Simultaneous inference of haplotypes and alleles at a causal gene.

We present a methodology which jointly infers haplotypes and the causal alleles at a gene influencing a given trait. Often in human genetic studies, the available data consists of genotypes (series of genetic markers along the chromosomes) and a phenotype. However, for many genetic analyses, one needs haplotypes instead of genotypes. Our methodology is not only able to estimate haplotypes conditionally on the disease status, but is also able to infer the alleles at the unknown disease locus. Some applications of our methodology are in genetic mapping and in genetic counseling.

A new method for estimating the demographic history from DNA sequences: an importance sampling approach.

The effective population size over time (demographic history) can be retraced from a sample of contemporary DNA sequences. In this paper, we propose a novel methodology based on importance sampling (IS) for exploring such demographic histories. Our starting point is the generalized skyline plot with the main difference being that our procedure, skywis plot, uses a large number of genealogies. The information provided by these genealogies is combined according to the IS weights. Thus, we compute a weighted average of the effective population sizes on specific time intervals (epochs), where the genealogies that agree more with the data are given more weight. We illustrate by a simulation study that the skywis plot correctly reconstructs the recent demographic history under the scenarios most commonly considered in the literature. In particular, our method can capture a change point in the effective population size, and its overall performance is comparable with the one of the bayesian skyline plot. We also introduce the case of serially sampled sequences and illustrate that it is possible to improve the performance of the skywis plot in the case of an exponential expansion of the effective population size.

Toxic risks and nutritional benefits of traditional diet on near visual contrast sensitivity and color vision in the Brazilian Amazon.

BACKGROUND: Visual functions are known to be sensitive to toxins such as mercury (Hg) and lead (Pb), while omega-3 fatty acids (FA) and selenium (Se) may be protective. In the Tapajós region of the Brazilian Amazon, all of these elements are present in the local diet. OBJECTIVE: Examine how near visual contrast sensitivity and acquired color vision loss vary with biomarkers of toxic exposures (Hg and Pb) and the nutrients Se and omega-3 FA in riverside communities of the Tapajós. METHODS: Complete visuo-ocular examinations were performed. Near visual contrast sensitivity and color vision were assessed in 228 participants (≥15 years) without diagnosed age-related cataracts or ocular pathologies and with near visual acuity refracted to at least 20/40. Biomarkers of Hg (hair), Pb (blood), Se (plasma), and the omega-3 FAs eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in plasma phospholipids were measured. Multiple linear regressions were used to examine the relations between visual outcomes and biomarkers, taking into account age, sex, drinking and smoking. RESULTS: Reduced contrast sensitivity at all spatial frequencies was associated with hair Hg, while %EPA, and to a lesser extent %EPA+DHA, were associated with better visual function. The intermediate spatial frequency of contrast sensitivity (12 cycles/degree) was negatively related to blood Pb and positively associated with plasma Se. Acquired color vision loss increased with hair Hg and decreased with plasma Se and %EPA. CONCLUSIONS: These findings suggest that the local diet of riverside communities of the Amazon contain toxic substances that can have deleterious effects on vision as well as nutrients that are beneficial for visual function. Since remediation at the source is a long process, a better knowledge of the nutrient content and health effects of traditional foods would be useful to minimize harmful effects of Hg and Pb exposure.

Visual acuity in fish consumers of the Brazilian Amazon: risks and benefits from local diet.

OBJECTIVE: To examine the associations between near and distant visual acuity and biomarkers of Hg, Pb, n-3 fatty acids and Se from the local diet of fish-eating communities of the Tapajós River in the Brazilian Amazon. DESIGN: Visuo-ocular health and biomarkers of Hg (hair, whole blood, plasma), Pb (whole blood), Se (whole blood and plasma) and n-3 fatty acids (plasma total phospholipids) were assessed in a cross-sectional study. SETTING: Lower Tapajós River Basin (State of Pará, Brazil), May to July 2006. SUBJECTS: Two hundred and forty-three adults (≥15 years) without diagnosed age-related cataracts or ocular pathologies. RESULTS: Near visual acuity was negatively associated with hair Hg and positively associated with %DHA, with a highly significant Log Hg × age interaction term. Stratifying for age showed that while young people presented good acuity, for those aged ≥40 years, clinical presbyopia was associated with hair Hg ≥ 15 µg/g (OR = 3·93, 95% CI 1·25, 14·18) and %DHA (OR = 0·37, 95% CI 0·11, 1·11). A similar age-related pattern was observed for distant visual acuity in relation to blood Pb, but the evidence was weaker. CONCLUSIONS: These findings suggest that Hg and Pb may affect visual acuity in older persons, while DHA appears to be protective for near visual acuity loss. In this population, with little access to eye care, diet may have an important influence on visuo-ocular ageing.

A composite-conditional-likelihood approach for gene mapping based on linkage disequilibrium in windows of marker loci.

A composite-conditional-likelihood (CCL) approach is proposed to map the position of a trait-influencing mutation (TIM) using the ancestral recombination graph (ARG) and importance sampling to reconstruct the genealogy of DNA sequences with respect to windows of marker loci and predict the linkage disequilibrium pattern observed in a sample of cases and controls. The method is designed to fine-map the location of a disease mutation, not as an association study. The CCL function proposed for the position of the TIM is a weighted product of conditional likelihood functions for windows of a given number of marker loci that encompass the TIM locus, given the sample configuration at the marker loci in those windows. A rare recessive allele is assumed for the TIM and single nucleotide polymorphisms (SNPs) are considered as markers. The method is applied to a range of simulated data sets. Not only do the CCL profiles converge more rapidly with smaller window sizes as the number of simulated histories of the sampled sequences increases, but the maximum-likelihood estimates for the position of the TIM remain as satisfactory, while requiring significantly less computing time. The simulations also suggest that non-random samples, more precisely, a non-proportional number of controls versus the number of cases, has little effect on the estimation procedure as well as sample size and marker density beyond some threshold values. Moreover, when compared with some other recent methods under the same assumptions, the CCL approach proves to be competitive.

Past occupational exposure to airborne manganese in a manganese alloy plant.

A retrospective exposure assessment of a group of manganese (Mn) alloy workers was performed in conjunction with a 2004 follow-up study, 14 years after cessation of exposure, to evaluate the long-term effects of occupational Mn exposure on neurobehavioral functions. The ferro- and silico-Mn alloy plant opened in 1973 and closed in 1991. The airborne total Mn (TMn) exposures for job groupings were established using personal sampling data from a 1991 industrial hygiene survey. Historical short-term total dust (TDust) data were used to estimate past TDust exposure for job groupings and plant areas. Relationships between Mn content and TDust from the 1991 survey, supported by sparse historical data, were used to estimate TMn content in the historical TDust data. Results showed past personal TDust exposure levels much higher than those found in 1991. Changes in TDust levels and corresponding TMn levels were a function of changes in ventilation, work practices, and operations, not of product (ferro- or silico-Mn). Relationships between TMn and respirable Mn (RMn) from area sampling in 1991 were used to estimate RMn exposure for the job groups. Work histories for 112 workers were developed from payroll records, questionnaires, and interviews and combined with Mn exposure estimates to develop cumulative exposure indices (CEIs). The TMn CEI ranged from 0.27 mg/m(3)x years to 100.24 mg/m(3)x years, with an AM of 24.40 mg/m(3)x years and a GM of 14.06 mg/m(3)x years. The RMn CEI had an AM of 2.95 mg/m(3)x years and a GM of 1.78 mg/m(3)x years with a range of 0.05-12.03 mg/m(3)x years. Overall average TMn exposure intensity, the TMn CEI divided by time worked in years for each worker, had an AM of 1.6 mg Mn/m(3), a GM of 1.0 mg Mn/m(3), range 0.02-6.2 6 mg Mn/m(3). The results of the 2004 follow-up study showed several concentration-response relationships between TMn CEI and neurobehavioral outcomes, which suggest that increase in cumulative TMn exposure level has long-term consequences on the nervous system.

A preliminary study of mercury exposure and blood pressure in the Brazilian Amazon.

BACKGROUND: Fish is considered protective for coronary heart disease (CHD), but mercury (Hg) intake from fish may counterbalance beneficial effects. Although neurotoxic effects of methylmercury (MeHg) are well established, cardiovascular effects are still debated. The objective of the present study was to evaluate blood pressure in relation to Hg exposure and fish consumption among a non-indigenous fish-eating population in the Brazilian Amazon. METHODS: The study was conducted among 251 persons from six communities along the Tapajós River, a major tributary of the Amazon. Data was obtained for socio-demographic information, fish consumption, height and weight to determine body mass index (BMI), systolic and diastolic blood pressure, and Hg concentration in hair samples. RESULTS: Results showed that overall, systolic and diastolic blood pressure, were relatively low (mean: 113.9 mmHg +/- 14.6 and 73.7 mmHg +/- 11.0). Blood pressure was significantly associated with hair total Hg (H-Hg), age, BMI and gender. No association was observed between fish consumption and blood pressure, although there were significant inter-community differences. Logistic regression analyses showed that the Odds Ratio (OR) for elevated systolic blood pressure (> or = 130 mmHg) with H-Hg > or = 10 microg/g was 2.91 [1.26-7.28], taking into account age, BMI, smoking, gender and community. CONCLUSION: The findings of this preliminary study add further support for Hg cardiovascular toxicity.

Eating tropical fruit reduces mercury exposure from fish consumption in the Brazilian Amazon.

This study aimed to examine the influence of the consumption of traditional foods on the relationship between fish consumption and mercury (Hg) exposure. A 12-month prospective dietary survey was carried out with 26 adult women from a fish-eating community in the Brazilian Amazon. Food ingestion was determined using a daily food diary, and total hair Hg levels were assessed for each month through sequential analyses using cold vapor atomic absorption spectrometry. Simple and multiple regression analyses showed that the strong relationship between fish consumption and Hg exposure was significantly modified by fruit consumption: for the same number of fish meals, those who ate more tropical fruits had lower hair mercury levels. The findings of this study indicate different ways of maintaining fish consumption while reducing Hg exposure in the Amazon. A number of phytochemicals and nutritional fibers present in fruits might be interacting with Hg in several ways: absorption and excretion, transport, binding to target proteins, metabolism, and sequestration. More studies are required on larger populations to further elucidate the extent and public health implications of the use of fruits to counteract the toxic action of methylmercury.

Gene mapping via the ancestral recombination graph.

We present a multilocus gene mapping method based on linkage disequilibrium, which uses the ancestral recombination graph to model the history of sequences that may harbor an influential variant. We describe the construction of a recurrence equation used to make inferences about the location of a trait-influencing mutation. We demonstrate how a Monte Carlo algorithm combined with a local importance sampling scheme can be used for mapping. We explain how to simulate the timing of events in the coalescent in the presence of recombination and mutation, which accomodates variable population size. We provide an example to illustrate the use of the method, which can be easily extended to more general situations. Although the method is computationally intensive and variation in the likelihood profiles can occur, the method offers a great deal of promise.