14 research outputs found
Effects of natural selection and gene conversion on the evolution of human glycophorins coding for MNS blood polymorphisms in malaria-endemic African populations
No full textMalaria has been a very strong selection pressure in recent human evolution, particularly in Africa. Of the one million deaths per year due to malaria, more than 90% are in sub-Saharan Africa, a region with high levels of genetic variation and population substructure. However, there have been few studies of nucleotide variation at genetic loci that are relevant to malaria susceptibility across geographically and genetically diverse ethnic groups in Africa. Invasion of erythrocytes by Plasmodium falciparum parasites is central to the pathology of malaria. Glycophorin A (GYPA) and B (GYPB), which determine MN and Ss blood types, are two major receptors that are expressed on erythrocyte surfaces and interact with parasite ligands. We analyzed nucleotide diversity of the glycophorin gene family in 15 African populations with different levels of malaria exposure. High levels of nucleotide diversity and gene conversion were found at these genes. We observed divergent patterns of genetic variation between these duplicated genes and between different extracellular domains of GYPA. Specifically, we identified fixed adaptive changes at exons 3-4 of GYPA. By contrast, we observed an allele frequency spectrum skewed toward a significant excess of intermediate-frequency alleles at GYPA exon 2 in many populations; the degree of spectrum distortion is correlated with malaria exposure, possibly because of the joint effects of gene conversion and balancing selection. We also identified a haplotype causing three amino acid changes in the extracellular domain of glycophorin B. This haplotype might have evolved adaptively in five populations with high exposure to malaria
Characterization of genetic variation and natural selection at the arylamine N-acetyltransferase genes in global human populations
No full textFunctional variability at the arylamine N-acetyltransferase genes is associated with drug response in humans and may have been adaptive in the past owing to selection pressure from diet and exposure to toxins during human evolution. Aims: We have characterized nucleotide variation at the NAT1 and NAT2 genes, and at the NATP1 pseudogene in global human populations, including many previously under-represented African populations, in order to identify potential functional variants and to understand the role that natural selection has played in shaping variation at these loci in globally diverse populations. Materials & methods: We have resequenced approximately 2800 bp for each of the NAT1 and NAT2 gene regions, as well as the pseudogene NATP1, in 197 African and 132 nonAfrican individuals. Results & conclusion: We observe a signature of balancing selection maintaining variation in the 3'-UTR of NAT1, suggesting that these variants may play a functional role that is currently undefined. In addition, we observed high levels of nonsynonymous functional variation at the NAT2 locus that differs amongst ethnically diverse populations
PROBING COMPETITIVE NONCOVALENT INTERACTIONS: RESONANCE ENHANCED TWO-PHOTON IONIZATION (R2PI) SPECTROSCOPY OF HALOAROMATIC CLUSTERS
No full textAuthor Institution: Department of Chemistry, Marquette University, Milwaukee, WI 53233Non-covalent interactions in bromobenzene have been studied here using resonance two-photon ionization (R2PI) spectroscopy combined with a linear TOF-mass spectrometer. Bromobenzene clusters were created in a supersonic expansion with helium as a carrier gas. The molecules were excited and ionized from the ground state in a two stage process. The general trend observed in the R2PI spectra of all the clusters is the broadness and a red-shift relative to the monomer absorption. Optimized dimer and trimer structures were calculated at the M06-2x/aug-cc-pVDZ level, which show that -stacked and C-H/ interactions are most important in these clusters. TD-DFT calculations of the different cluster conformers have been carried out to assess the geometry changes active upon electronic excitation. The theoretical studies are helpful in explaining trends observed in the R2PI spectra
RESONANCE ENHANCED MULTIPHOTON IONIZATION (REMPI) SPECTROSCOPY OF WEAKLY BOUND COMPLEXES
No full textAuthor Institution: Department of Chemistry, Marquette University, Milwaukee, WI 53233We have recently implemented Resonance Enhanced Multiphoton Ionization (REMPI) spectroscopy in our laboratory as a spectroscopic probe of transient species. We will report on initial gas-phase studies of the spectra of weakly bound van der Waals and halogen bonded complexes involving aromatic organic donors. The complexes are formed in the rarified environment of a supersonic molecular beam, which is skimmed prior to passing into the differentially pumped flight tube of a linear time-of-flight mass spectrometer. Ionization is initiated both by 1+1 and 1+1' REMPI schemes; the latter is used to minimize fragmentation. Our initial studies have examined van der Waals and halogen bonded complexes involving the phenol and toluene chromophores. Progress in the coupling of a discharge source into this apparatus will also be discussed
Development of an AFASS assessment and screening tool towards prevention of Mother-To-Child HIV transmission in Sub-Saharan Africa : A Delphi Survey
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Drug resistance to sulphadoxine-pyrimethamine in Plasmodium falciparum malaria in Mlimba, Tanzania.
Get PDFBACKGROUND\ud
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Sulphadoxine-pyrimethamine (SP) has been and is currently used for treatment of uncomplicated Plasmodium falciparum malaria in many African countries. Nevertheless, the response of parasites to SP treatment has shown significant variation between individuals.\ud
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METHODS\ud
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The genes for dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps) were used as markers, to investigate parasite resistance to SP in 141 children aged less than 5 years. Parasite DNA was extracted by Chelex method from blood samples collected and preserved on filter papers. Subsequently, polymerase chain reaction (PCR) and restriction fragment length polymorphism (PCR-RFLP) were applied to detect the SP resistance-associated point mutations on dhfr and dhps. Commonly reported point mutations at codons 51, 59, 108 and 164 in the dhfr and codons 437, 540 and 581 in the dhps domains were examined.\ud
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RESULTS\ud
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Children infected with parasites harbouring a range of single to quintuple dhfr/dhps mutations were erratically cured with SP. However, the quintuple dhfr/dhps mutant genotypes were mostly associated with treatment failures. High proportion of SP resistance-associated point mutations was detected in this study but the adequate clinical response (89.4%) observed clinically at day 14 of follow up reflects the role of semi-immunity protection and parasite clearance in the population.\ud
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CONCLUSION\ud
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In monitoring drug resistance to SP, concurrent studies on possible confounding factors pertaining to development of resistance in falciparum malaria should be considered. The SP resistance potential detected in this study, cautions on its useful therapeutic life as an interim first-line drug against malaria in Tanzania and other malaria-endemic countries
Identifying darwinian selection acting on different human APOL1 variants among diverse African populations
No full textDisease susceptibility can arise as a consequence of adaptation to infectious disease. Recent findings have suggested that higher rates of chronic kidney disease (CKD) in individuals with recent African ancestry might be attributed to two risk alleles (G1 and G2) at the serum-resistance-associated (SRA)-interacting-domain-encoding region of APOL1. These two alleles appear to have arisen adaptively, possibly as a result of their protective effects against human African trypanosomiasis (HAT), or African sleeping sickness. In order to explore the distribution of potential functional variation at APOL1, we studied nucleotide variation in 187 individuals across ten geographically and genetically diverse African ethnic groups with exposure to two Trypanosoma brucei subspecies that cause HAT. We observed unusually high levels of nonsynonymous polymorphism in the regions encoding the functional domains that are required for lysing parasites. Whereas allele frequencies of G2 were similar across all populations (3%-8%), the G1 allele was only common in the Yoruba (39%). Additionally, we identified a haplo type (termed G3) that contains a nonsynonymous change at the membrane-addressing-domain-encoding region of APOL1 and is present in all populations except for the Yoruba. Analyses of long-range patterns of linkage disequilibrium indicate evidence of recent selection acting on the G3 haplotype in Fulani from Cameroon. Our results indicate that the G1 and G2 variants in APOL1 are geographically restricted and that there might be other functional variants that could play a role in HAT resistance and CKD risk in African populations
Evolutionary history and adaptation from high-coverage whole-genome sequences of diverse African hunter-gatherers
No full textTo reconstruct modern human evolutionary history and identify loci that have shaped hunter-gatherer adaptation, we sequenced the whole genomes of five individuals in each of three different hunter-gatherer populations at >60x coverage: Pygmies from Cameroon and Khoesan-speaking Hadza and Sandawe from Tanzania. We identify 13.4 million variants, substantially increasing the set of known human variation. We found evidence of archaic intro-gression in all three populations, and the distribution of time to most recent common ancestors from these regions is similar to that observed for introgressed regions in Europeans. Additionally, we identify numerous loci that harbor signatures of local adaptation, including genes involved in immunity, metabolism, olfactory and taste perception, reproduction, and wound healing. Within the Pygmy population, we identify multiple highly differentiated loci that play a role in growth and anterior pituitary function and are associated with height
African evolutionary history inferred from whole genome sequence data of 44 indigenous African populations [plus Correction]
No full textBackground : Africa is the origin of modern humans within the past 300 thousand years. To infer the complex demographic history of African populations and adaptation to diverse environments, we sequenced the genomes of 92 individuals from 44 indigenous African populations. Results : Genetic structure analyses indicate that among Africans, genetic ancestry is largely partitioned by geography and language, though we observe mixed ancestry in many individuals, consistent with both short- and long-range migration events followed by admixture. Phylogenetic analysis indicates that the San genetic lineage is basal to all modern human lineages. The San and Niger-Congo, Afroasiatic, and Nilo-Saharan lineages were substantially diverged by 160 kya (thousand years ago). In contrast, the San and Central African rainforest hunter-gatherer (CRHG), Hadza hunter-gatherer, and Sandawe hunter-gatherer lineages were diverged by ~ 120–100 kya. Niger-Congo, Nilo-Saharan, and Afroasiatic lineages diverged more recently by ~ 54–16 kya. Eastern and western CRHG lineages diverged by ~ 50–31 kya, and the western CRHG lineages diverged by ~ 18–12 kya. The San and CRHG populations maintained the largest effective population size compared to other populations prior to 60 kya. Further, we observed signatures of positive selection at genes involved in muscle development, bone synthesis, reproduction, immune function, energy metabolism, and cell signaling, which may contribute to local adaptation of African populations. Conclusions : We observe high levels of genomic variation between ethnically diverse Africans which is largely correlated with geography and language. Our study indicates ancient population substructure and local adaptation of Africans
The Genetic Structure and History of Africans and African Americans.
Get PDFAfrica is the source of all modern humans, but characterization of genetic variation and of relationships among populations across the continent has been enigmatic. We studied 121 African populations, four African American populations, and 60 non-African populations for patterns of variation at 1327 nuclear microsatellite and insertion/deletion markers. We identified 14 ancestral population clusters in Africa that correlate with self-described ethnicity and shared cultural and/or linguistic properties. We observed high levels of mixed ancestry in most populations, reflecting historical migration events across the continent. Our data also provide evidence for shared ancestry among geographically diverse hunter-gatherer populations (Khoesan speakers and Pygmies). The ancestry of African Americans is predominantly from Niger-Kordofanian (approximately 71%), European (approximately 13%), and other African (approximately 8%) populations, although admixture levels varied considerably among individuals. This study helps tease apart the complex evolutionary history of Africans and African Americans, aiding both anthropological and genetic epidemiologic studies
