Additional file 5: Additional Table S5. Results of Global Linkage Disequilibrium (GLD) PRS signif... more Additional file 5: Additional Table S5. Results of Global Linkage Disequilibrium (GLD) PRS significance test1 between different pairs of MHC loci in individual chimpanzee cohorts and in the pooled cohort.
Additional file 9: Additional Table S9. Results of the simulations on linkage desequilibrium. For... more Additional file 9: Additional Table S9. Results of the simulations on linkage desequilibrium. For each population, the number of simulated samples presenting global linkage disequilibrium (according to the LRT and PRS tests) as well as the average, the standard deviation and the 95% confidence interval of the proportion of haplotypes in linkage disequilibrium in the simulated samples. The values for the original population sample are given as a reminder.
Additional file 1: Additional Table S1. Allele frequencies and results of HWE and SEW tests at ea... more Additional file 1: Additional Table S1. Allele frequencies and results of HWE and SEW tests at each Patr locus in the pooled and the four cohorts of chimpanzees.
Additional file 17: Additional Figure S1. Genetic diversity in chimpanzees (pooled cohort) and hu... more Additional file 17: Additional Figure S1. Genetic diversity in chimpanzees (pooled cohort) and humans (multiple populations). A) Allelic richness B) heterozygosity, C) nucleotide diversity at each locus under study for the pooled cohort of chimpanzees (in red empty circle) and for the human populations (in blue) represented as violin plots; An average number of k = 70 (s.d 15.9) human population samples of average size N = 109.2 (s.d 17.31) were used. The width of the violin varies so as to represent the probability density of the data, the thick blue bar in the centre represents the interquartile range, the thin black line extended from it represents the 95% confidence intervals, and the green dot is the median. The MHC loci are presented according to their position on the chromosome from the centromere (left) to the telomere (right).
Additional file 11: Additional Table S11. List of individuals of the four cohorts of chimpanzees.... more Additional file 11: Additional Table S11. List of individuals of the four cohorts of chimpanzees. For each chimpanzee, its name, birth status (wild-born or captive-born), its origin (as defined in the publication), its country of origin (if known), its gender, its sub-species, the publication and the Patr gene studied is given.
Rhesus haplotype frequencies computed for 804 and 546 Wallisians from New Caledonia are compared ... more Rhesus haplotype frequencies computed for 804 and 546 Wallisians from New Caledonia are compared to the data collected for 13 Oceanian samples belonging to the same Austronesian linguistic family. Genetic distances are computed between the 15 populations and used for a principal coordinate analysis. Kanaks are genetically close to Fidjians, while the Wallisian sample share a high genetic similarity with the Tonga islanders. The results obtained for the whole area including the Wallis homeland for the Wallisian sample indicate a tight relationship between geographical and genetic differentiations in the Pacific, supported by a high correlation coefficient between the two distance matrices. However, the observed patterns are better explained by the history of migrations reconstructed from archaeological and linguistic data than by a pure isolation-by-distance model.
From a biogeographic perspective Africa is subdivided into distinct horizontal belts. Human popul... more From a biogeographic perspective Africa is subdivided into distinct horizontal belts. Human populations living along the Sahel/Savannah belt south of the Sahara Desert have often been overshadowed by extensive studies focusing on other African populations such as hunter-gatherers or Bantu in particular. However, the Sahel together with the savannah bordering it in the south, is a
Fibromyalgia syndrome (FMS) is characterized by widespread pain and increased sensitivity to noci... more Fibromyalgia syndrome (FMS) is characterized by widespread pain and increased sensitivity to nociceptive stimulus or tenderness. While familial aggregation could suggest a potential hereditary component in FMS development, isolation of genetic determinants has proven difficult due to the multi-factorial nature and complexity of the syndrome. Central sensitization is thought to be one of the key mechanisms leading to FMS in a subset of patients. Enhanced central pain signaling can be measured using the Nociceptive Flexion Reflex (NFR) or RIII threshold. We performed a genome-wide association study (GWAS) using an array to genotype 258,756 human genetic polymorphisms in 225 FMS patients and 77 healthy volunteers and searched for genetic variants associated with a lowered NFR threshold. We have identified a potential association between a single nucleotide polymorphism resulting in a common non-synonymous coding mutation in the Huntingtin associated protein 1 (HAP1) gene (rs4796604, MA...
ObjectivesMode of subsistence is an important factor influencing dietary habits and the genetic s... more ObjectivesMode of subsistence is an important factor influencing dietary habits and the genetic structure of various populations through differential intensity of gene flow and selection pressures. Previous studies suggest that in Africa Taste 2 Receptor Member 16 (TAS2R16), which encodes the 7‐transmembrane receptor protein for bitterness, might also be under positive selection pressure.MethodsHowever, since sampling coverage of populations was limited, we created a new TAS2R16 population dataset from across the African Sahel/Savannah belt representing various local populations of differing subsistence modes, linguistic affiliations, and geographic provenience. We sequenced the TAS2R16 exon gene and analyzed 2250 haplotypes among 19 populations.ResultsWe found no evidence for selection as a driving force of genetic variation at this locus; instead, we discovered a highly significant correlation between TAS2R16 genetic and geographical distances based on provenience of the sampled p...
Introduction and Objective Cytochrome P450 enzymes are the major drug-metabolizing enzymes in hum... more Introduction and Objective Cytochrome P450 enzymes are the major drug-metabolizing enzymes in humans and the importance of drug transport proteins, in particular P-glycoprotein, in the variability of drug response has also been highlighted. Activity of cytochrome P450 enzymes and P-glycoprotein can vary widely between individuals and genotyping and/or phenotyping can help assess their activity. Several phenotyping cocktails have been developed. The Geneva cocktail is composed of a specific probe for six different cytochrome P450 enzymes and one for P-glycoprotein and was used in the context of a research aiming at exploring genotypes and phenotypes in distinct human populations (NCT02789527). The aim of the present study is to solely report the safety results of the Geneva cocktail in the healthy volunteers of these populations. Materials and Methods The Geneva cocktail is composed of caffeine, bupropion, flurbiprofen, omeprazole, dextromethorphan, midazolam, and fexofenadine. The volunteers fasted and avoided drinking caffeine-containing beverages or food and grapefruit juice overnight before receiving the cocktail orally. They provided blood spots for the probes' concentrations at 2, 3, and 6 h after ingestion and were asked about adverse events. Results A total of 265 healthy adult volunteers were included from Ethiopia, Oman, and the Czech Republic. The mean plasma concentrations at the 2-h sampling time of each probe drug in the total sample were: 1663 ng/mL for caffeine, 8 ng/ mL for bupropion, 789 ng/mL for flurbiprofen, 6 ng/mL for dextromethorphan, 2 ng/mL for midazolam, 35 ng/mL for fexofenadine, and 103 ng/mL for omeprazole. Four adverse events were observed representing an occurrence of 1.5%. All these events were categorized as mild to moderate, non-serious, and resolved spontaneously. A causal link with the cocktail cannot be excluded because of the temporal relationship but is at most evaluated as possible according to the World Health Organization-Uppsala Monitoring Centre causal assessment system. Conclusions In this research, healthy volunteers from three different human populations were phenotyped with the Geneva cocktail. Four adverse events were observed, confirming the safety of this cocktail that is given at lower than clinically relevant doses and therefore results in concentrations lower than those reported to cause adverse events. Victoria Rollason, Médéric Mouterde contributed equally to this work.
BackgroundMany species are threatened with extinction as their population sizes decrease with cha... more BackgroundMany species are threatened with extinction as their population sizes decrease with changing environments or face novel pathogenic threats. A reduction of genetic diversity at major histocompatibility complex (MHC) genes may have dramatic effects on populations’ survival, as these genes play a key role in adaptive immunity. This might be the case for chimpanzees, theMHCgenes of which reveal signatures of an ancient selective sweep likely due to a viral epidemic that reduced their population size a few million years ago. To better assess how this past event affectedMHCvariation in chimpanzees compared to humans, we analysed several indexes of genetic diversity and linkage disequilibrium across sevenMHCgenes on four cohorts of chimpanzees and we compared them to those estimated at orthologousHLAgenes in a large set of human populations.ResultsInterestingly, the analyses uncovered similar patterns of both molecular diversity and linkage disequilibrium across the sevenMHCgenes...
Objectives: Genetic and archaeological research supports the theory that Arabia was the first reg... more Objectives: Genetic and archaeological research supports the theory that Arabia was the first region traversed by modern humans as they left Africa and dispersed throughout Eurasia. However, the role of Arabia from the initial migration out of Africa until more recent times is still unclear. Materials and Methods: We have generated 379 new hypervariable segment 1 (HVS-1) sequences from a range of geographic locations throughout Yemen. We compare these data to published HVS-1 sequences representing Arabia and neighboring regions to build a unique dataset of 186 populations and 14,290 sequences. Results: We identify 4,563 haplotypes unevenly distributed across Arabia and neighboring regions. Arabia contains higher proportions of shared haplotypes than the regions with which it shares these haplotypes, suggesting high levels of migration through the region. Populations in Arabia show higher levels of population expansion than those in East Africa, but lower levels than the Near East, Middle East or India. Arabian populations also show very high levels of genetic variation that overlaps with variation from most other regions. Conclusion: We take a population genetics approach to provide a comprehensive view of the relationships of Arabian and neighboring populations. We show that Arabian populations share closest links to the Near East and North Africa, but have a more ancient origin with slower demographic growth and/or lower migration rates. Our conclusions are supported by phylogenetic studies but also suggest that recent migrations have erased signals of earlier events.
Additional file 5: Additional Table S5. Results of Global Linkage Disequilibrium (GLD) PRS signif... more Additional file 5: Additional Table S5. Results of Global Linkage Disequilibrium (GLD) PRS significance test1 between different pairs of MHC loci in individual chimpanzee cohorts and in the pooled cohort.
Additional file 9: Additional Table S9. Results of the simulations on linkage desequilibrium. For... more Additional file 9: Additional Table S9. Results of the simulations on linkage desequilibrium. For each population, the number of simulated samples presenting global linkage disequilibrium (according to the LRT and PRS tests) as well as the average, the standard deviation and the 95% confidence interval of the proportion of haplotypes in linkage disequilibrium in the simulated samples. The values for the original population sample are given as a reminder.
Additional file 1: Additional Table S1. Allele frequencies and results of HWE and SEW tests at ea... more Additional file 1: Additional Table S1. Allele frequencies and results of HWE and SEW tests at each Patr locus in the pooled and the four cohorts of chimpanzees.
Additional file 17: Additional Figure S1. Genetic diversity in chimpanzees (pooled cohort) and hu... more Additional file 17: Additional Figure S1. Genetic diversity in chimpanzees (pooled cohort) and humans (multiple populations). A) Allelic richness B) heterozygosity, C) nucleotide diversity at each locus under study for the pooled cohort of chimpanzees (in red empty circle) and for the human populations (in blue) represented as violin plots; An average number of k = 70 (s.d 15.9) human population samples of average size N = 109.2 (s.d 17.31) were used. The width of the violin varies so as to represent the probability density of the data, the thick blue bar in the centre represents the interquartile range, the thin black line extended from it represents the 95% confidence intervals, and the green dot is the median. The MHC loci are presented according to their position on the chromosome from the centromere (left) to the telomere (right).
Additional file 11: Additional Table S11. List of individuals of the four cohorts of chimpanzees.... more Additional file 11: Additional Table S11. List of individuals of the four cohorts of chimpanzees. For each chimpanzee, its name, birth status (wild-born or captive-born), its origin (as defined in the publication), its country of origin (if known), its gender, its sub-species, the publication and the Patr gene studied is given.
Rhesus haplotype frequencies computed for 804 and 546 Wallisians from New Caledonia are compared ... more Rhesus haplotype frequencies computed for 804 and 546 Wallisians from New Caledonia are compared to the data collected for 13 Oceanian samples belonging to the same Austronesian linguistic family. Genetic distances are computed between the 15 populations and used for a principal coordinate analysis. Kanaks are genetically close to Fidjians, while the Wallisian sample share a high genetic similarity with the Tonga islanders. The results obtained for the whole area including the Wallis homeland for the Wallisian sample indicate a tight relationship between geographical and genetic differentiations in the Pacific, supported by a high correlation coefficient between the two distance matrices. However, the observed patterns are better explained by the history of migrations reconstructed from archaeological and linguistic data than by a pure isolation-by-distance model.
From a biogeographic perspective Africa is subdivided into distinct horizontal belts. Human popul... more From a biogeographic perspective Africa is subdivided into distinct horizontal belts. Human populations living along the Sahel/Savannah belt south of the Sahara Desert have often been overshadowed by extensive studies focusing on other African populations such as hunter-gatherers or Bantu in particular. However, the Sahel together with the savannah bordering it in the south, is a
Fibromyalgia syndrome (FMS) is characterized by widespread pain and increased sensitivity to noci... more Fibromyalgia syndrome (FMS) is characterized by widespread pain and increased sensitivity to nociceptive stimulus or tenderness. While familial aggregation could suggest a potential hereditary component in FMS development, isolation of genetic determinants has proven difficult due to the multi-factorial nature and complexity of the syndrome. Central sensitization is thought to be one of the key mechanisms leading to FMS in a subset of patients. Enhanced central pain signaling can be measured using the Nociceptive Flexion Reflex (NFR) or RIII threshold. We performed a genome-wide association study (GWAS) using an array to genotype 258,756 human genetic polymorphisms in 225 FMS patients and 77 healthy volunteers and searched for genetic variants associated with a lowered NFR threshold. We have identified a potential association between a single nucleotide polymorphism resulting in a common non-synonymous coding mutation in the Huntingtin associated protein 1 (HAP1) gene (rs4796604, MA...
ObjectivesMode of subsistence is an important factor influencing dietary habits and the genetic s... more ObjectivesMode of subsistence is an important factor influencing dietary habits and the genetic structure of various populations through differential intensity of gene flow and selection pressures. Previous studies suggest that in Africa Taste 2 Receptor Member 16 (TAS2R16), which encodes the 7‐transmembrane receptor protein for bitterness, might also be under positive selection pressure.MethodsHowever, since sampling coverage of populations was limited, we created a new TAS2R16 population dataset from across the African Sahel/Savannah belt representing various local populations of differing subsistence modes, linguistic affiliations, and geographic provenience. We sequenced the TAS2R16 exon gene and analyzed 2250 haplotypes among 19 populations.ResultsWe found no evidence for selection as a driving force of genetic variation at this locus; instead, we discovered a highly significant correlation between TAS2R16 genetic and geographical distances based on provenience of the sampled p...
Introduction and Objective Cytochrome P450 enzymes are the major drug-metabolizing enzymes in hum... more Introduction and Objective Cytochrome P450 enzymes are the major drug-metabolizing enzymes in humans and the importance of drug transport proteins, in particular P-glycoprotein, in the variability of drug response has also been highlighted. Activity of cytochrome P450 enzymes and P-glycoprotein can vary widely between individuals and genotyping and/or phenotyping can help assess their activity. Several phenotyping cocktails have been developed. The Geneva cocktail is composed of a specific probe for six different cytochrome P450 enzymes and one for P-glycoprotein and was used in the context of a research aiming at exploring genotypes and phenotypes in distinct human populations (NCT02789527). The aim of the present study is to solely report the safety results of the Geneva cocktail in the healthy volunteers of these populations. Materials and Methods The Geneva cocktail is composed of caffeine, bupropion, flurbiprofen, omeprazole, dextromethorphan, midazolam, and fexofenadine. The volunteers fasted and avoided drinking caffeine-containing beverages or food and grapefruit juice overnight before receiving the cocktail orally. They provided blood spots for the probes' concentrations at 2, 3, and 6 h after ingestion and were asked about adverse events. Results A total of 265 healthy adult volunteers were included from Ethiopia, Oman, and the Czech Republic. The mean plasma concentrations at the 2-h sampling time of each probe drug in the total sample were: 1663 ng/mL for caffeine, 8 ng/ mL for bupropion, 789 ng/mL for flurbiprofen, 6 ng/mL for dextromethorphan, 2 ng/mL for midazolam, 35 ng/mL for fexofenadine, and 103 ng/mL for omeprazole. Four adverse events were observed representing an occurrence of 1.5%. All these events were categorized as mild to moderate, non-serious, and resolved spontaneously. A causal link with the cocktail cannot be excluded because of the temporal relationship but is at most evaluated as possible according to the World Health Organization-Uppsala Monitoring Centre causal assessment system. Conclusions In this research, healthy volunteers from three different human populations were phenotyped with the Geneva cocktail. Four adverse events were observed, confirming the safety of this cocktail that is given at lower than clinically relevant doses and therefore results in concentrations lower than those reported to cause adverse events. Victoria Rollason, Médéric Mouterde contributed equally to this work.
BackgroundMany species are threatened with extinction as their population sizes decrease with cha... more BackgroundMany species are threatened with extinction as their population sizes decrease with changing environments or face novel pathogenic threats. A reduction of genetic diversity at major histocompatibility complex (MHC) genes may have dramatic effects on populations’ survival, as these genes play a key role in adaptive immunity. This might be the case for chimpanzees, theMHCgenes of which reveal signatures of an ancient selective sweep likely due to a viral epidemic that reduced their population size a few million years ago. To better assess how this past event affectedMHCvariation in chimpanzees compared to humans, we analysed several indexes of genetic diversity and linkage disequilibrium across sevenMHCgenes on four cohorts of chimpanzees and we compared them to those estimated at orthologousHLAgenes in a large set of human populations.ResultsInterestingly, the analyses uncovered similar patterns of both molecular diversity and linkage disequilibrium across the sevenMHCgenes...
Objectives: Genetic and archaeological research supports the theory that Arabia was the first reg... more Objectives: Genetic and archaeological research supports the theory that Arabia was the first region traversed by modern humans as they left Africa and dispersed throughout Eurasia. However, the role of Arabia from the initial migration out of Africa until more recent times is still unclear. Materials and Methods: We have generated 379 new hypervariable segment 1 (HVS-1) sequences from a range of geographic locations throughout Yemen. We compare these data to published HVS-1 sequences representing Arabia and neighboring regions to build a unique dataset of 186 populations and 14,290 sequences. Results: We identify 4,563 haplotypes unevenly distributed across Arabia and neighboring regions. Arabia contains higher proportions of shared haplotypes than the regions with which it shares these haplotypes, suggesting high levels of migration through the region. Populations in Arabia show higher levels of population expansion than those in East Africa, but lower levels than the Near East, Middle East or India. Arabian populations also show very high levels of genetic variation that overlaps with variation from most other regions. Conclusion: We take a population genetics approach to provide a comprehensive view of the relationships of Arabian and neighboring populations. We show that Arabian populations share closest links to the Near East and North Africa, but have a more ancient origin with slower demographic growth and/or lower migration rates. Our conclusions are supported by phylogenetic studies but also suggest that recent migrations have erased signals of earlier events.
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