Transmission, distribution and drug resistance-conferring mutations of extensively drug-resistant tuberculosis in the Western Cape Province, South Africa

Extensively drug-resistant tuberculosis (XDR-TB), defined as resistance to at least isoniazid (INH), rifampicin (RIF), a fluoroqui-nolone (FQ) and a second-line injectable drug (SLID), is difficult to treat and poses a major threat to TB control. The transmission dynamics and distribution of XDR Mycobacterium tuberculosis (Mtb) strains have not been thoroughly investigated. Using whole genome sequencing data on 461 XDR-Mtb strains, we aimed to investigate the geographical distribution of XDR-Mtb strains in the Western Cape Province of South Africa over a 10 year period (2006-2017) and assess the association between Mtb sub-lineage, age, gender, geographical patient location and membership or size of XDR-TB clusters. First, we identified transmission clusters by excluding drug resistance-conferring mutations and using the 5 SNP cutoff, followed by merging clusters based on their most recent common ancestor. We then consecutively included variants conferring resistance to INH, RIF, ethambutol (EMB), pyrazinamide (PZA), SLIDs and FQs in the cluster definition. Cluster sizes were classified as small (2-4 isolates), medium (5-20 isolates), large (21-100 isolates) or very large (>100 isolates) to reflect the success of individual strains. We found that most XDR-TB strains were clustered and that including variants conferring resistance to INH, RIF, EMB, PZA and SLIDs in the cluster definition did not significantly reduce the proportion of clustered isolates (85.5-82.2 %) but increased the number of patients belonging to small clusters (4.3-12.4 %, P=0.56). Inclusion of FQ resistance-conferring variants had the greatest effect, with 11 clustered isolates reclassified as unique while the number of clusters increased from 17 to 37. Lineage 2 strains (lineage 2.2.1 typical Beijing or lineage 2.2.2 atypical Beijing) showed the large clusters which were spread across all health districts of the Western Cape Province. We identified a significant association between residence in the Cape Town metropole and cluster membership (P=0.016) but no association between gender, age and cluster membership or cluster size (P=0.39). Our data suggest that the XDR-TB epidemic in South Africa probably has its origin in the endemic spread of MDR Mtb and pre-XDR Mtb strains followed by acquisition of FQ resistance, with more limited transmission of XDR Mtb strains. This only became apparent with the inclusion of drug resistance-conferring variants in the definition of a cluster. In addition to the prevention of amplification of resistance, rapid diagnosis of MDR, pre-XDR and XDR-TB and timely initiation of appropriate treatment is needed to reduce transmission of difficult-to-treat TB

Aboriginal Australian mitochondrial genome variation - An increased understanding of population antiquity and diversity

Aboriginal Australians represent one of the oldest continuous cultures outside Africa, with evidence indicating that their ancestors arrived in the ancient landmass of Sahul (present-day New Guinea and Australia) ∼55 thousand years ago. Genetic studies, though limited, have demonstrated both the uniqueness and antiquity of Aboriginal Australian genomes. We have further resolved known Aboriginal Australian mitochondrial haplogroups and discovered novel indigenous lineages by sequencing the mitogenomes of 127 contemporary Aboriginal Australians. In particular, the more common haplogroups observed in our dataset included M42a, M42c, S, P5 and P12, followed by rarer haplogroups M15, M16, N13, O, P3, P6 and P8. We propose some major phylogenetic rearrangements, such as in haplogroup P where we delinked P4a and P4b and redefined them as P4 (New Guinean) and P11 (Australian), respectively. Haplogroup P2b was identified as a novel clade potentially restricted to Torres Strait Islanders. Nearly all Aboriginal Australian mitochondrial haplogroups detected appear to be ancient, with no evidence of later introgression during the Holocene. Our findings greatly increase knowledge about the geographic distribution and phylogenetic structure of mitochondrial lineages that have survived in contemporary descendants of Australia's first settlers. © The Author(s) 2017

Revising mtDNA haplotypes of the ancient Hungarian conquerors with next generation sequencing

As part of the effort to create a high resolution representative sequence database of the medieval Hungarian conquerors we have resequenced the entire mtDNA genome of 24 published ancient samples with Next Generation Sequencing, whose haplotypes had been previously determined with traditional PCR based methods. We show that PCR based methods are prone to erroneous haplotype or haplogroup determination due to ambiguous sequence reads, and many of the resequenced samples had been classified inaccurately. The SNaPshot method applied with published ancient DNA authenticity criteria is the most straightforward and cheapest PCR based approach for testing a large number of coding region SNP-s, which greatly facilitates correct haplogroup determination

Whole-genome sequencing for TB source investigations: principles of ethical precision public health

Whole-genome sequencing (WGS) of allows rapid, accurate inferences about the sources, location and timing of transmission. However, in an era of heightened concern for personal privacy and science distrust, such inferences could result in unintended harm and undermine the public´s trust. We held interdisciplinary stakeholder discussions and performed ethical analyses of real-world illustrative cases to identify principles that optimise benefit and mitigate harm of WGS-driven TB source investigations. The speed and precision with which real-time WGS can be used to associate strains with sensitive information has raised important concerns. While detailed understanding of transmission events could mitigate harm to vulnerable patients and communities when otherwise unfairly blamed for TB outbreaks, the precision of WGS can also identify transmission events resulting in social blame, fear, discrimination, individual or location stigma, and the use of defaming language by the public, politicians and scientists. Public health programmes should balance the need to safeguard privacy with public health goals, transparency and individual rights, including the right to know who infects whom or where. Ethical challenges raised by real-time WGS-driven TB source investigation requires public health authorities to move beyond their current legal mandate and embrace transparency, privacy and community&nbsp;engagement.</p

Mitochondrial DNA analysis shows a Near Eastern Neolithic origin for domestic cattle and no indication of domestication of European aurochs

The extinct aurochs (Bos primigenius primigenius) was a large type of cattle that ranged over almost the whole Eurasian continent. The aurochs is the wild progenitor of modern cattle, but it is unclear whether European aurochs contributed to this process. To provide new insights into the demographic history of aurochs and domestic cattle, we have generated high-confidence mitochondrial DNA sequences from 59 archaeological skeletal finds, which were attributed to wild European cattle populations based on their chronological date and/or morphology. All pre-Neolithic aurochs belonged to the previously designated P haplogroup, indicating that this represents the Late Glacial Central European signature. We also report one new and highly divergent haplotype in a Neolithic aurochs sample from Germany, which points to greater variability during the Pleistocene. Furthermore, the Neolithic and Bronze Age samples that were classified with confidence as European aurochs using morphological criteria all carry P haplotype mitochondrial DNA, suggesting continuity of Late Glacial and Early Holocene aurochs populations in Europe. Bayesian analysis indicates that recent population growth gives a significantly better fit to our data than a constant-sized population, an observation consistent with a postglacial expansion scenario, possibly from a single European refugial population. Previous work has shown that most ancient and modern European domestic cattle carry haplotypes previously designated T. This, in combination with our new finding of a T haplotype in a very Early Neolithic site in Syria, lends persuasive support to a scenario whereby gracile Near Eastern domestic populations, carrying predominantly T haplotypes, replaced P haplotype-carrying robust autochthonous aurochs populations in Europe, from the Early Neolithic onward. During the period of coexistence, it appears that domestic cattle were kept separate from wild aurochs and introgression was extremely rare

A genomic history of Aboriginal Australia

The population history of Aboriginal Australians remains largely uncharacterised, not least because of a lack of extensive genomic data. We generated high-coverage genomes for 83 geographically diverse Aboriginal Australians (all speakers of Pama-Nyungan languages) and 25 Papuans from the New Guinea Highlands. We find that Papuan and Aboriginal Australian ancestors diversified from each other 25-40 thousand years ago (kya), suggesting early population structure in the ancient continent of Sahul (Australia, New Guinea and Tasmania). However, all contemporary Aboriginal Australians studied descend from a single founding population that differentiated around 10-32 kya. We infer a population expansion in northeast Australia during the Holocene (past c.10 kya) associated with limited gene flow from this region to the rest of Australia. This is broadly consistent with the spread of the Pama-Nyungan languages and cultural changes taking place across the continent in the mid-Holocene. We estimate that Aboriginal Australians and Papuans diverged from Eurasians 60-100 kya, following a single out of Africa dispersal and subsequent admixture with different archaic populations. Finally, we report evidence of selection in Aboriginal Australians potentially associated with living in the desert

Climate-driven range shifts of the king penguin in a fragmented ecosystem

none10openCristofari, Robin; Liu, Xiaoming; Bonadonna, Francesco; Cherel, Yves; Pistorius, Pierre; Le Maho, Yvon; Raybaud, Virginie; Stenseth, Nils Christian; Le Bohec, Céline; Trucchi, EmilianoCristofari, Robin; Liu, Xiaoming; Bonadonna, Francesco; Cherel, Yves; Pistorius, Pierre; Le Maho, Yvon; Raybaud, Virginie; Stenseth, Nils Christian; Le Bohec, Céline; Trucchi, Emilian