Reliable selfing rate estimates from imperfect population genetic data.

Genotypic frequencies at codominant marker loci in population samples convey information on mating systems. A classical way to extract this information is to measure heterozygote deficiencies (FIS) and obtain the selfing rate s from FIS = s/(2 - s), assuming inbreeding equilibrium. A major drawback is that heterozygote deficiencies are often present without selfing, owing largely to technical artefacts such as null alleles or partial dominance. We show here that, in the absence of gametic disequilibrium, the multilocus structure can be used to derive estimates of s independent of FIS and free of technical biases. Their statistical power and precision are comparable to those of FIS, although they are sensitive to certain types of gametic disequilibria, a bias shared with progeny-array methods but not FIS. We analyse four real data sets spanning a range of mating systems. In two examples, we obtain s = 0 despite positive FIS, strongly suggesting that the latter are artefactual. In the remaining examples, all estimates are consistent. All the computations have been implemented in a open-access and user-friendly software called rmes (robust multilocus estimate of selfing) available at http://ftp.cefe.cnrs.fr, and can be used on any multilocus data. Being able to extract the reliable information from imperfect data, our method opens the way to make use of the ever-growing number of published population genetic studies, in addition to the more demanding progeny-array approaches, to investigate selfing rates.

Variable queen number in ant colonies: no impact on queen turnover, inbreeding, and population genetic differentiation in the ant Formica selysi.

Variation in queen number alters the genetic structure of social insect colonies, which in turn affects patterns of kin-selected conflict and cooperation. Theory suggests that shifts from single- to multiple-queen colonies are often associated with other changes in the breeding system, such as higher queen turnover, more local mating, and restricted dispersal. These changes may restrict gene flow between the two types of colonies and it has been suggested that this might ultimately lead to sympatric speciation. We performed a detailed microsatellite analysis of a large population of the ant Formica selysi, which revealed extensive variation in social structure, with 71 colonies headed by a single queen and 41 by multiple queens. This polymorphism in social structure appeared stable over time, since little change in the number of queens per colony was detected over a five-year period. Apart from queen number, single- and multiple-queen colonies had very similar breeding systems. Queen turnover was absent or very low in both types of colonies. Single- and multiple-queen colonies exhibited very small but significant levels of inbreeding, which indicates a slight deviation from random mating at a local scale and suggests that a small proportion of queens mate with related males. For both types of colonies, there was very little genetic structuring above the level of the nest, with no sign of isolation by distance. These similarities in the breeding systems were associated with a complete lack of genetic differentiation between single- and multiple-queen colonies, which provides no support for the hypothesis that change in queen number leads to restricted gene flow between social forms. Overall, this study suggests that the higher rates of queen turnover, local mating, and population structuring that are often associated with multiple-queen colonies do not appear when single- and multiple-queen colonies still coexist within the same population, but build up over time in populations consisting mostly of multiple-queen colonies.

Species-specific population structure in rock-specialized sympatric cichlid species in Lake Tanganyika, East Africa.

Species richness and geographical phenotypic variation in East African lacustrine cichlids are often correlated with ecological specializations and limited dispersal. This study compares mitochondrial and microsatellite genetic diversity and structure among three sympatric rock-dwelling cichlids of Lake Tanganyika, Eretmodus cyanostictus, Tropheus moorii, and Ophthalmotilapia ventralis. The species represent three endemic, phylogenetically distinct tribes (Eretmodini, Tropheini, and Ectodini), and display divergent ecomorphological and behavioral specialization. Sample locations span both continuous, rocky shoreline and a potential dispersal barrier in the form of a muddy bay. High genetic diversity and population differentiation were detected in T. moorii and E. cyanostictus, whereas much lower variation and structure were found in O. ventralis. In particular, while a 7-km-wide muddy bay curtails dispersal in all three species to a similar extent, gene flow along mostly continuous habitat appeared to be controlled by distance in E. cyanostictus, further restricted by site philopatry and/or minor habitat discontinuities in T. moorii, and unrestrained in O. ventralis. In contrast to the general pattern of high gene flow along continuous shorelines in rock-dwelling cichlids of Lake Malawi, our study identifies differences in population structure among stenotopic Lake Tanganyika species. The amount of genetic differentiation among populations was not related to the degree of geographical variation of body color, especially since more phenotypic variation is observed in O. ventralis than in the genetically highly structured E. cyanostictus.

Searching for sex-reversals to explain population demography and the evolution of sex chromosomes.

Sex determination can be purely genetic (as in mammals and birds), purely environmental (as in many reptiles), or genetic but reversible by environmental factors during a sensitive period in life, as in many fish and amphibians (Wallace et al. 1999; Baroiller et al. 2009a; Stelkens & Wedekind 2010). Such environmental sex reversal (ESR) can be induced, for example, by temperature changes or by exposure to hormone-active substances. ESR has long been recognized as a means to produce more profitable single-sex cultures in fish farms (Cnaani & Levavi-Sivan 2009), but we know very little about its prevalence in the wild. Obviously, induced feminization or masculinization may immediately distort population sex ratios, and distorted sex ratios are indeed reported from some amphibian and fish populations (Olsen et al. 2006; Alho et al. 2008; Brykov et al. 2008). However, sex ratios can also be skewed by, for example, segregation distorters or sex-specific mortality. Demonstrating ESR in the wild therefore requires the identification of sex-linked genetic markers (in the absence of heteromorphic sex chromosomes) followed by comparison of genotypes and phenotypes, or experimental crosses with individuals who seem sex reversed, followed by sexing of offspring after rearing under non-ESR conditions and at low mortality. In this issue, Alho et al. (2010) investigate the role of ESR in the common frog (Rana temporaria) and a population that has a distorted adult sex ratio. They developed new sex-linked microsatellite markers and tested wild-caught male and female adults for potential mismatches between phenotype and genotype. They found a significant proportion of phenotypic males with a female genotype. This suggests environmental masculinization, here with a prevalence of 9%. The authors then tested whether XX males naturally reproduce with XX females. They collected egg clutches and found that some had indeed a primary sex ratio of 100% daughters. Other clutches seemed to result from multi-male fertilizations of which at least one male had the female genotype. These results suggest that sex-reversed individuals affect the sex ratio in the following generation. But how relevant is ESR if its prevalence is rather low, and what are the implications of successful reproduction of sex-reversed individuals in the wild?

Molecular genetics of narcolepsy

1 Abstract Sleep is a vital necessity, yet its basic physiological function is still unknown, despite numerous studies both in healthy humans and animal models. The study of patients with sleep disorders may help uncover major biological pathways in sleep regulation and thus shed light on the actual function of sleep. Narcolepsy is a well defined but rare sleep disorder characterized by excessive daytime sleepiness and cataplexy, thought to be caused by a combination of genetic and environmental factors. The aim of this work was to identify genes or genetic variants, which contribute to the pathogenesis of sporadic and familial narcolepsy. Sporadic narcolepsy is the disorder with the strongest human leukocyte antigen (HLA) association ever reported. Since the associated HLA-DRB1 *1501-DQB1 *0602 haplotype is common in the general population (15-25%), it has been suggested that it is necessary but not sufficient for developing narcolepsy. To further define the genetic basis of narcolepsy risk, we performed a genome-wide association study (GWAS) in 562 European individuals with narcolepsy (cases) and 702 ethnically matched controls, with independent replication in 370 cases and 495 controls, all heterozygous for DRB1*1501-DQB1*0602. We found association with a protective variant near HLA-DQA2. Further analysis revealed that the identified SNP is strongly linked to DRB1*03-DQB1*02 and DRBΠ 301-DQB1*0603. Cases almost never carried a trans DRB1*1301-DQB1*0603 haplotype. This unexpected protective HLA haplotype suggests a causal involvement of the HLA region in narcolepsy susceptibility. Familial cases of narcolepsy account for 10% of all narcolepsy cases. However, due to low number of affected family members, narcolepsy families are usually not eligible for genetic linkage studies. We identified and characterized a large Spanish family with 11 affected family members representing the largest ever reported narcolepsy family. We ran a genetic linkage analysis using DNA of 11 affected and 15 unaffected family members and hereby identified a chromosomal candidate region on chromosome 6 encompassing 163 kb with a maximum multipoint LOD score of 5.02. The coding sequences of 4 genes within this haplotype block as well as 2 neighboring genes were screened for pathogenetic mutations in 2 affected and 1 healthy family members. So far no pathogenic mutation could be identified. Further in-depth sequencing of our candidate region as well as whole genome exome sequencing are underway to identify the pathogenic mutation(s) in this family and will further improve our understanding of the genetic basis of narcolepsy. 2 Résumé Le sommeil est un processus vital, dont la fonction physiologique est encore inconnue, malgré de nombreuses études chez des sujets humains sains ainsi que dans des modèles animaux. L'étude de patients souffrant de troubles du sommeil peut permettre la découverte de voies biologiques jouant un rôle majeur dans la régulation du sommeil. L'un de ces troubles, la narcolepsie, est une maladie rare mais néanmoins bien définie, caractérisée par une somnolence diurne excessive accompagnée de cataplexies. Les connaissances actuelles suggèrent qu'une combinaison de facteurs génétiques et environnementaux en est à l'origine. Le but du présent travail était d'identifier !e(s) gène(s) ou les polymorphismes constituant des facteurs de risque dans les formes sporadique et familiale de narcolepsie. La narcolepsie sporadique est la maladie possédant la plus forte association avec le complexe majeur d'histocompatibilité humain (HLA) jamais reportée. La fréquence au sein de la population générale de l'haplotype associé HLA-DRB1*1501- DQB1*0602 (15-25%) suggère que ce dernier est nécessaire, mais pas suffisant, pour (e développement de la maladie. Nous avons voulu approfondir la recherche de facteurs génétiques augmentant le risque de la narcolepsie. A cette fin, nous avons entrepris une étude d'association à l'échelle du génome (genome-wide association study, GWAS) parmi 562 sujets narcoleptiques européens (cas) et 702 individus contrôle de même origine ethnique et nous avons trouvé une association avec un variant protecteur près du gène HLA- DQA2. Ce résultat a été répliqué indépendamment dans 370 cas et 495 contrôles, tous hétérozygotes au locus DRB1*1501-DQB1*0602. Une analyse plus fine montre que le polymorphisme identifié est fortement lié aux allèles DRB1*03-DQB1*02 et DRB1*1301-DQB1*0603. Nous notons que seul un cas était porteur d'un haplotype en trans DRB1*1301-DQBr0603. La découverte de cet allele HLA protecteur suggère que la région HLA joue un rôle causal dans la susceptibilité à la narcolepsie. Dix pourcents des cas de narcolepsie sont familiaux. Cependant, le faible nombre de membres affectés rend ces familles inéligibles pour des études de liaison génétique. Nous avons identifié et caractérisé une grande famille espagnole, dont 11 membres sont atteints par la maladie, ce qui représente la plus grande famille narcoleptique rapportée jusqu'à ce jour. A partir de l'ADN de 11 membres atteints et 15 non- atteints, nous avons identifié par étude de liaison une région candidate de 163 kîlobases (kb) sur le chromosome 6, correspondant à un LOD score multipoints de 5.02. Nous avons cherché, sans succès, des mutations pathogéniques dans la séquence codante de deux gènes situés à l'intérieur de ce segment, ainsi que 4 gènes adjacents. Un séquençage plus approfondi de la région ainsi que le séquençage des exons de tout le génome est en cours et doit s'avérer plus fructueux et révéler la ou tes mutation(s) pathogénique(s) dans cette famille, ce qui contribuerait à une meilleure compréhension des causes génétiques de la narcolepsie. 3 Résumé pour un large public Le sommeil est une nécessité vitale, dont le rôle physiologique exact reste inconnu malgré de nombreuses études sur des sujets humains sains ainsi que sur des modèles animaux. C'est pourquoi les troubles du sommeil intéressent les chercheurs, car l'élucidation des mécanismes responsables peut permettre de mieux comprendre le fonctionnement du sommeil normal. La narcolepsie est une maladie du sommeil caractérisée par une somnolence diurne excessive. Les personnes atteintes peuvent s'endormir involontairement à tout moment de la journée, et souffrent également de pertes du tonus musculaire (cataplexie) lors de fortes émotions, par exemple un fou rire. La narcolepsie est une maladie rare, apparaissant dans 1 personne sur 2000. Les connaissances actuelles suggèrent qu'une combinaison de facteurs génétiques et environnementaux en est à l'origine. Nous avons voulu identifier les facteurs génétiques influençant le déclenchement de la maladie, d'abord dans sa forme sporadique, puis dans une famille comptant de nombreux membres atteints. En comparant les variations génétiques de près de 1000 sujets narcoleptiques européens avec ceux de 1200 individus sains, nous avons trouvé chez 30% de ces derniers un variant protecteur, qui diminue de 50 fois le risque de développer la maladie, ce qui constitue le plus puissant facteur génétique protecteur décrit à ce jour. Nous avons ensuite étudié une grande famille espagnole comptant une trentaine de membres, dont 11 sont atteints de narcolepsie. De nouveau, nous avons comparé les variations génétiques des membres atteints avec ceux des membres sains. Nous avons ainsi pu identifier une région dans le génome où se trouverait le(s) gène(s) impliqué(s) dans la maladie dans cette famille, mais n'avons pas encore trouvé le(s) variant(s) exact(s). Une étude plus approfondie devrait permettre de P(les) identifier et ainsi contribuer à l'élucidation des mécanismes menant au développement de la narcolepsie.

The PsyCoLaus study: methodology and characteristics of the sample of a population-based survey on psychiatric disorders and their association with genetic and cardiovascular risk factors.

ABSTRACT: BACKGROUND: The Psychiatric arm of the population-based CoLaus study (PsyCoLaus) is designed to: 1) establish the prevalence of threshold and subthreshold psychiatric syndromes in the 35 to 66 year-old population of the city of Lausanne (Switzerland); 2) test the validity of postulated definitions for subthreshold mood and anxiety syndromes; 3) determine the associations between psychiatric disorders, personality traits and cardiovascular diseases (CVD), 4) identify genetic variants that can modify the risk for psychiatric disorders and determine whether genetic risk factors are shared between psychiatric disorders and CVD. This paper presents the method as well as somatic and sociodemographic characteristics of the sample. METHODS: All 35 to 66 year-old persons previously selected for the population-based CoLaus survey on risk factors for CVD were asked to participate in a substudy assessing psychiatric conditions. This investigation included the Diagnostic Interview for Genetic Studies to elicit diagnostic criteria for threshold disorders according to DSM-IV and algorithmically defined subthreshold syndromes. Complementary information was gathered on potential risk and protective factors for psychiatric disorders, migraine and on the morbidity of first-degree family members, whereas the collection of DNA and plasma samples was part of the original somatic study (CoLaus). RESULTS: A total of 3,691 individuals completed the psychiatric evaluation (67% participation). The gender distribution of the sample did not differ significantly from that of the general population in the same age range. Although the youngest 5-year band of the cohort was underrepresented and the oldest 5-year band overrepresented, participants of PsyCoLaus and individuals who refused to participate revealed comparable scores on the General Health Questionnaire, a self-rating instrument completed at the somatic exam. CONCLUSIONS: Despite limitations resulting from the relatively low participation in the context of a comprehensive and time-consuming investigation, the PsyCoLaus study should significantly contribute to the current understanding of psychiatric disorders and comorbid somatic conditions by: 1) establishing the clinical relevance of specific psychiatric syndromes below the DSM-IV threshold; 2) determining comorbidity between risk factors for CVD and psychiatric disorders; 3) assessing genetic variants associated with common psychiatric disorders and 4) identifying DNA markers shared between CVD and psychiatric disorders.

Obesity-related phenotypes are associated to parental longevity in a Swiss population-based study

METHODS. We analyzed data from a population-based sample of 2561 participants (1163 men and 1398 women) aged 55-75 years from the city of Lausanne, Switzerland (CoLaus study). Participants were stratified by the number of parents (0, 1, 2) who survived to 85 years or more. Trend across these strata was assessed using a non-parametric kmean test. The associations of parental age (independent covariate used as a proxy for longevity) with fasting blood glucose, blood pressures, blood lipids, body mass index (BMI), weight, height or liver enzymes (continuous dependent variables) were analyzed using multiple linear regressions. Models were adjusted for age, sex, alcohol consumption, smoking and educational level, and BMI for liver enzymes. RESULTS. For subjects with 0 (N = 1298), 1 (N = 991) and 2 (N = 272) long-lived parents, median BMI (interquartile range) was 25.4 (6.5), 24.9 (6.1) and 23.7 (4.8) kg/m2 in women (P <0.001), and 27.3 (4.8), 27.0 (4.5) and 25.9 (4.9) kg/m2 in men (P = 0.04), respectively; median weight was 66.5 (16.1), 65.0 (16.4) and 63.4 (13.7) kg in women (P = 0.003), and 81.5 (17.0), 81.4 (16.4) and 80.3 (17.1) kg in men (P = 0.36). Median height was 161 (8), 162 (9) and 163 (8) cm in women (P = 0.005) and 173 (9), 174 (9) and 174 (11) cm in men (P = 0.09). The corresponding medians for AST (Aspartate Aminotransferase) were 31 (13), 29 (11) and 28 (10) U/L (P = 0.002), and 28 (17), 27 (14) and 26 (19) U/L for ALT (Alanin Aminotransferase, P = 0.053) in men. In multivariable analyses, greater parental longevity was associated with lower BMI, lower weight and taller stature in women (P < 0.01) and lower AST in men (P = 0.011). No significant associations were observed for the other variables analyzed. Sensitivity analyses restricted to subjects whose parents were dead (N = 1844) led to similar results, with even stronger associations of parental longevity with liver enzymes in men. CONCLUSIONS. In women, increased parental longevity was associated with smaller BMI, attributable to lower weight and taller stature. In men, the association of increased parental longevity with lower liver enzymes, independently of BMI, suggests that parental longevity may be associated with decreased nonalcoholic fatty liver disease.

Evolutionary aspects of population structure for molecular and quantitative traits in the freshwater snail Radix balthica.

Detecting the action of selection in natural populations can be achieved using the QST-FST comparison that relies on the estimation of FST with neutral markers, and QST using quantitative traits potentially under selection. QST higher than FST suggests the action of directional selection and thus potential local adaptation. In this article, we apply the QST-FST comparison to four populations of the hermaphroditic freshwater snail Radix balthica located in a floodplain habitat. In contrast to most studies published so far, we did not detect evidence of directional selection for local optima for any of the traits we measured: QST calculated using three different methods was never higher than FST. A strong inbreeding depression was also detected, indicating that outcrossing is probably predominant over selfing in the studied populations. Our results suggest that in this floodplain habitat, local adaptation of R. balthica populations may be hindered by genetic drift, and possibly altered by uneven gene flow linked to flood frequency.

BAFF binds to the tumor necrosis factor receptor-like molecule B cell maturation antigen and is important for maintaining the peripheral B cell population.

The tumor necrosis factor (TNF) family member B cell activating factor (BAFF) binds B cells and enhances B cell receptor-triggered proliferation. We find that B cell maturation antigen (BCMA), a predicted member of the TNF receptor family expressed primarily in mature B cells, is a receptor for BAFF. Although BCMA was previously localized to the Golgi apparatus, BCMA was found to be expressed on the surface of transfected cells and tonsillar B cells. A soluble form of BCMA, which inhibited the binding of BAFF to a B cell line, induced a dramatic decrease in the number of peripheral B cells when administered in vivo. Moreover, culturing splenic cells in the presence of BAFF increased survival of a percentage of the B cells. These results are consistent with a role for BAFF in maintaining homeostasis of the B cell population.

Association of MMP-2 polymorphisms with severe and very severe COPD: a case control study of MMPs-1, 9 and 12 in a European population.

BACKGROUND: Genetic factors play a role in chronic obstructive pulmonary disease (COPD) but are poorly understood. A number of candidate genes have been proposed on the basis of the pathogenesis of COPD. These include the matrix metalloproteinase (MMP) genes which play a role in tissue remodelling and fit in with the protease--antiprotease imbalance theory for the cause of COPD. Previous genetic studies of MMPs in COPD have had inadequate coverage of the genes, and have reported conflicting associations of both single nucleotide polymorphisms (SNPs) and SNP haplotypes, plausibly due to under-powered studies. METHODS: To address these issues we genotyped 26 SNPs, providing comprehensive coverage of reported SNP variation, in MMPs- 1, 9 and 12 from 977 COPD patients and 876 non-diseased smokers of European descent and evaluated their association with disease singly and in haplotype combinations. We used logistic regression to adjust for age, gender, centre and smoking history. RESULTS: Haplotypes of two SNPs in MMP-12 (rs652438 and rs2276109), showed an association with severe/very severe disease, corresponding to GOLD Stages III and IV. CONCLUSIONS: Those with the common A-A haplotype for these two SNPs were at greater risk of developing severe/very severe disease (p = 0.0039) while possession of the minor G variants at either SNP locus had a protective effect (adjusted odds ratio of 0.76; 95% CI 0.61 - 0.94). The A-A haplotype was also associated with significantly lower predicted FEV1 (42.62% versus 44.79%; p = 0.0129). This implicates haplotypes of MMP-12 as modifiers of disease severity.

Orosomucoid (alpha-1 acid glycoprotein) phenotyping by use of immobilized pH gradients with 8 M urea and immunoblotting. A new variant encountered in a population study.

Orosomucoid (ORM) phenotyping has been performed on 329 unrelated Swiss subjects, using immobilized pH gradients with 8 M urea and 2% v/v 2-mercaptoethanol followed by immunoblotting. After desialylation the band patterns of ORM confirmed that the polymorphism of the structural locus ORM1 is controlled by three codominant autosomal alleles (ORM1*F1, ORM1*S and ORM1*F2). One rare and one new allele were detected. The rare variant, tentatively assigned to the second structural locus ORM2, is observed in a cathodal position and named ORM2 B1. The new variant, tentatively assigned to the first structural locus ORM1, is observed in a region located between ORM1 S and ORM1 F2, and named ORM1 F3. Moreover, the pI values of the ORM variants have been measured accurately with Immobiline Dry Plates (LKB): they were found to be within the pH range 4.93-5.14.

An expression of mixed animal model equations to account for different means and variances in the base population

This paper presents a general expression to predict breeding values using animal models when the base population is selected, i.e. the means and variances of breeding values in the base generation differ among individuals. Rules for forming the mixed model equations are also presented. A numerical example illustrates the procedure.

Meckel-Gruber Syndrome: a population-based study on prevalence, prenatal diagnosis, clinical features, and survival in Europe.

Meckel-Gruber Syndrome is a rare autosomal recessive lethal ciliopathy characterized by the triad of cystic renal dysplasia, occipital encephalocele and postaxial polydactyly. We present the largest population-based epidemiological study to date using data provided by the European Surveillance of Congenital Anomalies (EUROCAT) network. The study population consisted of 191 cases of MKS identified between January 1990 and December 2011 in 34 European registries. The mean prevalence was 2.6 per 100 000 births in a subset of registries with good ascertainment. The prevalence was stable over time, but regional differences were observed. There were 145 (75.9%) terminations of pregnancy after prenatal diagnosis, 13 (6.8%) fetal deaths, 33 (17.3%) live births. In addition to cystic kidneys (97.7%), encephalocele (83.8%) and polydactyly (87.3%), frequent features include other central nervous system anomalies (51.4%), fibrotic/cystic changes of the liver (65.5% of cases with post mortem examination) and orofacial clefts (31.8%). Various other anomalies were present in 64 (37%) patients. As nowadays most patients are detected very early in pregnancy when liver or kidney changes may not yet be developed or may be difficult to assess, none of the anomalies should be considered obligatory for the diagnosis. Most cases (90.2%) are diagnosed prenatally at 14.3±2.6 (range 11-36) gestational weeks and pregnancies are mainly terminated, reducing the number of LB to one-fifth of the total prevalence rate. Early diagnosis is important for timely counseling of affected couples regarding the option of pregnancy termination and prenatal genetic testing in future pregnancies.

Effect of biogeographic history on population vulnerability in European amphibians.

The genetic diversity of populations, which contributes greatly to their adaptive potential, is negatively affected by anthropogenic habitat fragmentation and destruction. However, continental-scale losses of genetic diversity also resulted from the population expansions that followed the end of the last glaciation, an element that is rarely considered in a conservation context. We addressed this issue in a meta-analysis in which we compared the spatial patterns of vulnerability of 18 widespread European amphibians in light of phylogeographic histories (glacial refugia and postglacial routes) and anthropogenic disturbances. Conservation statuses significantly worsened with distances from refugia, particularly in the context of industrial agriculture; human population density also had a negative effect. These findings suggest that features associated with the loss of genetic diversity in post-glacial amphibian populations (such as enhanced fixation load or depressed adaptive potential) may increase their susceptibility to current threats (e.g., habitat fragmentation and pesticide use). We propose that the phylogeographic status of populations (i.e., refugial vs. post-glacial) should be considered in conservation assessments for regional and national red lists.

Worldwide Population Structure, Long-Term Demography, and Local Adaptation of Helicobacter pylori.

Helicobacter pylori is an important human pathogen associated with serious gastric diseases. Owing to its medical importance and close relationship with its human host, understanding genomic patterns of global and local adaptation in H. pylori may be of particular significance for both clinical and evolutionary studies. Here we present the first such whole genome analysis of 60 globally distributed strains, from which we inferred worldwide population structure and demographic history and shed light on interesting global and local events of positive selection, with particular emphasis on the evolution of San-associated lineages. Our results indicate a more ancient origin for the association of humans and H. pylori than previously thought. We identify several important perspectives for future clinical research on candidate selected regions that include both previously characterized genes (e.g., transcription elongation factor NusA and tumor necrosis factor alpha-inducing protein Tipα) and hitherto unknown functional genes.