Population-specific Effects Research Articles

CASP8 variants D302H and −652 6N ins/del do not influence the risk of colorectal cancer in the United Kingdom population

Polymorphisms in CASP8 at 2q33.1 have been associated with the risk of developing cancer, specifically, the D302H variant (rs1045485) with breast cancer in the European population and the −652 6N ins/del promoter variant (rs3834129) with multiple tumours including colorectal cancer (CRC) in the Chinese population. We evaluated the relationship between −652 6N ins/del and D302H variants and risk of developing CRC in the UK population by genotyping 4016 cases and 3749 controls. Both variants showed no evidence of an association with risk of developing CRC (P=0.42 and 0.22, respectively). In contrast, the recently identified CRC susceptibility allele rs6983267 mapping to 8q24 was significantly associated with disease risk (P=8.94 × 10−8). It is thus very unlikely that variation in CASP8 defined by −652 6N ins/del or D302H influences the risk of CRC in European populations. The implications of our findings both in terms of population-specific effects and publication bias are discussed.

Global meta-analysis of the C-11377G alteration in the ADIPOQ gene indicates the presence of population-specific effects: challenge for global health initiatives

Type II diabetes mellitus is currently globally one of the fastest growing non-communicable diseases, especially in developing countries. This investigation reports on a meta-analysis undertaken of the C-11377G locus within the adiponectin gene in a black South African, a Cuban Hispanic and a German Caucasian cohort. Genotyping was performed via a real-time PCR strategy. Both fixed- and random-effects models were tested to describe the diabetes risk at both the cohort and population levels. The 2,2 genotype may only be associated with increased diabetes risk in the Cuban Hispanic cohort. Population-specific effects may have masked these associations upon meta-analytical analysis, as no significant odds ratio could be determined. Thus, to examine diabetes risk, a more global approach including the design of population-specific experimental strategies should be used, which will be crucial in developing health education and policies in a global health programme.

Bayesian Variable Selection for Detecting Adaptive Genomic Differences Among Populations

We extend an F(st)-based Bayesian hierarchical model, implemented via Markov chain Monte Carlo, for the detection of loci that might be subject to positive selection. This model divides the F(st)-influencing factors into locus-specific effects, population-specific effects, and effects that are specific for the locus in combination with the population. We introduce a Bayesian auxiliary variable for each locus effect to automatically select nonneutral locus effects. As a by-product, the efficiency of the original approach is improved by using a reparameterization of the model. The statistical power of the extended algorithm is assessed with simulated data sets from a Wright-Fisher model with migration. We find that the inclusion of model selection suggests a clear improvement in discrimination as measured by the area under the receiver operating characteristic (ROC) curve. Additionally, we illustrate and discuss the quality of the newly developed method on the basis of an allozyme data set of the fruit fly Drosophila melanogaster and a sequence data set of the wild tomato Solanum chilense. For data sets with small sample sizes, high mutation rates, and/or long sequences, however, methods based on nucleotide statistics should be preferred.

"Contrasting Patterns of Selection at Pinus pinaster Ait. Drought Stress Candidate Genes as Revealed by Genetic Differentiation Analyses"

The importance of natural selection for shaping adaptive trait differentiation among natural populations of allogamous tree species has long been recognized. Determining the molecular basis of local adaptation remains largely unresolved, and the respective roles of selection and demography in shaping population structure are actively debated. Using a multilocus scan that aims to detect outliers from simulated neutral expectations, we analyzed patterns of nucleotide diversity and genetic differentiation at 11 polymorphic candidate genes for drought stress tolerance in phenotypically contrasted Pinus pinaster Ait. populations across its geographical range. We compared 3 coalescent-based methods: 2 frequentist-like, including 1 approach specifically developed for biallelic single nucleotide polymorphisms (SNPs) here and 1 Bayesian. Five genes showed outlier patterns that were robust across methods at the haplotype level for 2 of them. Two genes presented higher F(ST) values than expected (PR-AGP4 and erd3), suggesting that they could have been affected by the action of diversifying selection among populations. In contrast, 3 genes presented lower F(ST) values than expected (dhn-1, dhn2, and lp3-1), which could represent signatures of homogenizing selection among populations. A smaller proportion of outliers were detected at the SNP level suggesting the potential functional significance of particular combinations of sites in drought-response candidate genes. The Bayesian method appeared robust to low sample sizes, flexible to assumptions regarding migration rates, and powerful for detecting selection at the haplotype level, but the frequentist-like method adapted to SNPs was more efficient for the identification of outlier SNPs showing low differentiation. Population-specific effects estimated in the Bayesian method also revealed populations with lower immigration rates, which could have led to favorable situations for local adaptation. Outlier patterns are discussed in relation to the different genes' putative involvement in drought tolerance responses, from published results in transcriptomics and association mapping in P. pinaster and other related species. These genes clearly constitute relevant candidates for future association studies in P. pinaster.

Population-specific effects of the Asn40Asp polymorphism at the μ-opioid receptor gene (OPRM1) on HPA-axis activation

Studies in European Americans (EAs) have shown that the hypothalamic-pituitary-adrenal (HPA)-axis activation by the opioid blockade is moderated by the single nucleotide polymorphism (SNP) A118G (Asn40Asp) at the mu-opioid receptor locus (OPRM1). We examined the effect of this, and of five intronic OPRM1 SNPs, on adrenocorticotropic hormone and cortisol concentrations, following the placebo-controlled administration of naloxone to healthy individuals who were of EA or Asian ancestry. We used a balanced, within-participant design with two test sessions to examine the hormonal responses to intravenous naloxone (an opioid antagonist) (125 microg/kg) or placebo in 29 healthy participants (62% men, 59% of Asian ancestry). DNA isolated from whole blood was PCR amplified and genotyped using a fluorogenic 5 nuclease assay (TaqMan) method. Consistent with earlier reports, participants with one or two Asp40 alleles (n=16) had a significantly greater cortisol response to naloxone than Asn40 homozygotes, but the effect was limited to EAs. Asians with the Asp40 allele did not show a greater increase in cortisol response compared with Asn40 homozygotes. None of the intronic SNPs was associated with cortisol response either directly or via an interaction effect with Asn40Asp. Effects of the Asn40Asp polymorphism at OPRM1 on HPA-axis activation seem to be population-specific. The association between the Asn40Asp and the HPA-axis response to naloxone cannot, therefore, be explained with reference only to the amino acid substitution encoded by that polymorphism. Further research to understand the basis for the observed association is warranted.

Association of Human Leukocyte Antigen-A11 With Resistance and B40 and DR2 With Susceptibility to HIV-1 Infection in South India

Association of Human Leukocyte Antigen-A11 With Resistance and B40 and DR2 With Susceptibility to HIV-1 Infection in South India

Family Studies and Positional Cloning of Genes for Asthma and Related Phenotypes

Although it is not yet known how many genes may contribute to the susceptibility or the severity of asthma and related phenotypes, genome-wide screens and positional cloning techniques have been successful in identifying contributing genes in multiple populations. The results of these studies provide additional insight into the molecular mechanisms responsible for the development of a variety of phenotypes. Replication with additional populations--particularly in large-scale studies--has been used to distinguish between false positive results or population-specific effects or to further quantify the conferred risk. Even when individual markers do not replicate in multiple population, association of the same region or gene has been useful in directing future studies. As further understanding of linkage disequilibrium patterns within the genome has allowed greater efficiency for genetic studies, advances in high-throughput genotyping technology, genetic analysis methodologies, and a more in-depth understanding of clinical phenotypes has made genome-wide studies more accessible and cost-effective. In the future, identification of function variants with clinical relevance may be used to influence the diagnosis and treatment of asthma.

Slug species- and population-specific effects on the end points of the Slug Mucosal Irritation test

The Slug Mucosal Irritation test seems to be a promising method for the evaluation of the local tolerance of products applied to the mucosa. Furthermore, the Slug Mucosal Irritation test is a reliable method to classify chemicals accurately into three eye irritation categories based on the mucus production and the score for tissue damage. Until now the slug Arion lusitanicus collected in Belgium was always used as test organism. The present study investigated the effects of the slug population and species on the end points of the test and on the eye irritation classification. For this purpose, the eye irritation/damage test procedure and eye reference chemicals were used. Comparison of the results of one Belgian and two Swiss A. lusitanicus populations indicated that the geographic and ecological origins of slug populations did neither influence the mucus production, nor the score for tissue damage. Slug species-specific effects on the test end points were investigated by comparing the data of Belgian Limax flavus with corresponding data of Belgian A. lusitanicus. L. flavus produced more mucus than A. lusitanicus, so that the mucus production cut-off values had to be increased. Therefore, the results indicated that the test procedure and prediction model have to be optimised and validated, if other slug species are used instead of A. lusitanicus.

Is Variation in the GABA(B) Receptor 1 Gene Associated with Temporal Lobe Epilepsy?

gamma-Aminobutyric acid (GABA)-receptor genes are prime candidates for a role in seizure susceptibility. An association between the c.1465G-->A variant in the GABA(B) receptor 1 gene (GABBR1) and susceptibility to temporal lobe epilepsy (TLE) has been reported in an Italian cohort. We sought to replicate this association in an independent Australian cohort. The 234 patients with TLE and 164 healthy controls were genotyped for the c.1465G-->A variant, by using inclusion criteria identical to those of the first study. The c.1465G-->A variant was found in one TLE patient and one control subject. Genotype and allele frequencies did not differ between groups. We did not replicate the reported associations between the c.1465G-->A variant and susceptibility to TLE. We suggest that the initial positive association may be due to undetected population stratification; the importance of genomic control is emphasized. Population-specific effects also may play a role, and we highlight the need to demonstrate an in vitro functional effect to give biologic meaning to any proposed association.

The Jewish–Arab divide in life expectancy in Israel

Life expectancy at birth in Israel in 2001 was 77.7 years for males and 81.6 years for females among Jews, and 74.5 and 77.8 years for males and females, respectively, among Israeli Arabs. In spite of vast improvements in health conditions of the two populations since Israel's statehood in 1948, persistent disparities in life expectancy between the two groups have challenged the Israeli socialized health care system. These disparities are influenced primarily by differences between the two population groups in infant and child mortality rates. This early study suggests that the distribution of life expectancy across localities in Israel reflects the distribution of those localities’ socio-economic condition index (not including health and medical care), and the distribution of medical services. The positive association between life expectancy and the index is pronounced, however, only within the Jewish population but not among Arabs. While there may be no significant difference in life expectancy among Jews and Arabs living in poorer communities, there are fewer Arabs living in relatively affluent communities. Thus, persistent higher concentration of poverty among Arabs than among Jews has sufficed to maintain the gap in life expectancy between them. In addition, however, there are population-specific effects: wealth and education are more protective among Jews than among Arabs, while medical services are more protective among Arabs.

Maternal investment in egg size: environment- and population-specific effects on offspring performance

Geographic variation in maternal investment in offspring size can be adaptive if differences in investment translate into improved offspring performance in the given environments. We compared two moor frog, Rana arvalis, populations in the laboratory to test the hypothesis that investment in large eggs in populations originating from stressful (acid) environments improves offspring performance when reared in stressful (acid) conditions. We found that large initial size (hatchling mass) had moderate to strong, environment-dependent positive effects on larval and metamorphic traits in the acidic origin population, but only weak effects in the neutral origin population. Our results suggest that interactions between environmental conditions and initial size can be important determinants of individual performance, and that investment in large eggs is adaptive in acid environments. These findings emphasize the role of maternal effects as adaptations to environmental stress.

The impact of host genetics on HIV infection and disease progression in the era of highly active antiretroviral therapy.

Suspicion that host genetic factors determine variability in the course of natural HIV-1 infection deepened throughout the 1980s and early 1990s [1,2], but only relatively recently have we recognized the impact of human genetic variation on HIV/AIDS as a complex phenomenon [3–11]. As the control and prevention of HIV-1 infection with highly active antiretroviral therapy (HAART) became more widely available, the growing opportunity for pharmacogenetic studies [12– 14] was also accompanied by uncertainty about the residual host genetic influences on HIV/AIDS.

Identification and ethnic distribution of major haplotypes in the gene GNB3 encoding the G-protein beta3 subunit.

The 825T-allele of the gene GNB3 encoding the G protein beta3 subunit is associated with hypertension and obesity, and identifies individuals highly responsive to diuretic therapy. Gbeta3s, a Gbeta3 protein variant generated by alternative splicing in carriers of the 825T-allele, is linked to increased signal transduction and is a potential cause for the observed pathophysiology. Here, we searched the entire GNB3 gene for additional polymorphisms and analysed their prevalence in Caucasian, black African and Asian populations. We detected six novel single nucleotide polymorphisms which were termed according to their location as G76A, G1906T, G2906A, A3882C, G5177A, and G5249A. Furthermore, we found a CACA-insertion-deletion polymorphism at position 6496. Genotyping and association studies resulted in the definition of two major GNB3 haplotypes, termed 'C-haplotype' (alleles 825C, 3882A, 5249G, 6496CACA-) and 'T-haplotype' (alleles 825T, 3882C, 5249A, 6496CACA+). Molecular modelling studies revealed that the pre-mRNA structures of both haplotypes exhibit marked differences which may account for the alternative splicing predominantly observed with the T-haplotype. The prevalence of these haplotypes in major ethnic populations differs considerably. Furthermore, we detected additional frequent GNB3 polymorphisms. These variants were restricted to one or two major ethnic populations. Our results will aid future studies on population-specific effects of the GNB3 variants on risk and course of frequent diseases, including hypertension, obesity, stroke and myocardial infarction. Furthermore, they will contribute to the understanding of GNB3-related population-specific pharmacogenetic differences in the response to major drugs, as already shown for diuretics and antidepressants.

Food chemical cues elicit general and population‐specific effects on lingual and biting behaviors in the lacertid lizard Podarcis lilfordi

Actively foraging lizards are capable of identifying prey using only chemical cues sampled by tongue-flicking, and the relatively few omnivorous and herbivorous lizards tested similarly can identify both animal and plant foods from chemical cues. Whether lizards that eat plants respond to cues specific to preferred plant types and whether there is geographic variability in responses to cues from various plants correlated with the importance of those plants in local diets is unknown. In three populations of an omnivorous lacertid, the Balearic lizard Podarcis lilfordi, we studied chemosensory sampling and feeding responses to chemical cues from plant and animal foods presented on cotton swabs. Each lizard population is endemic to one islet off the coast of Menorca, Balearic Islands, Spain. Lizards in all three populations discriminated chemical cues from plant and animal foods from control substances. Our results extend findings of prey chemical discrimination and plant chemical discrimination in omnivores, increasing confidence that correlated evolution has occurred between plant diet and chemosensory response to palatable plants. There were no consistent differences among populations in tongue-flicking and biting responses to stimuli from flowers of syntopic and allopatric plant species. The lizards may respond to cues indicative of palatability in a wide range of plant species rather than exhibiting strong responses only to locally available plant species. Nevertheless, tongue-flicking and biting frequencies varied among plant species, perhaps indicating food preferences. In addition, there were differences among populations in tongue-flick rates, latency to bite, and licking behavior. Licking was observed in only one lizard population as a response to floral chemicals from only one of the plants species tested, raising the possibility of a population-specific linkage between identification of a particular plant species and performance of an appropriate feeding response.

Global survey of genetic variation in CCR5, RANTES, and MIP-1alpha: impact on the epidemiology of the HIV-1 pandemic.

Expression of CC chemokine receptor 5 (CCR5), the major coreceptor for HIV-1 cell entry, and its ligands (e.g., RANTES and MIP-1alpha) is widely regarded as central to the pathogenesis of HIV-1 infection. By surveying nearly 3,000 HIV+ and HIV- individuals from worldwide populations for polymorphisms in the genes encoding RANTES, MIP-1alpha, and CCR5, we show that the evolutionary histories of human populations have had a significant impact on the distribution of variation in these genes, and that this may be responsible, in part, for the heterogeneous nature of the epidemiology of the HIV-1 pandemic. The varied distribution of RANTES haplotypes (AC, GC, and AG) associated with population-specific HIV-1 transmission- and disease-modifying effects is a striking example. Homozygosity for the AC haplotype was associated with an increased risk of acquiring HIV-1 as well as accelerated disease progression in European Americans, but not in African Americans. Yet, the prevalence of the ancestral AC haplotype is high in individuals of African origin, but substantially lower in non-Africans. In a Japanese cohort, AG-containing RANTES haplotype pairs were associated with a delay in disease progression; however, we now show that their contribution to HIV-1 pathogenesis and epidemiology in other parts of the world is negligible because the AG haplotype is infrequent in non-Far East Asians. Thus, the varied distribution of RANTES, MIP-1alpha, and CCR5 haplotype pairs and their population-specific phenotypic effects on HIV-1 susceptibility and disease progression results in a complex pattern of biological determinants of HIV-1 epidemiology. These findings have important implications for the design, assessment, and implementation of effective HIV-1 intervention and prevention strategies.

Race-specific HIV-1 disease-modifying effects associated with CCR5 haplotypes.

Genetic variation in CC chemokine receptor 5 (CCR5), the major HIV-1 coreceptor, has been shown to influence HIV-1 transmission and disease progression. However, it is generally assumed that the same CCR5 genotype (or haplotype) has similar phenotypic effects in different populations. To test this assumption, we used an evolutionary-based classification of CCR5 haplotypes to determine their associated HIV-1 disease-modifying effects in a large well-characterized racially mixed cohort of HIV-1-seropositive individuals. We demonstrate that the spectrum of CCR5 haplotypes associated with disease acceleration or retardation differs between African Americans and Caucasians. Also, we show that there is a strong interactive effect between CCR5 haplotypes with different evolutionary histories. The striking population-specific phenotypic effects associated with CCR5 haplotypes emphasize the importance of understanding the evolutionary context in which disease susceptibility genes are expressed.

Fecundity above the Species Level: Ovule Number and Brood Size in the Genisteae (Fabaceae: Papilionoideae).

Per-fruit components of fecundity (ovules per ovary, seeds per fruit, seed : ovule ratio, and patterns of seed maturation within pods) were studied in 33 species of the Genisteae, a legume tribe of mostly Mediterranean shrubs, e.g., Cytisus, Ulex, that also includes more widespread herbs such as Lupinus. Species identity explained most variance in both potential (ovules) and realized (seeds per fruit and seed : ovule ratio) fecundity, and although significant population-specific effects existed, these were relatively small, indicating that estimates of fecundity were not particularly prone to environment-induced changes. Average seed : ovule ratios varied between 20% (for a few species in which fixed rates of embryo abortion result into single seeded pods) and 100% (annuals), but most taxa were in the 40%-60% range. The probability that an ovule near the base of the ovary matured into a seed was significantly lower than the pod average in the majority of species. As indicated by the large size of stigmatic pollen loads, this was unlikely to result from insufficient pollination but rather from preferential embryo abortion. High abortion rates next to pod base occurred in both presumed selfers and obligate outcrossers. Evidence points to relatively stereotyped reproductive ways and high reproductive coherence in the tribe, with major departures from the norm being high seed : ovule ratios exhibited by annual Lupinus (associated with selfing), and low ratios shown by species with single seeded pods (associated with fixed rates of embryo abortion).

Individual animal model estimates of genetic parameters for performance test traits of male and female landrace pigs tested in a commercial nucleus herd

AbstractEstimates of heritabilities, common litter of birth effects and additive maternal genetic effects were produced for ultrasonic backfat depth, average daily food intake, average daily gain and food conversion ratio of Landrace boars and gilts. Boars and gilts were performance tested under different regimes. A bivariate derivative-free restricted maximum likelihood procedure was used to estimate genetic correlations between the performance test traits as recorded in the two sexes.Heritability estimates from the analysis including the common litter of birth effect tended to be towards the low end of the range of recently published estimates. This may reflect either population specific effects, such as effects of long-term selection, or the use of an individual animal model.Estimates of the common litter of birth effect were around 0·05, and generally had a significant effect upon the fit of the model, while additive maternal genetic effect estimates were negligible. Therefore, it is expected that omission of maternal effects from models for evaluation by best linear unbiased prediction will not hinder genetic progress. Inclusion of common litter of birth effects would be recommended, although this result may not hold for populations given food ad libitum.The estimates of genetic correlations between performance test traits of boars and gilts indicate that the levels of genotype-environment interaction (G × E) and genotype-sex interaction were low across most traits and data sets, with all genetic correlation estimates lying between 0·8 and 1·0. The lowest estimates of the genetic correlations, which were observed in data sets where the environments appeared to differ most, indicate that G × E interactions may be a problem in populations where males and females are subject to test regimes with greater differences than those seen here.