Arylamine N-Acetyltransferase 2 (NAT2) Genetic Diversity and Traditional Subsistence: A Worldwide Population Survey

Arylamine N-acetyltransferase 2 (NAT2) is involved in human physiological responses to a variety of xenobiotic compounds, including common therapeutic drugs and exogenous chemicals present in the diet and the environment. Many questions remain about the evolutionary mechanisms that have led to the high prevalence of slow acetylators in the human species. Evidence from recent surveys of NAT2 gene variation suggests that NAT2 slow-causing variants might have become targets of positive selection as a consequence of the shift in modes of subsistence and lifestyle in human populations in the last 10,000 years. We aimed to test more extensively the hypothesis that slow acetylation prevalence in humans is related to the subsistence strategy adopted by the past populations. To this end, published frequency data on the most relevant genetic variants of NAT2 were collected from 128 population samples (14,679 individuals) representing different subsistence modes and dietary habits, allowing a thorough analysis at both a worldwide and continent scale. A significantly higher prevalence of the slow acetylation phenotype was observed in populations practicing farming (45.4%) and herding (48.2%) as compared to populations mostly relying on hunting and gathering (22.4%) (P = 0.0007). This was closely mirrored by the frequency of the slow 590A variant that was found to occur at a three-fold higher frequency in food producers (25%) as compared to hunter-gatherers (8%). These findings are consistent with the hypothesis that the Neolithic transition to subsistence economies based on agricultural and pastoral resources modified the selective regime affecting the NAT2 acetylation pathway. Furthermore, the vast amount of data collected enabled us to provide a comprehensive and up-to-date description of NAT2 worldwide genetic diversity, thus building up a useful resource of frequency data for further studies interested in epidemiological or anthropological research questions involving NAT2

Comparative analysis of xenobiotic metabolising N-acetyltransferases from ten non-human primates as in vitro models of human homologues

Xenobiotic metabolising N-acetyltransferases (NATs) perform biotransformation of drugs and carcinogens. Human NAT1 is associated with endogenous metabolic pathways of cells and is a candidate drug target for cancer. Human NAT2 is a well-characterised polymorphic xenobiotic metabolising enzyme, modulating susceptibility to drug-induced toxicity. Human NATs are difficult to express to high purification yields, complicating large-scale production for high-throughput screens or use in sophisticated enzymology assays and crystallography. We undertake comparative functional investigation of the NAT homologues of ten non-human primates, to characterise their properties and evaluate their suitability as models of human NATs. Considering the amount of generated recombinant protein, the enzymatic activity and thermal stability, the NAT homologues of non-human primates are demonstrated to be a much more effective resource for in vitro studies compared with human NATs. Certain NAT homologues are proposed as better models, such as the NAT1 of macaques Macaca mulatta and M. sylvanus, the NAT2 of Erythrocebus patas, and both NAT proteins of the gibbon Nomascus gabriellae which show highest homology to human NATs. This comparative investigation will facilitate in vitro screens towards discovery and optimisation of candidate pharmaceutical compounds for human NAT isoenzymes, while enabling better understanding of NAT function and evolution in primates

Genomic plasticity of the immune-related Mhc class I B region in macaque species

<p>Abstract</p> <p>Background</p> <p>In sharp contrast to humans and great apes, the expanded <it>Mhc</it>-<it>B </it>region of rhesus and cynomolgus macaques is characterized by the presence of differential numbers and unique combinations of polymorphic class I <it>B </it>genes per haplotype. The MIB microsatellite is closely linked to the single class I <it>B </it>gene in human and in some great apes studied. The physical map of the <it>Mhc </it>of a heterozygous rhesus monkey provides unique material to analyze MIB and <it>Mamu</it>-<it>B </it>copy number variation and then allows one to decipher the compound evolutionary history of this region in primate species.</p> <p>Results</p> <p><it>In silico </it>research pinpointed 12 MIB copies (duplicons), most of which are associated with expressed <it>B</it>-genes that cluster in a separate clade in the phylogenetic tree. Generic primers tested on homozygous rhesus and pedigreed cynomolgus macaques allowed the identification of eight to eleven MIB copies per individual. The number of MIB copies present per haplotype varies from a minimum of three to six in cynomolgus macaques and from five to eight copies in rhesus macaques. Phylogenetic analyses highlight a strong transpecific sharing of MIB duplicons. Using the physical map, we observed that, similar to MIB duplicons, highly divergent <it>Mamu</it>-<it>B </it>genes can be present on the same haplotype. Haplotype variation as reflected by the copy number variation of class I <it>B </it>loci is best explained by recombination events, which are found to occur between MIBs and <it>Mamu</it>-<it>B</it>.</p> <p>Conclusion</p> <p>The data suggest the existence of highly divergent MIB and <it>Mamu-B </it>lineages on a given haplotype, as well as variable MIB and <it>B </it>copy numbers and configurations, at least in rhesus macaque. Recombination seems to occur between MIB and <it>Mamu</it>-<it>B </it>loci, and the resulting haplotypic plasticity at the individual level may be a strategy to better cope with pathogens. Therefore, evolutionary inferences based on the multiplicated MIB loci but also other markers close to <it>B</it>-genes appear to be promising for the study of <it>B</it>-region organization and evolution in primates.</p

A highly polymorphic insertion in the Y-chromosome amelogenin gene can be used for evolutionary biology, population genetics and sexing in Cetacea and Artiodactyla

<p>Abstract</p> <p>Background</p> <p>The early radiation of the <it>Cetartiodactyla </it>is complex, and unambiguous molecular characters are needed to clarify the positions of hippotamuses, camels and pigs relative to the remaining taxa (<it>Cetacea </it>and <it>Ruminantia</it>). There is also a need for informative genealogic markers for Y-chromosome population genetics as well as a sexing method applicable to all species from this group. We therefore studied the sequence variation of a partial sequence of the evolutionary conserved amelogenin gene to assess its potential use in each of these fields.</p> <p>Results and discussion</p> <p>We report a large interstitial insertion in the Y amelogenin locus in most of the <it>Cetartiodactyla </it>lineages (cetaceans and ruminants). This sex-linked size polymorphism is the result of a 460–465 bp inserted element in intron 4 of the amelogenin gene of Ruminants and Cetaceans. Therefore, this polymorphism can easily be used in a sexing assay for these species.</p> <p>When taking into account this shared character in addition to nucleotide sequence, gene genealogy follows sex-chromosome divergence in <it>Cetartiodactyla </it>whereas it is more congruent with zoological history when ignoring these characters. This could be related to a loss of homology between chromosomal copies given the old age of the insertion.</p> <p>The 1 kbp <it>Amel-Y </it>amplified fragment is also characterized by high nucleotide diversity (64 polymorphic sites spanning over 1 kbp in seven haplotypes) which is greater than for other Y-chromosome sequence markers studied so far but less than the mitochondrial control region.</p> <p>Conclusion</p> <p>The gender-dependent polymorphism we have identified is relevant not only for phylogenic inference within the <it>Cetartiodactyla </it>but also for Y-chromosome based population genetics and gender determination in cetaceans and ruminants. One single protocol can therefore be used for studies in population and evolutionary genetics, reproductive biotechnologies, and forensic science.</p

Compound Evolutionary History of the Rhesus Macaque Mhc Class I B Region Revealed by Microsatellite Analysis and Localization of Retroviral Sequences

In humans, the single polymorphic B locus of the major histocompatibility complex is linked to the microsatellite MIB. In rhesus macaques, however, haplotypes are characterized by the presence of unique combinations of multiple B genes, which may display different levels of polymorphism. The aim of the study was to shed light on the evolutionary history of this highly complex region. First, the robustness of the microsatellite MIB-linked to almost half of the B genes in rhesus macaques (Mamu-B)–for accurate B haplotyping was studied. Based on the physical map of an established haplotype comprising 7 MIB loci, each located next to a certain Mamu-B gene, two MIB loci, MIB1 and MIB6, were investigated in a panel of MHC homozygous monkeys. MIB1 revealed a complex genotyping pattern, whereas MIB6 analysis resulted in the detection of one or no amplicon. Both patterns are specific for a given B haplotype, show Mendelian segregation, and even allow a more precise haplotype definition than do traditional typing methods. Second, a search was performed for retroelements that may have played a role in duplication processes as observed in the macaque B region. This resulted in the description of two types of duplicons. One basic unit comprises an expressed Mamu-B gene, adjacent to an HERV16 copy closely linked to MIB. The second type of duplicon comprises a Mamu-B (pseudo)gene, linked to a truncated HERV16 structure lacking its MIB segment. Such truncation seems to coincide with the loss of B gene transcription. Subsequent to the duplication processes, recombination between MIB and Mamu-B loci appears to have occurred, resulting in a hyperplastic B region. Thus, analysis of MIB in addition to B loci allows deciphering of the compound evolutionary history of the class I B region in Old World monkeys

Genetic structure of cave-dwelling beetles populations: significant deficienci of heterozygotes. Heredity

An analysis of departure from Hardy-Weinberg equilibrium is presented for a set of three troglobitic beetles each with one larval stage (Speonomus hydrophilus, zophosinus and colluvii) from the central Pyrenees. These populations show an important deficiency of heterozygotes (positive 1 and F1 values: 0.4) for all polymorphic loci. Several hypotheses are put forward and examined in relation with the species&apos; biology. The local populations are highly subdivided into demes receiving limited numbers of immigrants from neighboring demes. The spatial structure of the underground environment, associated with the trapping methods used, could lead to the pooling of individuals from a number of separate demes; within these demes the close cohabitation of individuals of several generations, the lack of a larval dispersal stage, the female fertility and the rhythm of matings may give rise to an important inbreeding effect. D U CTI ON The classical models of populations genetic assume that natural populations behave as panmictic units and that such populations or groups are in Hardy-Weinberg equilibrium (H-WE). In reality, natural populations are subject to disturbances of random mating relations, unlike the theoreticians&apos; panmictic populations of infinite size in which gametic combinations occur at random; this is due to such factors as their subdivision, assortative mating, sampling fluctuations in gene frequencies, and the division of the total population range into ecologically diverse subranges with specific selective effects and limited inter-range migratio

Processus démographiques et sélectifs expliquant les profils de diversité et de différenciation génétique des populations du macaque cynomolgus (Macaca fascicularis), espèce à vaste distribution discontinue

TOULOUSE3-BU Sciences (315552104) / SudocSudocFranceF

Dynamique intra- et inter-spécifique d'une famille de microsatellites localisés sur les chromosomes sexuels des primates

Cette thèse, à l'interface de l'évolution moléculaire et de la génétique des populations, a un double objectif: (i) comprendre les facteurs impliqués dans la dynamique évolutive de microsatellites dupliqués et homologues localisés sur les chromosomes sexuels et (ii) utiliser cette information pour interpréter des profils de diversité en génétique des populations. Notre modèle d'étude est une famille de 6 microsatellites (CAIII) localisée dans une région d'homologie sur les chromosomes sexuels. Par une approche bio-informatique, nous montrons que ces microsatellites sont localisés sur des duplications segmentaires à proximité des gènes VCXY (~ 2.5 kb). Par une approche évolutive, basée sur la comparaison des microsatellites chez treize espèces de primates nous montrons: (i) une évolution différente de leur structure moléculaire malgré un environnement génomique identique, suggérant l'existence de facteurs locus-spécifiques (e.g. taux de mutation régional), et (ii) une divergence des séquences flanquantes 3 à 4 fois plus faible qu'attendue en régions non codantes, probablement liée à la proximité des gènes VCXY: influence indirecte (effet auto-stop) ou directe (gène régulé par le microsatellite). Le génotypage de dix populations humaines d'Afrique et d'Europe montre que (i) la diversité génétique sur le Y est plus faible que sur le X, nous démontrons que ceci peut s'expliquer par des migrations 4 fois plus importantes ou/et un effectif efficace 10 fois plus important chez les femmes que chez les hommes; (ii) les distances génétiques entre populations sont plus faibles que celles de la littérature, ce qui pourrait s'expliquer par des contraintes de taille sur les microsatellites. Pour expliquer ce dernier résultat , nous émettons l' hypothèse que la sélection agit sur les microsatellites. Cette hypothèse est renforcée par (i) la proximité des gènes VCXY qui limiterait la divergence interspécifique et (ii) des distributions alléliques liées au chromosome X différentes entre hommes et femmes: ceci suggère une sélection intra-locus sexe-spécifique. Enfin, les microsatellites sur le chromosome Y sont localisés sur des duplications segmentaires présentant une homologie > 99.997%, maintenue par conversion génique. Cette quasi-parfaite homologie soulève un problème méthodologique en génétique des populations car la co-amplification de ces microsatellites empêche de définir des haplotypes ordonnés. Nous proposons et testons 4 méthodes d'assignation des allèles en haplotypes ordonnés. La méthode choisie a une influence sur l'estimation de la diversité intra-population mais l'estimation de la différenciation inter-populations reste inchangée. Par conséquent, il semble qu'une bonne connaissance de l'histoire évolutive et l'environnement génomique des microsatellites sont essentiels à l'élaboration de scénarii démographiques ou sélectifs précis pour expliquer l'évolution de la diversité génétique des populationsPARIS-Museum Hist.Naturelle (751052304) / SudocSudocFranceF

Statut démographique et génétique des populations de magots (Macaca sylvanus) en Algérie et au Maroc.

International audienceLa connaissance des caractéristiques démographiques et génétiques de populations d’espèces en danger est indispensable dans un but de conservation. La dégradation de l’habitat du magot a conduit à la réduction et à la fragmentation de ses populations avec la formation d’isolats de taille très variable. Tous les groupes étudiés ont une composition de type multimâles-multifemelles comparable avec un sexe ratio des adultes relativement équilibré. Cependant, la population du Moyen Atlas (Maroc) comporte une faible proportion d’immatures (24%) comparé à celle des populations d’Algérie ou à celle qu’elle avait 20 ans plus tôt (48-56%). Ceci suggère une modification de la structure d’âge de cette population probablement due à un déficit en recrutement des jeunes, conséquence d’une réduction des ressources alimentaires. L’analyse génétique, à partir de 10 marqueurs microsatellites, a montré que les populations d’Algérie (2000 individus) ont une diversité génétique comparable à celle du Moyen Atlas (plus de 10 000 individus). Les différences observées viennent de la présence d’allèles caractéristiques de chacune des populations. La forte promiscuité sexuelle caractérisant le système de reproduction, pourrait favoriser une taille efficace élevée et contribuer au maintien de la diversité génétique en dépit de la réduction de taille des populations et de leur isolement