetic information, provides a valuable resource for further studies of the genetic influences on late-life diseases in mice.

Mounting evidence points to dietary habits as an important determinant of cancer risk and tumor behavior. Although the linkages with diet are intriguing, the literature is also laden with inconsistencies. The reasons for these inconsistencies are likely multi-factorial, but probably reflect variations in the ability of bioactive constituents to reach or affect critical molecular targets. Fluctuations in the foods consumed not only influence the intake of particular bioactive components, but may alter metabolism and potentially influence the sites of action of both essential and nonessential nutrients. Genetic polymorphisms are increasingly recognized as another factor that can alter the response to dietary components (nutritional transcriptomic effect) by influencing the absorption, metabolism, or sites of action. Likewise, variation in DNA methylation patterns and other epigenetic events that influence overall gene expression can be influenced by dietary intakes. Furthermore, variation in the ability of food components to increase or depress gene expression (nutrigenomic effect) may account for some of the observed inconsistencies in the response to dietary change. Because a host of food components are recognized to influence phosphorylation and other posttranslational events, it is also likely that these and other proteomic modifications account for at least part of the response and variation that is reported in the literature. Collectively, it is clear that bioactive food components can influence a number of key molecular events that are involved in health and disease resistance. As the era of molecular nutrition unfolds, a greater understanding of how these foods and components influence cancer will surely arise. Such information will be critical in the development of effective tailored strategies for reducing cancer burden. Just as important, however, is that as this information unfolds it is utilized within a responsible bioethical framework. KEY WORDS: * bioactive * nutrigenomics * nutrigenetics * proteomics * metabolomics

The response of plasma lipids to dietary cholesterol and fat varies among individuals. Variations in genes involved in cholesterol metabolism can be important in these interindividual differences. The rate-limiting enzyme in the conversion of cholesterol into bile acids is cholesterol 7[alpha]-hydroxylase (CYP7A1). We investigated the effect of the A278-C promoter polymorphism in the CYP7A1 gene on responses of plasma lipids to an increased intake in dietary cholesterol (742 [+ or -] 114 mg/d), cafestol (57 [+ or -] 6 mg/d), saturated fat [change of 8-9 energy percent/d (en%/d)] and trans fat (change of 10-11 en%/d) in 496 normolipidemic subjects. These responses were measured in 26 previously published dietary trials. After adjustment for the apolipoprotein E genotype effect, AA-subjects consuming a cholesterol-rich diet had a smaller increase in plasma HDL cholesterol than CC-subjects (0.00 [+ or -] 0.02 vs. 0.17 [+ or -] 0.04 mmol/L; P < 0.001). Upon intake of cafestol, AA-subjects had a smaller increase in plasma total cholesterol than CC-subjects (0.69 [+ or -] 0.10 vs. 1.01 [+ or -] 0.10 mmol/L; P = 0.028). No effects of the polymorphism were found in the saturated and trans fat interventions. In conclusion, the CYP7A1 polymorphism has a small but significant effect on the increase in plasma HDL cholesterol and plasma total cholesterol after an increased intake of dietary cholesterol and cafestol, respectively. KEY WORDS: * CYP7A1 * polymorphism * cholesterol * cafestol * dietary interventions

Much remains unknown of the phylogeny and evolution of Mycobacterium tuberculosis, an organism that kills 2 million people annually. Using a population-based approach that analyzes multiple loci around the chromosome, [...]

The current knowledge about molecular and clinical predictors of drug-induced prolongation of the QT interval associated with polymorphism ventricular tachycardia, which can be fatal, is summarized. The ways in which new predictors of a drug's activity might be incorporated into drug development programs for a more general approach is discussed.

Research shows that the natural polymorphisms of amino acid residues and mutations of the drug-resistance domain together influence the viability of the HIV-1 protease inhibitors and by implication the inhibition therapies. Data also indicate that the polymorphism may occur outside the active site of the inhibitors without any consequence on their binding properties.

Habitat selection behavior is an important predator-avoidance strategy for many organisms. Its particular expression is often explained as the result of a tradeoff between avoiding antagonists and acquiring resources. However, there is need for a broader perspective on this behavior, as organisms are often simultaneously involved in complex antagonistic relationships with multiple types of enemies. We show experimentally that a tradeoff between predator and parasite avoidance may be important in the evolution of habitat selection behavior in the waterflea, Daphnia magna. In this species, negatively phototactic clones suffer less from visually hunting predators by residing in deeper and darker portions of the water column during the day. However, this behavior increases the risk of parasitic infections when the Daphnia are exposed to pond sediments containing parasite spores. Positively phototactic clones, which are at a higher risk of predation, are less exposed to parasite spores in the sediment and consequently suffer less from parasitic infection. We show that the increased risk of infection remains even if the animals change their phototactic behavior on exposure to chemical cues from fish. This tradeoff highlights a substantial cost of predator-induced changes in habitat selection behavior. Tradeoffs caused by multiple enemies may explain genetic polymorphism for habitat selection behavior in many natural populations.

Malaria has been invoked, perhaps more than any other infectious disease, as a force for the selection of human genetic polymorphisms. Evidence for genome-shaping interactions can be found in the geographic and ethnic distributions of the hemoglobins, blood group antigens, thalassemias, red cell membrane molecules, human lymphocyte antigen (HLA) classes, and cytokines. Human immune responses and genetic variations can correspondingly influence the structure and polymorphisms of Plasmodium populations, notably in genes that affect the success and virulence of infection. In Africa, where the burden from Plasmodium falciparum predominates, disease severity and manifestations vary in prevalence among human populations. The evolutionary history and spread of Plasmodium species inform our assessment of malaria as a selective force. Longstanding host-pathogen relationships, as well as recent changes in this dynamic, illustrate the selective pressures human and Plasmodium species place on one another. Investigations of malaria protection determinants and virulence factors that contribute to the complexity of the disease should advance our understanding of malaria pathogenesis.

Gene-environment interactions are presumed to shape human behavior during early development. However, no human research has demonstrated that such interactions lead to stable individual differences in fear responses. We tested this possibility by focusing on a polymorphism in the promoter region of the gene for the serotonin transporter (5-HTT). This polymorphism has been linked to many indices of serotonin activity. Specifically, we tested the hypothesis that an interaction between children's 5-HTT status and maternal reports of social support predicts inhibited behavior with unfamiliar peers in middle childhood. Results were consistent with this hypothesis: Children with the combination of the short 5-HTT allele and low social support had increased risk for behavioral inhibition in middle childhood.

The role of dopaminergic genes in the smoking cessation program and the response to bupropion treatment in a placebo-controlled clinical trial are examined. The evidence from the clinical trial shows that the genes that alter dopamine function may influence smoking cessation and may relapse during the treatment phase.

This review discusses the role of drug-metabolizing enzyme genotypes in improving the therapeutic index by enhancing drug efficacy and reducing adverse response to chemotherapeutic regimens. The influence of pharmacogenetic determinants on the treatment outcome and transporter pharmacogenetics in drug bioavailability are also discussed.

Research shows that the genetic variability of the high-density lipoprotein-associated serum paraoxonase position 192 isoforms affect sensitivity of the paraoxonase to insecticides or nerve agents and pose risk for cardiovascular disease. The review also presents data on its role in drug metabolism.

A debate of long-standing interest in human evolution centers around whether archaic human populations (such as the Neanderthals) have contributed to the modern gene pool. A model of ancient population structure with recent mixing is introduced, and it is determined how much information (i.e., sequence data from how many unlinked nuclear loci) would be necessary to distinguish between different demographic scenarios. It is found that ~50-100 loci are necessary if plausible parameter estimates are used. There are not enough data available at the present to support either the 'single origin' or the 'multiregional' model of modern human evolution. However, this information should be available in a few years.