Haplotype heterogeneity and low linkage disequilibrium reduce reliable prediction of genotypes for the ‑α form of α-thalassaemia using genome-wide microarray data.

The -α -thalassaemia deletion is very common throughout Africa because it protects against malaria. When undertaking studies to investigate human genetic adaptations to malaria or other diseases, it is important to account for any confounding effects of α-thalassaemia to rule out spurious associations. In this study, we have used direct α-thalassaemia genotyping to understand why GWAS data from a large malaria association study in Kilifi Kenya did not identify the α-thalassaemia signal.

Factors influencing the higher incidence of tuberculosis among migrants and ethnic minorities in the UK.

Migrants and ethnic minorities in the UK have higher rates of tuberculosis (TB) compared with the general population. Historically, much of the disparity in incidence between UK-born and migrant populations has been attributed to differential pathogen exposure, due to migration from high-incidence regions and the transnational connections maintained with TB endemic countries of birth or ethnic origin. However, focusing solely on exposure fails to address the relatively high rates of progression to active disease observed in some populations of latently infected individuals.

Effects of control interventions on Clostridium difficile infection in England: an observational study.

Background: The control of Clostridium difficile infections is an international clinical challenge. The incidence of C difficile in England declined by roughly 80% after 2006, following the implementation of national control policies; we tested two hypotheses to investigate their role in this decline. First, if C difficile infection declines in England were driven by reductions in use of particular antibiotics, then incidence of C difficile infections caused by resistant isolates should decline faster than that caused by susceptible isolates across multiple genotypes.

Diverse sources of C. difficile infection identified on whole-genome sequencing.

Background: It has been thought that Clostridium difficile infection is transmitted predominantly within health care settings. However, endemic spread has hampered identification of precise sources of infection and the assessment of the efficacy of interventions.

Methods: From September 2007 through March 2011, we performed whole-genome sequencing on isolates obtained from all symptomatic patients with C.

Identification of another module involved in the horizontal transfer of the Haemophilus genomic island ICEHin1056.

A significant part of horizontal gene transfer is facilitated by genomic islands. Haemophilus influenzae genomic island ICEHin1056 is an archetype of a genomic island that accounts for pandemic spread of antibiotics resistance. ICEHin1056 has modular structure and harbors modules involved in type IV secretion and integration.

Within-host evolution of Staphylococcus aureus during asymptomatic carriage.

Background: Staphylococcus aureus is a major cause of healthcare associated mortality, but like many important bacterial pathogens, it is a common constituent of the normal human body flora. Around a third of healthy adults are carriers. Recent evidence suggests that evolution of S.

Microevolutionary analysis of Clostridium difficile genomes to investigate transmission.

Background: The control of Clostridium difficile infection is a major international healthcare priority, hindered by a limited understanding of transmission epidemiology for these bacteria. However, transmission studies of bacterial pathogens are rapidly being transformed by the advent of next generation sequencing.

Results: Here we sequence whole C.

Evolutionary dynamics of Staphylococcus aureus during progression from carriage to disease.

Whole-genome sequencing offers new insights into the evolution of bacterial pathogens and the etiology of bacterial disease. Staphylococcus aureus is a major cause of bacteria-associated mortality and invasive disease and is carried asymptomatically by 27% of adults. Eighty percent of bacteremias match the carried strain.

Characterisation of Clostridium difficile hospital ward-based transmission using extensive epidemiological data and molecular typing.

Background: Clostridium difficile infection (CDI) is a leading cause of antibiotic-associated diarrhoea and is endemic in hospitals, hindering the identification of sources and routes of transmission based on shared time and space alone. This may compromise rational control despite costly prevention strategies. This study aimed to investigate ward-based transmission of C.

Pneumococcal genome sequencing tracks a vaccine escape variant formed through a multi-fragment recombination event.

Streptococcus pneumoniae ('pneumococcus') causes an estimated 14.5 million cases of serious disease and 826,000 deaths annually in children under 5 years of age(1). The highly effective introduction of the PCV7 pneumococcal vaccine in 2000 in the United States(2,3) provided an unprecedented opportunity to investigate the response of an important pathogen to widespread, vaccine-induced selective pressure.

Understanding the evolution of human pigmentation: recent contributions from population genetics.

Variation in human skin and hair color is one of the most striking aspects of human variability, and explaining this diversity is one of the central questions of human biology. Only in the last decade or so has it been realistically possible to address this question experimentally using population genetic approaches. On the basis of earlier studies in mice, and on studies in humans with various Mendelian disorders, many of the genes underpinning population variation in skin color have been identified.

Molecular epidemiology of Clostridium difficile strains in children compared with that of strains circulating in adults with Clostridium difficile-associated infection.

Molecular analysis of Clostridium difficile (28 isolates) from children (n = 128) in Oxfordshire, United Kingdom, identified eight toxigenic genotypes. Six of these were isolated from 27% of concurrent adult C. difficile-associated infections studied (n = 83).

Clinical Clostridium difficile: clonality and pathogenicity locus diversity.

Clostridium difficile infection (CDI) is an important cause of mortality and morbidity in healthcare settings. The major virulence determinants are large clostridial toxins, toxin A (tcdA) and toxin B (tcdB), encoded within the pathogenicity locus (PaLoc). Isolates vary in pathogenicity from hypervirulent PCR-ribotypes 027 and 078 with high mortality, to benign non-toxigenic strains carried asymptomatically.

Multilocus sequence typing of Clostridium difficile.

A robust high-throughput multilocus sequence typing (MLST) scheme for Clostridium difficile was developed and validated using a diverse collection of 50 reference isolates representing 45 different PCR ribotypes and 102 isolates from recent clinical samples. A total of 49 PCR ribotypes were represented overall. All isolates were typed by MLST and yielded 40 sequence types (STs).

Genomic islands: tools of bacterial horizontal gene transfer and evolution.

Bacterial genomes evolve through mutations, rearrangements or horizontal gene transfer. Besides the core genes encoding essential metabolic functions, bacterial genomes also harbour a number of accessory genes acquired by horizontal gene transfer that might be beneficial under certain environmental conditions. The horizontal gene transfer contributes to the diversification and adaptation of microorganisms, thus having an impact on the genome plasticity.

Sequence and functional analyses of Haemophilus spp. genomic islands.

Background: A major part of horizontal gene transfer that contributes to the diversification and adaptation of bacteria is facilitated by genomic islands. The evolution of these islands is poorly understood. Some progress was made with the identification of a set of phylogenetically related genomic islands among the Proteobacteria, recognized from the investigation of the evolutionary origins of a Haemophilus influenzae antibiotic resistance island, namely ICEHin1056.

The evolution of genetic structure in the marine pathogen, Vibrio vulnificus.

Multi-locus sequence types (MLST) from a global collection of Vibrio vulnificus isolates were analysed for the contribution of recombination to the evolution of two divergent clusters of strains and a human-pathogenic hybrid genotype, which caused a disease outbreak in Israel. Recombination contributes more substantially than mutation to generating strain diversity. For allelic diversity within loci, the ratio of recombination to mutation events is approximately 2:1.

Classical sickle beta-globin haplotypes exhibit a high degree of long-range haplotype similarity in African and Afro-Caribbean populations.

Background: The sickle (betas) mutation in the beta-globin gene (HBB) occurs on five "classical" betas haplotype backgrounds in ethnic groups of African ancestry. Strong selection in favour of the betas allele - a consequence of protection from severe malarial infection afforded by heterozygotes - has been associated with a high degree of extended haplotype similarity. The relationship between classical betas haplotypes and long-range haplotype similarity may have both anthropological and clinical implications, but to date has not been explored.

Diversity of antibiotic resistance integrative and conjugative elements among haemophili.

The objective of this study was to investigate the sequence diversity in a single country of a family of integrative and conjugative elements (ICEs) that are vectors of antibiotic resistance in Haemophilus influenzae and Haemophilus parainfluenzae, and test the hypothesis that they emerged from a single lineage. Sixty subjects aged 9 months - 13 years were recruited and oropharyngeal samples cultured. Up to 10 morphologically distinct Pasteurellaceae spp.

Novel type IV secretion system involved in propagation of genomic islands.

Type IV secretion systems (T4SSs) mediate horizontal gene transfer, thus contributing to genome plasticity, evolution of infectious pathogens, and dissemination of antibiotic resistance and other virulence traits. A gene cluster of the Haemophilus influenzae genomic island ICEHin1056 has been identified as a T4SS involved in the propagation of genomic islands. This T4SS is novel and evolutionarily distant from the previously described systems.

Epistatic interactions: how strong in disease and evolution?

When the chimpanzee genome sequence was released, human deleterious alleles associated with simple mendelian diseases were observed as wild-type alleles in six genes (AIRE, MKKS, MLH1, MYOC, OTC and PRSS1). The absence of recognizable phenotypic effects in chimpanzee, contrary to the clinical effect observed in humans, is attributed to epistatic interactions (compensation) between potentially deleterious and compensatory alleles. In this report we investigate the possible evolutionary histories by which substitution of alternative variants in these six genes either ameliorates or avoids pathological consequences.

Mitochondrial genomics identifies major haplogroups in Aboriginal Australians.

We classified diversity in eight new complete mitochondrial genome sequences and 41 partial sequences from living Aboriginal Australians into five haplogroups. Haplogroup AuB belongs to global lineage M, and AuA, AuC, AuD, and AuE to N. Within N, we recognize subdivisions, assigning AuA to haplogroup S, AuD to haplogroup O, AuC to P4, and AuE to P8.

Enhanced invasiveness of bovine-derived neonatal sequence type 17 group B streptococcus is independent of capsular serotype.

Background: A defined geographical area (Oxford, United Kingdom) was investigated for the role of group B Streptococcus (GBS) as a human pathogen.

Methods: GBS carriage in pregnant women and invasive disease in neonates and adults >60 years of age was studied over a 3-year period. Multilocus sequence typing and capsular serotyping were used to study 369 isolates of GBS from carriage in pregnant women (n=190) and invasive disease in neonates (n=109) and adults >60 years of age (n=70).

Deciphering the ancient and complex evolutionary history of human arylamine N-acetyltransferase genes.

The human N-acetyltransferase genes NAT1 and NAT2 encode two phase-II enzymes that metabolize various drugs and carcinogens. Functional variability at these genes has been associated with adverse drug reactions and cancer susceptibility. Mutations in NAT2 leading to the so-called slow-acetylation phenotype reach high frequencies worldwide, which questions the significance of altered acetylation in human adaptation.