Admixture in Latin America: geographic structure, phenotypic diversity and self-perception of ancestry based on 7,342 individuals.

The current genetic makeup of Latin America has been shaped by a history of extensive admixture between Africans, Europeans and Native Americans, a process taking place within the context of extensive geographic and social stratification. We estimated individual ancestry proportions in a sample of 7,342 subjects ascertained in five countries (Brazil, Chile, Colombia, México and Perú). These individuals were also characterized for a range of physical appearance traits and for self-perception of ancestry. The geographic distribution of admixture proportions in this sample reveals extensive population structure, illustrating the continuing impact of demographic history on the genetic diversity of Latin America. Significant ancestry effects were detected for most phenotypes studied. However, ancestry generally explains only a modest proportion of total phenotypic variation. Genetically estimated and self-perceived ancestry correlate significantly, but certain physical attributes have a strong impact on self-perception and bias self-perception of ancestry relative to genetically estimated ancestry.

Contrasting patterns of nuclear and mtDNA diversity in Native American populations.

We report an integrated analysis of nuclear (autosomal, X- and Y-chromosome) short tandem repeat (STR) data and mtDNA D-loop sequences obtained in the same set of 22 Native populations from across the Americas. A north to south gradient of decreasing population diversity was observed, in agreement with a settlement of the Americas from the extreme northwest of the continent. This correlation is stronger with "least cost distances," which consider the coasts as facilitators of migration. Continent-wide estimates of population structure are highest for the Y-chromosome and lowest for the autosomes, consistent with the effective size of the different marker systems examined. Population differentiation is highest in East South America and lowest in Meso America and the Andean region. Regional analyses suggest a deviation from mutation-drift equilibrium consistent with population expansion in Meso America and the Andes and population contraction in Northwest and East South America. These data hint at an early divergence of Andean and non-Andean South Americans and at a contrasting demographic history for populations from these regions.

A gain-of-function mutation in TRPA1 causes familial episodic pain syndrome.

Human monogenic pain syndromes have provided important insights into the molecular mechanisms that underlie normal and pathological pain states. We describe an autosomal-dominant familial episodic pain syndrome characterized by episodes of debilitating upper body pain, triggered by fasting and physical stress. Linkage and haplotype analysis mapped this phenotype to a 25 cM region on chromosome 8q12-8q13. Candidate gene sequencing identified a point mutation (N855S) in the S4 transmembrane segment of TRPA1, a key sensor for environmental irritants. The mutant channel showed a normal pharmacological profile but altered biophysical properties, with a 5-fold increase in inward current on activation at normal resting potentials. Quantitative sensory testing demonstrated normal baseline sensory thresholds but an enhanced secondary hyperalgesia to punctate stimuli on treatment with mustard oil. TRPA1 antagonists inhibit the mutant channel, promising a useful therapy for this disorder. Our findings provide evidence that variation in the TRPA1 gene can alter pain perception in humans.

Lack of support for a role for RLIP76 (RALBP1) in response to treatment or predisposition to epilepsy.

BACKGROUND: Multidrug transporters are postulated to contribute to antiepileptic drug (AED) resistance. The transporter best studied is P-glycoprotein, an ATP-Binding Cassette (ABC) transporter superfamily member. RLIP76 is suggested to be an energy-dependent non-ABC transporter, reducing AED blood-brain barrier penetration, with a more important role than P-glycoprotein. Knowledge of which transporters may be critical in drug resistance is important for design of potential therapies. We tested the hypothesis that RLIP76 mediates AED resistance using methods complementary to those in the original report. METHODS: Double-labeling fluorescent immunohistochemistry localized RLIP76 expression. Population genetics was used to explore association of variation in the RLIP76-encoding gene with drug-response and epilepsy phenotypes. Comparative protein structure modeling and bioinformatic annotation were used to predict RLIP76 structure and features. RESULTS: In normal and epileptogenic brain tissue, immunoreactivity for RLIP76 was cytoplasmic, with colocalization with a neuronal, but not an endothelial, marker. Genotyping of six tagging SNPs, representing common genetic variation in RLIP76, in patients with epilepsy responsive (n = 262) or resistant (n = 107) to AEDs showed no association with phenotype at any level. RLIP76 genotypic and haplotypic frequencies in 783 patients with epilepsy and 359 healthy controls showed no association with epilepsy susceptibility. RLIP76 is not predicted to have transmembrane localization or ATPase activity. CONCLUSIONS: No support for RLIP76 itself in directly mediating resistance to AEDs nor in increasing susceptibility to epilepsy was found. More evidence is required before either a role for RLIP76 in drug resistance can be accepted or focus directed away from other transporters, such as P-glycoprotein.

Failure to replicate previously reported genetic associations with sporadic temporal lobe epilepsy: where to from here?

Temporal lobe epilepsy (TLE), traditionally thought to develop largely due to environmental factors, has recently become the focus of association studies in an effort to determine genetic risk factors. Here we examine all previous claims of association of genetic polymorphisms with TLE by attempting replication in a cohort of 339 TLE patients of European origin. We also examine if these variants contribute to other types of epilepsy by examination in a larger cohort of 752 patients representing a range of different epilepsies. We fail to clearly replicate any of the previously reported associations and also fail to show a role for these variants in the development of other forms of epilepsy. Although our results cannot definitively rule out a role for these genes, they do suggest that most and perhaps all of the previous associations are false positives. As has been the experience with other diseases, these results highlight the importance of larger sample sizes and replication. In TLE, it appears that collaboration before publication is the best option to increase sample size sufficiently in the short term. These general principles are applicable to other studies undertaken for common complex diseases.