Project description:The genetic structure of some native Bolivians has been substantially influenced by admixture from Europeans, which we estimate to have occurred approximately 360 – 384 years ago. Consistent with historical accounts of male admixture, Y-chromosome haplogroups typical of Europeans were found in 39% of our Bolivian samples. No evidence of African admixture was found in native Bolivians. The Mesoamerican Totonacs have little evidence of European or African admixture. Our analysis indicates that some admixed Bolivians have Native American mtDNA and Y-chromosomes but harbor up to 30% European autosomal ancestry, demonstrating the need for autosomal markers to assess ancestry in admixed populations. From a dense genome-wide panel of 815,377 markers, we developed a set of 324 AIMs, specific for Native American ancestry. As few a 40-50 of these markers successfully predict New World ancestry in the ascertainment panel of Bolivians and Totonacs. The markers easily distinguish New World from Old World ancestry, even for populations more closely related to the Americas such as central and eastern Asians, and were effective for New World vs. Old World comparisons in five other geographically and culturally distinct populations of the Americas. SNPs demonstrating very high divergence between the two Native American populations and major Old World populations are found on haplotypes that are shared and occur at similar frequencies in other indigenous low-admixture American populations examined here (i.e. Pima, Maya, Colombian, Karitiana, and Surui). After excluding the possibility of recent relatedness, our results indicate that native Bolivians and Totonacs share ancestry with other American populations through a substantial contribution from a common founding population, population bottlenecks, and possible natural selection on functional variation.
Project description:Background: Drug resistance is a major problem in leishmaniasis chemotherapy. RNA expression profiling using DNA microarrays is a suitable approach to study simultaneous events leading to a drug-resistance phenotype. Genomic analysis has been performed primarily with Old World Leishmania species and here we investigate molecular alterations in antimony resistance in the New World species L. amazonensis. Methods/Principal Findings: We selected populations of L. amazonensis for resistance to antimony by step-wise drug pressure. Gene expression of highly resistant mutants was studied using DNA microarrays. RNA expression profiling of antimony-resistant L. amazonensis revealed the overexpression of genes involved in drug resistance including the ABC transporter MRPA and several genes related to thiol metabolism. The MRPA overexpression was validated by quantitative real-time PCR and further analysis revealed that this increased expression was correlated to gene amplification as part of extrachromosomal linear amplicons in some mutants and as part of supernumerary chromosomes in other mutants. The expression of several other genes encoding hypothetical proteins but also nucleobase and glucose transporter encoding genes were found to be modulated. Conclusions/Significance: Mechanisms classically found in Old World antimony resistant Leishmania were also highlighted in New World antimony-resistant L. amazonensis. These studies were useful to the identification of resistance molecular markers.