Is the UN receiving ethical approval for its research with human participants?

This paper examines the institutional mechanisms supporting the ethical oversight of human participant research conducted by the United Nations (UN). The UN has served an instrumental role in shaping international standards on research ethics, which invariably require ethical oversight of all research studies with human participants. The authors' experiences of conducting research collaboratively with UN agencies, in contrast, have led to concern that the UN frequently sponsors, or participates in, studies with human participants that have not received appropriate ethical oversight. It is argued that the institutional mechanisms in place to prevent research with human participants from being undertaken by the UN without ethical oversight do not, at present, extend substantively beyond the provision of guidelines and online training offered by a minority of UN bodies. The WHO and UNICEF are identified as notable exceptions, having implemented various measures to prevent health research with human participants from being undertaken without ethical oversight. Yet, it is highlighted that the WHO and UNICEF are not the only UN bodies that undertake health research with human participants and there are countless actors under the umbrella of the UN system that are regularly involved in non-health research with human participants. Arguments for the pursuit of the highest standard of ethical oversight by UN bodies are presented. Moving forward, the paper asks the question: is it time for the UN to set the standards for the oversight of ethical oversight?

Knowledge, Expertise and Science Advice During COVID-19: In Search of Epistemic Justice for the 'Wicked' Problems of Post-Normal Times.

A consistent claim from governments around the world during the Coronavirus pandemic has been that they were following the science. This raises the question, central to this paper, of what and whose knowledge is or should be sought, which is being side-lined through the choice of particular framings and discourses, and with what consequences for the creation and implementation of evidence-based policy to tackle wicked problems. Through the lens of Fricker's epistemic injustice, I problematise the expertise that has guided the COVID-19 response as epistemically narrow and argue that counteracting a monolithic culture of expertise requires tackling the structural inequalities in the systems of knowledge production to diversify the social and epistemological foundations of science. Drawing on Post-normal Science (PNS) theory, I suggest that the expertise needed to respond to the challenges of a post-COVID world is one that embraces greater pluralism, avoids groupthink, challenges the accepted orthodoxy and helps us revert old models and rigid path dependencies that so often neglect the lived realities and demands of those left behind. This can only be realised by overcoming epistemic injustice and embracing epistemic democracy in the practice of evidence-based policy.

The Post-Normal Challenges of COVID-19: Constructing Effective and Legitimate Responses.

The ongoing COVID-19 emergency clearly presents novel challenges, both in terms of difficulties for maintaining public health and in assuring that governmental responses are ethically sound. Centrally, responses must respect, as best as possible, fundamental human rights and human values. Conflicts among values arise in response to the crisis, and public officials have no choice but to prioritize some while sacrificing others. Utilizing the concepts of effectiveness and legitimacy within the framework of post-normal science (PNS), we investigate and recommend processes and measures to address COVID-19 that support increased public health, while upholding established rights and values. The effectiveness and legitimacy of science-led policymaking requires investigation of how that policy ought to be made (e.g. concepts of policymaking and PNS), as well as how it ought to interact with diversely-constituted publics (e.g. public inclusion in policymaking and policy communication).

'Capacity for what? Capacity for whom?' A decolonial deconstruction of research capacity development practices in the Global South and a proposal for a value-centred approach.

Whilst North to South knowledge transfer patterns have been extensively problematised by Southern and decolonial perspectives, there is very little reflection on the practice of research capacity development (RCD), still strongly focused on technoscientific solutionism, yet largely uncritical of its underlying normative directions and power asymmetries. Without making transparent these normative and epistemological dimensions, RCD practices will continue to perpetuate approaches that are likely to be narrow, technocratic and unreflexive of colonial legacies, thus failing to achieve the aims of RCD, namely, the equitable and development-oriented production of knowledge in low- and middle-income societies. Informed by the authors' direct experience of RCD approaches and combining insights from decolonial works and other perspectives from the margins with Science and Technology Studies, the paper undertakes a normative and epistemological deconstruction of RCD mainstream practice. Highlighting asymmetries of power and material resources in knowledge production, the paper's decolonial lens seeks to aid the planning, implementation and evaluation of RCD interventions. Principles of cognitive justice and epistemic pluralism, accessibility enabled by systems thinking and sustainability grounded on localisation are suggested as the building blocks for more reflexive and equitable policies that promote research capacity for the purpose of creating social value and not solely for the sake of perpetuating technoscience.

Science, Technology and Innovation as Social Goods for Development: Rethinking Research Capacity Building from Sen's Capabilities Approach.

Science and technology are key to economic and social development, yet the capacity for scientific innovation remains globally unequally distributed. Although a priority for development cooperation, building or developing research capacity is often reduced in practice to promoting knowledge transfers, for example through North-South partnerships. Research capacity building/development tends to focus on developing scientists' technical competencies through training, without parallel investments to develop and sustain the socioeconomic and political structures that facilitate knowledge creation. This, the paper argues, significantly contributes to the scientific divide between developed and developing countries more than any skills shortage. Using Charles Taylor's concept of irreducibly social goods, the paper extends Sen's Capabilities Approach beyond its traditional focus on individual entitlements to present a view of scientific knowledge as a social good and the capability to produce it as a social capability. Expanding this capability requires going beyond current fragmented approaches to research capacity building to holistically strengthen the different social, political and economic structures that make up a nation's innovation system. This has implications for the interpretation of human rights instruments beyond their current focus on access to knowledge and for focusing science policy and global research partnerships to design approaches to capacity building/development beyond individual training/skills building.

A conceptual framework for training of trainers (ToT) interventions in global health.

BACKGROUND: Global health partnerships (GHP) between high or low-middle income countries are considered one of the best approaches to health systems strengthening. They typically involve highly skilled healthcare workers who volunteer to deliver capacity strengthening projects overseas, often in the form of peer-to-peer support through training and mentoring. Given GHP's strong focus on education and training, a common assumption is that training of trainers (ToT) is a strong predictor of sustainability because of its potential for up-skilling the workforce rapidly, cheaply and exponentially by developing local educators. Our aim is to test this assumption and identify the strengths and limitations of this approach by analysing qualitative data from a set of GHP funded by the UK Department for International Development through the Tropical Health and Education Trust. RESULTS: Our analysis identifies some of the common features of the ToT model and a number of limitations that can prevent it from being both effective and sustainable. Whilst most GHP strive for the long-term sustainability of the training by focusing on adequate training provision and support of local trainers, the wider issues that can facilitate or prevent the continuation of training are not always considered. We propose a conceptual framework (TRAIN) for ToT interventions to help inform practice and project evaluation. We illustrate the applicability of our framework through five case studies, each chosen to illustrate one aspect of the framework. CONCLUSIONS: TRAIN is intended as a starting point for further refinements and discussions about the factors affecting capacity building strategies based on training cascades. Although we envisage its usefulness to GHP as a guidance to design and operationalise ToT, we recognise that in practice it may be difficult to implement it in its entirety. The key message underlying TRAIN is that the sustainability of a cascade depends on a number of factors being present or developing at different operational levels during the course of a project. These are crucial to transform the opportunities that ToT affords to health systems in developing countries into the actual achievement of a training cascade that ultimately upskills the workforce and improves health outcomes in these countries.

Evidence of Early-Stage Selection on EPAS1 and GPR126 Genes in Andean High Altitude Populations.

The aim of this study is to identify genetic variants that harbour signatures of recent positive selection and may facilitate physiological adaptations to hypobaric hypoxia. To achieve this, we conducted whole genome sequencing and lung function tests in 19 Argentinean highlanders (>3500 m) comparing them to 16 Native American lowlanders. We developed a new statistical procedure using a combination of population branch statistics (PBS) and number of segregating sites by length (nSL) to detect beneficial alleles that arose since the settlement of the Andes and are currently present in 15-50% of the population. We identified two missense variants as significant targets of selection. One of these variants, located within the GPR126 gene, has been previously associated with the forced expiratory volume/forced vital capacity ratio. The other novel missense variant mapped to the EPAS1 gene encoding the hypoxia inducible factor 2α. EPAS1 is known to be the major selection candidate gene in Tibetans. The derived allele of GPR126 is associated with lung function in our sample of highlanders (p < 0.05). These variants may contribute to the physiological adaptations to hypobaric hypoxia, possibly by altering lung function. The new statistical approach might be a useful tool to detect selected variants in population studies.

Selective sweep on human amylase genes postdates the split with Neanderthals.

Humans have more copies of amylase genes than other primates. It is still poorly understood, however, when the copy number expansion occurred and whether its spread was enhanced by selection. Here we assess amylase copy numbers in a global sample of 480 high coverage genomes and find that regions flanking the amylase locus show notable depression of genetic diversity both in African and non-African populations. Analysis of genetic variation in these regions supports the model of an early selective sweep in the human lineage after the split of humans from Neanderthals which led to the fixation of multiple copies of AMY1 in place of a single copy. We find evidence of multiple secondary losses of copy number with the highest frequency (52%) of a deletion of AMY2A and associated low copy number of AMY1 in Northeast Siberian populations whose diet has been low in starch content.

Erratum to: Quantifying the legacy of the Chinese Neolithic on the maternal genetic heritage of Taiwan and Island Southeast Asia.

In the original article, one of the co-authors' (Ken Khong Eng) given name has been published incorrectly. The correct given name should be Ken Khong. The original article has been corrected.

Quantifying the legacy of the Chinese Neolithic on the maternal genetic heritage of Taiwan and Island Southeast Asia.

There has been a long-standing debate concerning the extent to which the spread of Neolithic ceramics and Malay-Polynesian languages in Island Southeast Asia (ISEA) were coupled to an agriculturally driven demic dispersal out of Taiwan 4000 years ago (4 ka). We previously addressed this question using founder analysis of mitochondrial DNA (mtDNA) control-region sequences to identify major lineage clusters most likely to have dispersed from Taiwan into ISEA, proposing that the dispersal had a relatively minor impact on the extant genetic structure of ISEA, and that the role of agriculture in the expansion of the Austronesian languages was therefore likely to have been correspondingly minor. Here we test these conclusions by sequencing whole mtDNAs from across Taiwan and ISEA, using their higher chronological precision to resolve the overall proportion that participated in the "out-of-Taiwan" mid-Holocene dispersal as opposed to earlier, postglacial expansions in the Early Holocene. We show that, in total, about 20% of mtDNA lineages in the modern ISEA pool result from the "out-of-Taiwan" dispersal, with most of the remainder signifying earlier processes, mainly due to sea-level rises after the Last Glacial Maximum. Notably, we show that every one of these founder clusters previously entered Taiwan from China, 6-7 ka, where rice-farming originated, and remained distinct from the indigenous Taiwanese population until after the subsequent dispersal into ISEA.

Resolving the ancestry of Austronesian-speaking populations.

There are two very different interpretations of the prehistory of Island Southeast Asia (ISEA), with genetic evidence invoked in support of both. The "out-of-Taiwan" model proposes a major Late Holocene expansion of Neolithic Austronesian speakers from Taiwan. An alternative, proposing that Late Glacial/postglacial sea-level rises triggered largely autochthonous dispersals, accounts for some otherwise enigmatic genetic patterns, but fails to explain the Austronesian language dispersal. Combining mitochondrial DNA (mtDNA), Y-chromosome and genome-wide data, we performed the most comprehensive analysis of the region to date, obtaining highly consistent results across all three systems and allowing us to reconcile the models. We infer a primarily common ancestry for Taiwan/ISEA populations established before the Neolithic, but also detected clear signals of two minor Late Holocene migrations, probably representing Neolithic input from both Mainland Southeast Asia and South China, via Taiwan. This latter may therefore have mediated the Austronesian language dispersal, implying small-scale migration and language shift rather than large-scale expansion.

Positive selection of AS3MT to arsenic water in Andean populations.

Arsenic is a carcinogen associated with skin lesions and cardiovascular diseases. The Colla population from the Puna region in Northwest Argentinean is exposed to levels of arsenic in drinking water exceeding the recommended maximum by a factor of 20. Yet, they thrive in this challenging environment since thousands of years and therefore we hypothesize strong selection signatures in genes involved in arsenic metabolism. We analyzed genome-wide genotype data for 730,000 loci in 25 Collas, considering 24 individuals of the neighbouring Calchaquíes and 24 Wichí from the Gran Chaco region in the Argentine province of Salta as control groups. We identified a strong signal of positive selection in the main arsenic methyltransferase AS3MT gene, which has been previously associated with lower concentrations of the most toxic product of arsenic metabolism monomethylarsonic acid. This study confirms recent studies reporting selection signals in the AS3MT gene albeit using different samples, tests and control populations.

Mosaic maternal ancestry in the Great Lakes region of East Africa.

The Great Lakes lie within a region of East Africa with very high human genetic diversity, home of many ethno-linguistic groups usually assumed to be the product of a small number of major dispersals. However, our knowledge of these dispersals relies primarily on the inferences of historical, linguistics and oral traditions, with attempts to match up the archaeological evidence where possible. This is an obvious area to which archaeogenetics can contribute, yet Uganda, at the heart of these developments, has not been studied for mitochondrial DNA (mtDNA) variation. Here, we compare mtDNA lineages at this putative genetic crossroads across 409 representatives of the major language groups: Bantu speakers and Eastern and Western Nilotic speakers. We show that Uganda harbours one of the highest mtDNA diversities within and between linguistic groups, with the various groups significantly differentiated from each other. Despite an inferred linguistic origin in South Sudan, the data from the two Nilotic-speaking groups point to a much more complex history, involving not only possible dispersals from Sudan and the Horn but also large-scale assimilation of autochthonous lineages within East Africa and even Uganda itself. The Eastern Nilotic group also carries signals characteristic of West-Central Africa, primarily due to Bantu influence, whereas a much stronger signal in the Western Nilotic group suggests direct West-Central African ancestry. Bantu speakers share lineages with both Nilotic groups, and also harbour East African lineages not found in Western Nilotic speakers, likely due to assimilating indigenous populations since arriving in the region ~3000 years ago.

Genetic and phenotypic differentiation of an Andean intermediate altitude population.

Highland populations living permanently under hypobaric hypoxia have been subject of extensive research because of the relevance of their physiological adaptations for the understanding of human health and disease. In this context, what is considered high altitude is a matter of interpretation and while the adaptive processes at high altitude (above 3000 m) are well documented, the effects of moderate altitude (below 3000 m) on the phenotype are less well established. In this study, we compare physiological and anthropometric characteristics as well as genetic variations in two Andean populations: the Calchaquíes (2300 m) and neighboring Collas (3500 m). We compare their phenotype and genotype to the sea-level Wichí population. We measured physiological (heart rate, oxygen saturation, respiration rate, and lung function) as well as anthropometric traits (height, sitting height, weight, forearm, and tibia length). We conducted genome-wide genotyping on a subset of the sample (n = 74) and performed various scans for positive selection. At the phenotypic level (n = 179), increased lung capacity stood out in both Andean groups, whereas a growth reduction in distal limbs was only observed at high altitude. At the genome level, Calchaquíes revealed strong signals around PRKG1, suggesting that the nitric oxide pathway may be a target of selection. PRKG1 was highlighted by one of four selection tests among the top five genes using the population branch statistic. Selection tests results of Collas were reported previously. Overall, our study shows that some phenotypic and genetic differentiation occurs at intermediate altitude in response to moderate lifelong selection pressures.

A recent bottleneck of Y chromosome diversity coincides with a global change in culture.

It is commonly thought that human genetic diversity in non-African populations was shaped primarily by an out-of-Africa dispersal 50-100 thousand yr ago (kya). Here, we present a study of 456 geographically diverse high-coverage Y chromosome sequences, including 299 newly reported samples. Applying ancient DNA calibration, we date the Y-chromosomal most recent common ancestor (MRCA) in Africa at 254 (95% CI 192-307) kya and detect a cluster of major non-African founder haplogroups in a narrow time interval at 47-52 kya, consistent with a rapid initial colonization model of Eurasia and Oceania after the out-of-Africa bottleneck. In contrast to demographic reconstructions based on mtDNA, we infer a second strong bottleneck in Y-chromosome lineages dating to the last 10 ky. We hypothesize that this bottleneck is caused by cultural changes affecting variance of reproductive success among males.

The Andean adaptive toolkit to counteract high altitude maladaptation: genome-wide and phenotypic analysis of the Collas.

During their migrations out of Africa, humans successfully colonised and adapted to a wide range of habitats, including extreme high altitude environments, where reduced atmospheric oxygen (hypoxia) imposes a number of physiological challenges. This study evaluates genetic and phenotypic variation in the Colla population living in the Argentinean Andes above 3500 m and compares it to the nearby lowland Wichí group in an attempt to pinpoint evolutionary mechanisms underlying adaptation to high altitude hypoxia. We genotyped 730,525 SNPs in 25 individuals from each population. In genome-wide scans of extended haplotype homozygosity Collas showed the strongest signal around VEGFB, which plays an essential role in the ischemic heart, and ELTD1, another gene crucial for heart development and prevention of cardiac hypertrophy. Moreover, pathway enrichment analysis showed an overrepresentation of pathways associated with cardiac morphology. Taken together, these findings suggest that Colla highlanders may have evolved a toolkit of adaptative mechanisms resulting in cardiac reinforcement, most likely to counteract the adverse effects of the permanently increased haematocrit and associated shear forces that characterise the Andean response to hypoxia. Regulation of cerebral vascular flow also appears to be part of the adaptive response in Collas. These findings are not only relevant to understand the evolution of hypoxia protection in high altitude populations but may also suggest new avenues for medical research into conditions where hypoxia constitutes a detrimental factor.

Genetic diversity and evidence for population admixture in Batak Negritos from Palawan.

Anthropologists have long been fascinated by the isolated hunter-gatherer populations in Southeast Asia (SEA) collectively known as "Negritos." However, the origins and affinities of these groups remain unresolved. Negritos are characterized by their short stature, dark skin color, and wiry hair, and they inhabit the Philippines, Malay Peninsula, and the Andaman Islands. Among Philippine Negritos, the Batak are of particular interest in understanding population interactions in the region due to their location on Palawan Island, which likely formed a corridor by which human migrations entered the rest of the Philippine archipelago from Island SEA. Here, we extend current understanding of the distribution of genetic diversity in Negritos by presenting the first analysis of mitochondrial DNA and Y-chromosome diversity among the Batak. We show that the Batak are genetically distinct from Negritos of the Andaman Islands and Malay Peninsula and instead bear most resemblance to geographically proximate Philippine Negritos and to non-Negrito populations from the Philippines and Island SEA. An extensive degree of recent admixture between the Batak and their neighbors is indicated by the high frequency of recently coalescing haplogroups in the Batak that are found throughout Island SEA. The comparison of results from these two loci further lends support to the hypothesis that male-biased admixture has, in particular, been a prominent feature of the interactions between the Batak and surrounding non-Negrito populations.

Ancient voyaging and Polynesian origins.

The "Polynesian motif" defines a lineage of human mtDNA that is restricted to Austronesian-speaking populations and is almost fixed in Polynesians. It is widely thought to support a rapid dispersal of maternal lineages from Taiwan ~4000 years ago (4 ka), but the chronological resolution of existing control-region data is poor, and an East Indonesian origin has also been proposed. By analyzing 157 complete mtDNA genomes, we show that the motif itself most likely originated >6 ka in the vicinity of the Bismarck Archipelago, and its immediate ancestor is >8 ka old and virtually restricted to Near Oceania. This indicates that Polynesian maternal lineages from Island Southeast Asia gained a foothold in Near Oceania much earlier than dispersal from either Taiwan or Indonesia 3-4 ka would predict. However, we find evidence in minor lineages for more recent two-way maternal gene flow between Island Southeast Asia and Near Oceania, likely reflecting movements along a "voyaging corridor" between them, as previously proposed on archaeological grounds. Small-scale mid-Holocene movements from Island Southeast Asia likely transmitted Austronesian languages to the long-established Southeast Asian colonies in the Bismarcks carrying the Polynesian motif, perhaps also providing the impetus for the expansion into Polynesia.

Complete mitochondrial DNA sequences provide new insights into the Polynesian motif and the peopling of Madagascar.

More than a decade of mitochondrial DNA (mtDNA) studies have given the 'Polynesian motif' renowned status as a marker for tracing the late-Holocene expansion of Austronesian speaking populations. Despite considerable research on the Polynesian motif in Oceania, there has been little equivalent work on the western edge of its expansion - leaving major issues unresolved regarding the motif's evolutionary history. This has also led to considerable uncertainty regarding the settlement of Madagascar. In this study, we assess mtDNA variation in 266 individuals from three Malagasy ethnic groups: the Mikea, Vezo, and Merina. Complete mtDNA genome sequencing reveals a new variant of the Polynesian motif in Madagascar; two coding region mutations define a Malagasy-specific sub-branch. This newly defined 'Malagasy motif' occurs at high frequency in all three ethnic groups (13-50%), and its phylogenetic position, geographic distribution, and estimated age all support a recent origin, but without conclusively identifying a specific source region. Nevertheless, the haplotype's limited diversity, similar to those of other mtDNA haplogroups found in our Malagasy groups, best supports a small number of initial settlers arriving to Madagascar through the same migratory process. Finally, the discovery of this lineage provides a set of new polymorphic positions to help localize the Austronesian ancestors of the Malagasy, as well as uncover the origin and evolution of the Polynesian motif itself.

A new deep branch of eurasian mtDNA macrohaplogroup M reveals additional complexity regarding the settlement of Madagascar.

BACKGROUND: Current models propose that mitochondrial DNA macrohaplogroups M and N evolved from haplogroup L3 soon after modern humans left Africa. Increasingly, however, analysis of isolated populations is filling in the details of, and in some cases challenging, aspects of this general model. RESULTS: Here, we present the first comprehensive study of three such isolated populations from Madagascar: the Mikea hunter-gatherers, the neighbouring Vezo fishermen, and the Merina central highlanders (n = 266). Complete mitochondrial DNA genome sequences reveal several unresolved lineages, and a new, deep branch of the out-of-Africa founder clade M has been identified. This new haplogroup, M23, has a limited global distribution, and is restricted to Madagascar and a limited range of African and Southwest Asian groups. CONCLUSIONS: The geographic distribution, phylogenetic placement and molecular age of M23 suggest that the colonization of Madagascar was more complex than previously thought.