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Background One-third of adults in the U.S. have metabolic syndrome, a combination of risk factors of chronic diseases such as heart disease, kidney disease, diabetes, and gout. These diseases are a burden for ethnic minorities, including Pacific Island peoples. Here, the metabolic conditions were described for a group of Pacific Island people, the CHamorus or natives of Guam, a U.S. Territory in the Mariana Islands in the Western Pacific. Methods A cross-sectional survey was conducted in Guam from August 2019 to January 2020. A non-random sample of 152 adults, ≥18 years old, with CHamoru ancestry were recruited and consented. Information collected included socio-demographics, metabolic history, lifestyle behaviors, height and weight, blood pressure, and non-fasting blood and urine. Statistical analyses included frequencies of metabolic conditions and Pearson’s Chi-square test for gender differences, alpha=0.05. Results Of the 152 CHamorus, 49.3% were male, 50% were female, and 0.7% was transgender. The mean age was 43±15.1 years. Mean education was 14.4±3.6 years and hyperuricemia he majority (69.7%) pursued postsecondary studies. Self-reported metabolic conditions included: diabetes (19.7%), gout (28.9%), hypertension (34.9%), dyslipidemia (17.8%), and heart conditions (9.9%). Compared to females, more males reported gout (40.5% versus 18.7%; P=.003) and measured to be hypertensive (48% versus 21.1%; P Conclusion Metabolic conditions were common among CHamorus, though gout, hypertension, hyperuricemia, and obesity were predominant in the men. Key messages Strategies to reduce the burden of metabolic conditions may be targeted to CHamoru men in this community.

Archaeological evidence indicates that the continent of Sahul has been continuously settled for almost as long as modern humans have lived outside of Africa. The relative isolation of the continent, and the difficulty involved in getting there, have meant that the populations have not been subject to the large-scale population replacement seen in other parts of the world. Recent advances in DNA sequencing technology, including the ability to sequence full genomes in both ancient and modern populations, have revealed that the genomes of the Indigenous peoples of Australia and New Guinea, and the local fauna, can contribute significantly to our understanding of early human migrations from Africa, human impacts on environments, as well as human evolution more broadly. Given the power of genomic data, it is of the utmost importance that genomic research of ancient and modern samples is conducted ethically, with full community consultation and engagement at all stages.

The inverted triangle shape of South America places Argentina territory as a geographical crossroads between the two principal peopling streams that followed either the Pacific or the Atlantic coasts, which could have then merged in Central Argentina (CA). Although the genetic diversity from this region is therefore crucial to decipher past population movements in South America, its characterization has been overlooked so far. We report 92 modern and 22 ancient mitogenomes spanning a temporal range of 5000 years, which were compared with a large set of previously reported data. Leveraging this dataset representative of the mitochondrial diversity of the subcontinent, we investigate the maternal history of CA populations within a wider geographical context. We describe a large number of novel clades within the mitochondrial DNA tree, thus providing new phylogenetic interpretations for South America. We also identify several local clades of great temporal depth with continuity until the present time, which stem directly from the founder haplotypes, suggesting that they originated in the region and expanded from there. Moreover, the presence of lineages characteristic of other South American regions reveals the existence of gene flow to CA. Finally, we report some lineages with discontinuous distribution across the Americas, which suggest the persistence of relic lineages likely linked to the first population arrivals. The present study represents to date the most exhaustive attempt to elaborate a Native American genetic map from modern and ancient complete mitochondrial genomes in Argentina and provides relevant information about the general process of settlement in South America., This work was supported by Agencia Nacional de Promoción de la Investigación, el Desarrollo Tecnológico y la Innovación (PICT 2007-1549, PICT 2012-711 and PICT 2015-3155), Secretaría de Ciencia y Tecnología (Universidad Nacional de Córdoba), Ministerio de Ciencia y Tecnología de la Provincia de Córdoba (PID 2018-79) and Consejo Nacional de Investigaciones Científicas y Técnicas (2015-11220150100953CO). M.P. is a postdoctoral fellow and A.G., R.N., J.M.B.M, C.M.B., M.F. and D.A.D. are research career members of CONICET, Argentina.

Simple Summary Anthropologists reconstructing the spread of domesticated animals into new regions can often rely on the archaeological remains of those animals being readily distinguishable from the remains of wild species. In southern Africa there are several wild species with bones as resemble those of cattle. Non-morphological techniques must therefore be employed to identify cattle bones in southern African archaeological sites. We have used ancient DNA analyses to identify the species of bones from four southern African archaeological that we had hoped might be those of cattle. They were not. All the analyzed specimens came from wild species. Unfortunately this means that we must await further research to identify the earliest spread of domesticated animals to southern Africa. Abstract Establishing robust temporal control of the arrival of domesticated stock and the associated husbandry skills and lifeways in Southern Africa remains frustrated by the osteological similarities between domestic stock and wild endemic fauna. We report the results of a systematic ancient DNA survey of appropriately sized bovid remains from Later Stone Age deposits in four South African archaeological sites. We show that none of the tested remains originated in domesticated cattle. The precise date of arrival of domestic cattle in the region awaits further study, although we also report new radiocarbon determinations which further refine the local chronology.

Gout is a common and treatable disease caused by the deposition of monosodium urate crystals in articular and non-articular structures. Increased concentration of serum urate (hyperuricaemia) is the most important risk factor for the development of gout. Serum urate is regulated by urate transporters in the kidney and gut, particularly GLUT9 (SLC2A9), URAT1 (SLC22A12), and ABCG2. Activation of the NLRP3 inflammasome by monosodium urate crystals with release of IL-1β plays a major role in the initiation of the gout flare; aggregated neutrophil extracellular traps are important in the resolution phase. Although presenting as an intermittent flaring condition, gout is a chronic disease. Long-term urate lowering therapy (eg, allopurinol) leads to the dissolution of monosodium urate crystals, ultimately resulting in the prevention of gout flares and tophi and in improved quality of life. Strategies such as nurse-led care are effective in delivering high-quality gout care and lead to major improvements in patient outcomes.

The Pacific region has had a complex human history. It has been subject to multiple major human dispersal and colonisation events, including some of the earliest Out-of-Africa migrations, the so-called Austronesian expansion of people out of Island Southeast Asia, and the more recent arrival of Europeans. Despite models of island isolation, evidence suggests significant levels of interconnectedness that vary in direction and frequency over time. The Pacific Ocean covers a vast area and its islands provide an array of different physical environments with variable pathogen loads and subsistence opportunities. These diverse environments likely caused Pacific peoples to adapt (both genetically and culturally) in unique ways. Differences in genetic background, in combination with adaptation, likely affect their susceptibility to non-communicable diseases.Here we provide an overview of some of the key issues in the natural and human history of the Pacific region which are likely to impact human health. We argue that understanding the evolutionary and cultural history of Pacific peoples is essential for the generation of testable hypotheses surrounding potential causes of elevated disease susceptibility among Pacific peoples.

ObjectiveMitochondria have an important role in the induction of the NLRP3 inflammasome response central in gout. The objective was to test whether mitochondrial genetic variation and copy number in New Zealand Māori and Pacific (Polynesian) people in Aotearoa New Zealand associate with susceptibility to gout.Methods437 whole mitochondrial genomes from Māori and Pacific people (predominantly men) from Aotearoa New Zealand (327 people with gout, 110 without gout) were sequenced. Mitochondrial DNA copy number variation was determined by assessing relative read depth using data produced from whole genome sequencing (32 cases, 43 controls) and targeted resequencing of urate loci (151 cases, 222 controls). Quantitative PCR was undertaken for replication of copy number findings in an extended sample set of 1159 Māori and Pacific men and women (612 cases, 547 controls).ResultsThere was relatively little mitochondrial genetic diversity, with around 96% of those sequenced in this study belonging to the B4a1a and derived sublineages. A B haplogroup heteroplasmy in hypervariable region I was found to associate with a higher risk of gout among the mitochondrial sequenced sample set (position 16181: OR=1.57, P=0.001). Increased copies of mitochondrial DNA were found to protect against gout risk with the effect being consistent when using hyperuricaemic controls across each of the three independent sample sets (OR=0.89, P=0.007; OR=0.90, P=0.002; OR=0.76, P=0.03). Paradoxically, an increase of mitochondrial DNA also associated with an increase in gout flare frequency in people with gout in the two larger sample sets used for the copy number analysis (β=0.003, P=7.1×10–7; β=0.08, P=1.2×10–4).ConclusionAssociation of reduced copy number with gout in hyperuricaemia was replicated over three Polynesian sample sets. Our data are consistent with emerging research showing that mitochondria are important for the colocalisation of the NLRP3 and ASC inflammasome subunits, a process essential for the generation of interleukin-1β in gout.

Serum urate is the end-product of purine metabolism. Elevated serum urate is causal of gout and a predictor of renal disease, cardiovascular disease and other metabolic conditions. Genome-wide association studies (GWAS) have reported dozens of loci associated with serum urate control, however there has been little progress in understanding the molecular basis of the associated loci. Here we employed trans-ancestral meta-analysis using data from European and East Asian populations to identify ten new loci for serum urate levels. Genome-wide colocalization withcis-expression quantitative trait loci (eQTL) identified a further five new loci. Bycis-andtrans-eQTL colocalization analysis we identified 24 and 20 genes respectively where the causal eQTL variant has a high likelihood that it is shared with the serum urate-associated locus. One new locus identified wasSLC22A9that encodes organic anion transporter 7 (OAT7). We demonstrate that OAT7 is a very weak urate-butyrate exchanger. Newly implicated genes identified in the eQTL analysis include those encoding proteins that make up the dystrophin complex, a scaffold for signaling proteins and transporters at the cell membrane;MLXIPthat, with the previously identifiedMLXIPL, is a transcription factor that may regulate serum urate via the pentose-phosphate pathway; andMRPS7andIDH2that encode proteins necessary for mitochondrial function. Trans-ancestral functional fine-mapping identified six loci (RREB1, INHBC, HLF, UBE2Q2, SFMBT1, HNF4G) with colocalized eQTL that contained putative causal SNPs (posterior probability of causality > 0.8). This systematic analysis of serum urate GWAS loci has identified candidate causal genes at 19 loci and a network of previously unidentified genes likely involved in control of serum urate levels, further illuminating the molecular mechanisms of urate control.Author SummaryHigh serum urate is a prerequisite for gout and a risk factor for metabolic disease. Previous GWAS have identified numerous loci that are associated with serum urate control, however, only a small handful of these loci have known molecular consequences. The majority of loci are within the non-coding regions of the genome and therefore it is difficult to ascertain how these variants might influence serum urate levels without tangible links to gene expression and / or protein function. We have applied a novel bioinformatic pipeline where we combined population-specific GWAS data with gene expression and genome connectivity information to identify putative causal genes for serum urate associated loci. Overall, we identified 15 novel serum urate loci and show that these loci along with previously identified loci are linked to the expression of 44 genes. We show that some of the variants within these loci have strong predicted regulatory function which can be further tested in functional analyses. This study expands on previous GWAS by identifying further loci implicated in serum urate control and new causal mechanisms supported by gene expression changes.

Archaeological evidence suggests that dogs were introduced to the islands of Oceania via Island Southeast Asia around 3,300 years ago, and reached the eastern islands of Polynesia by the fourteenth century AD. This dispersal is intimately tied to human expansion, but the involvement of dogs in Pacific migrations is not well understood. Our analyses of seven new complete ancient mitogenomes and five partial mtDNA sequences from archaeological dog specimens from Mainland and Island Southeast Asia and the Pacific suggests at least three dog dispersal events into the region, in addition to the introduction of dingoes to Australia. We see an early introduction of dogs to Island Southeast Asia, which does not appear to extend into the islands of Oceania. A shared haplogroup identified between Iron Age Taiwanese dogs, terminal-Lapita and post-Lapita dogs suggests that at least one dog lineage was introduced to Near Oceania by or as the result of interactions with Austronesian language speakers associated with the Lapita Cultural Complex. We did not find any evidence that these dogs were successfully transported beyond New Guinea. Finally, we identify a widespread dog clade found across the Pacific, including the islands of Polynesia, which likely suggests a post-Lapita dog introduction from southern Island Southeast Asia.

Background Mitochondria execute critical roles in diverse cellular pathways. As a danger signal mitochondria induce inflammation in response to stress through NLRP3 inflammasome activation, central to gout development. We recently reported association of reduced mtDNA copy number (CN) with prevalent gout in New Zealand Māori and Pacific (Polynesian) populations1. However the cause-effect relationship is unknown. This could be evaluated by testing for association with gout using nuclear genetic variants that associate with mtDNA CN. Objectives 1) Genome wide association study (GWAS) for mtDNA CN to identify nuclear and mitochondrial loci controlling mtDNA copy number 2) test any such loci for association with gout. Methods The mtDNA CN GWAS comprised 1340 Eastern Polynesian (EP), 816 Western Polynesian (WP) and 4579 European samples (New Zealand, Germany, The Netherlands, Scotland) genotyped on the Illumina CoreExome v24 array. 343 mitochondrial single nucleotide polymorphisms (SNPs) were evaluated. As previously described2 the median of the absolute difference in X and Y probe intensities was used as a measure of mtDNA CN, and additional 10 000 randomly selected autosomal SNPs were used to calculate the principal components (PCs). A mtDNA CN GWAS was run on chromosomes 1–22 and the mitochondrial genome using Plink 1.9 .v2, adjusting for the first 10 PCs, age and sex followed by association analysis with gout adjusting by age, sex and the first 10 PCs generated from a separate set of 3000 autosomal SNPs. Results The association of reduced mtDNA CN with gout in the EP and WP groups was reproduced but there was no evidence of association of mtDNA CN with gout in Europeans. Two genome-wide significant (p Conclusions That genetic variants associated with mitochondrial copy number also associate with gout provides evidence for a potential causal role of mitochondrial copy number in gout. However, the nuclear genetic variants support a causal relation of increased mtDNA CN with gout, conflicting with our previous observational report of association of reduced mtDNA CN with gout1. References [1] Gosling A, et al. Mitochondrial genetic variation and gout in Māori and Pacific people living in Aotearoa New Zealand. Ann Rheum Dis2017Dec 15. [Epub ahead of print]. [2] Asher FN, et al. Association of mitochondrial DNA levels with frailty and all-cause mortality. J Mol Med2015;93:177–86. Disclosure of Interest None declared

Understanding the timing and processes involved in the human settlement of Australia and the Pacific has significance for addressing some key debates relating to human origins and population expansions worldwide. Despite this, for many years, Pacific populations were seriously under-represented in genetic studies of human origins. The last 15 years, however, have seen some major genetic studies involving Australian and Pacific populations which have shed light on their origins and interactions, and the last five years have seen some major developments that are challenging long-held concepts of Pacific settlement.

The Phoenicians emerged in the Northern Levant around 1800 BCE and by the 9th century BCE had spread their culture across the Mediterranean Basin, establishing trading posts, and settlements in various European Mediterranean and North African locations. Despite their widespread influence, what is known of the Phoenicians comes from what was written about them by the Greeks and Egyptians. In this study, we investigate the extent of Phoenician integration with the Sardinian communities they settled. We present 14 new ancient mitogenome sequences from pre-Phoenician (~1800 BCE) and Phoenician (~700–400 BCE) samples from Lebanon (n = 4) and Sardinia (n = 10) and compare these with 87 new complete mitogenomes from modern Lebanese and 21 recently published pre-Phoenician ancient mitogenomes from Sardinia to investigate the population dynamics of the Phoenician (Punic) site of Monte Sirai, in southern Sardinia. Our results indicate evidence of continuity of some lineages from pre-Phoenician populations suggesting integration of indigenous Sardinians in the Monte Sirai Phoenician community. We also find evidence of the arrival of new, unique mitochondrial lineages, indicating the movement of women from sites in the Near East or North Africa to Sardinia, but also possibly from non-Mediterranean populations and the likely movement of women from Europe to Phoenician sites in Lebanon. Combined, this evidence suggests female mobility and genetic diversity in Phoenician communities, reflecting the inclusive and multicultural nature of Phoenician society.

Pacific populations have long been observed to suffer a high burden of metabolic disease, including obesity, type 2 diabetes and gout. The 'Thrifty Genotype' hypothesis has frequently been used to explain this high prevalence of disease. Here, the 'Thrifty Genotype' hypothesis and the evolutionary background of Pacific populations are examined. We question its relevance not only in the Pacific region but more generally. Not only has the hypothesis not been explicitly tested, but most archaeological and anthropological data from the Pacific fundamentally do not support its application.

Biological anthropological research, the study of both modern and past humans, is a burgeoning field in the Indo-Pacific region. It is becoming increasingly apparent that the unique environments of the Indo-Pacific have resulted in an archaeological record that does not necessarily align with those in the northern hemisphere. New, regionally-specific archaeological models are being developed, and biological anthropological research has an important role to play in establishing past human experience within these models. In the Indo-Pacific, research using ancient and modern human tissues is adding insight into global processes of prehistoric settlement and migrations, subsistence change and human biosocial adaptation. This review synthesises current themes in biological anthropology in this region. It highlights the diverse methods and approaches used by biological anthropologists to address globally-relevant archaeological questions. In recent decades a collaborative approach between archaeologists, biological anthropologists and local communities has become the norm in the region. The many positive outcomes of this multi-disciplinary approach are highlighted here through the use of regionally-specific case studies. This review ultimately aims to stimulate further collaborations between archaeologists, biological anthropologists and the communities in the region, and demonstrate how the evidence from Indo-Pacific research may be relevant to global archaeological models.

Large numbers of domestic stock have been reported among the faunal remains recovered from archaeological sites with predominantly forager-associated material culture in the highlands of Lesotho. These remains, in conjunction with the presence of artefacts of apparent agropastoralist origin, have led to the suggestion that either a process of neolithisation saw the adoption of livestock-keeping by traditionally foraging peoples, or that extensive contact and trade occurred between foraging groups in the mountains and distant agropastoralist communities. We present here ancient DNA evidence that the frequency of domestic stock in the faunal assemblages has been significantly overestimated and that, as a consequence, the nature of the relationships between highland foragers and agropastoralists has been misconstrued.

Pacific populations have long been observed to suffer a high burden of metabolic disease, including obesity, type 2 diabetes and gout. The 'Thrifty Genotype' hypothesis has frequently been used to explain this high prevalence of disease. Here, the 'Thrifty Genotype' hypothesis and the evolutionary background of Pacific populations are examined. We question its relevance not only in the Pacific region but more generally. Not only has the hypothesis not been explicitly tested, but most archaeological and anthropological data from the Pacific fundamentally do not support its application.

Pacific Island populations, particularly those of Polynesian descent, have a high prevalence of hyperuricaemia and gout. This is due to an inherently higher urate level among these populations with a demonstrated genetic predisposition. While an excess of urate can cause pathology, urate is also important for human health. It has been implicated as an antioxidant, has a neuroprotective role and is involved in innate immune responses. This paper provides a brief review of urate levels worldwide, with a particular focus on island Southeast Asia and the Pacific. We then present possible evolutionary explanations for the elevated serum urate levels among Pacific populations in the context of the physiological importance of urate and of the settlement history of the region. Finally, we propose that ancestry may play a significant role in hyperuricaemia in these populations and that exposure to malaria prior to population expansion into the wider Pacific may have driven genetic selection for variants contributing to high serum urate.

Background Mitochondria appear to play a central role in the induction of an NLRP3 inflammatory response, an immune response critical for the development of gouty pathology. Mitochondria are in part self-encoding, possessing a 16.5 kB circular genome which encodes 36 genes. Therefore mitochondrial genetic variation may contribute to susceptibility to gout. Objectives The objective of this study was to test whether mitochondrial genetic variation and copy number among New Zealand Polynesians may be contributing to susceptibility to gout. The Māori and Pacific (Polynesian) populations of New Zealand exhibit a high prevalence of gout (6 and 8%, respectively). Methods 439 whole mitochondrial genomes belonging to Māori and Pacific men from New Zealand (327 cases, 112 controls) were sequenced to explore whether mitochondrial DNA (mtDNA) variation may contribute risk to gout. mtDNA copy number variation was also investigated by looking at relative read depth using Next Generation Sequencing data produced from whole genome sequencing and resequencing of urate loci. Quantitative PCR was undertaken for replication in an extended sample set of 540 Polynesian male and female cases and 530 controls. Results Within Polynesia, there is relatively little mitochondrial genetic diversity, with around 96% of those sequenced in this study belonging to the B4a1a and derived sub-lineages. A lineage-specific heteroplasmy in hypervariable region I was found to associate with a greater than three-fold higher risk of gout among the mitochondrial sequenced sample set (e.g. heteroplasmy at position 16179: OR 3.28, P =0.009; heteroplasmy at position 16181: 3.86, P =9x10 –5 ; heteroplasmy at position 16182: 3.43, P =0.005). Quantitative PCR of mtDNA from the 1070 Polynesian gout cases and controls showed that individuals with gout possess less mtDNA, on average than healthy controls. With each unit increase in ΔCt (which reflects a decrease in mtDNA content), there was a 33% increase in gout risk (OR 1.33, P =0.003). The effect was stronger when looking at those participants who possessed urate levels exceeding 0.40 mmol L –1 (n=422, OR 1.69, P =0.0005). References It is unclear whether the reduced mtDNA copy number in gout is a result of the gouty pathology directly (i.e. the reduced mtDNA copy number is caused by the inflammatory processes underlying gout) or whether the reduced mtDNA copy number contributes to the risk of gout. The latter possibility is supported by the increase in risk using hyperuricemic controls suggesting that reduced mtDNA copy number plays a role in inflammation. Given emerging research is showing that mitochondria play a central role in the induction of the NLRP3 inflammasome, in particular with the co-localisation of the NLRP3 and ASC sub-units, a process essential for the generation of IL-1β, these observations may be significant. Exploring mitochondrial genetic variation may further elucidate the inflammatory processes underlying gout. Acknowledgement The New Zealand Health Research Council, Lottery Health New Zealand, Arthritis New Zealand and the National Institute of Health (United States) are thanked for funding this study. Disclosure of Interest T. Merriman Grant/research support from: ArdeaBio, A. Gosling: None declared, J. Boocock: None declared, N. Dalbeth Grant/research support from: AstraZeneca, Fonterra, ArdeaBio, Consultant for: Menarini, Takeda, Teijin, Pfizer, Crealta, Cymabay, L. Stamp: None declared, E. Stahl: None declared, H. Choi: None declared, L. Matisoo-Smith: None declared

Domesticated cattle were commonplace in northern Africa by about 7,000 years ago. Archaeological evidence, however, suggests they were not established in southern Africa until much later, no earlier than 2,000 years ago. Genetic reconstructions have started to shed light on the movement of African cattle, but efforts have been frustrated by a lack of data south of Ethiopia and the nature of the mitochondrial haplogroup T1 which is almost fixed across the continent. We sequenced 35 complete mitochondrial genomes from a South African herd of Nguni cattle, a breed historically associated with Bantu speaking farmers who were among the first to bring cattle to southern Africa. As expected, all individuals in the study were found to be members of haplogroup T1. Only half of the sub-haplogroups of T1 (T1a-T1f) are represented in our sample and the overwhelming majority (94%) in this study belong to subhaplogroup T1b. A previous study of African cattle found frequencies of T1b of 27% in Egypt and 69% in Ethiopia. These results are consistent with serial multiple founder effects significantly shaping the gene pool as cattle were moved from north to south across the continent. Interestingly, these mitochondrial data give no indication that the impacts of the founder effects were ameliorated by gene flow from recently introduced Indian cattle breeds.