Going local with ancient DNA: A review of human histories from regional perspectives.

Ancient DNA (aDNA) has added a wealth of information about our species' history, including insights on genetic origins, migrations and gene flow, genetic admixture, and health and disease. Much early work has focused on continental-level questions, leaving many regional questions, especially those relevant to the Global South, comparatively underexplored. A few success stories of aDNA studies from smaller laboratories involve more local aspects of human histories and health in the Americas, Africa, Asia, and Oceania. In this Review, we cover some of these contributions by synthesizing finer-scale questions of importance to the archaeogenetics field, as well as to Indigenous and Descendant communities. We further highlight the potential of aDNA to uncover past histories in regions where colonialism has neglected the oral histories of oppressed peoples.

Simulation-based Benchmarking of Ancient Haplotype Inference for Detecting Population Structure.

Paleogenomic data has informed us about the movements, growth, and relationships of ancient populations. It has also given us context for medically relevant adaptations that appear in present-day humans due to introgression from other hominids, and it continues to help us characterize the evolutionary history of humans. However, ancient DNA (aDNA) presents several practical challenges as various factors such as deamination, high fragmentation, environmental contamination of aDNA, and low amounts of recoverable endogenous DNA, make aDNA recovery and analysis more difficult than modern DNA. Most studies with aDNA leverage only SNP data, and only a few studies have made inferences on human demographic history based on haplotype data, possibly because haplotype estimation (or phasing) has not yet been systematically evaluated in the context of aDNA. Here, we evaluate how the unique challenges of aDNA can impact phasing quality. We also develop a software tool that simulates aDNA taking into account the features of aDNA as well as the evolutionary history of the population. We measured phasing error as a function of aDNA quality and demographic history, and found that low phasing error is achievable even for very ancient individuals (~ 400 generations in the past) as long as contamination and read depth are adequate. Our results show that population splits or bottleneck events occurring between the reference and phased populations affect phasing quality, with bottlenecks resulting in the highest average error rates. Finally, we found that using estimated haplotypes, even if not completely accurate, is superior to using the simulated genotype data when reconstructing changes in population structure after population splits between present-day and ancient populations.

The MUC19 gene in Denisovans, Neanderthals, and Modern Humans: An Evolutionary History of Recurrent Introgression and Natural Selection.

All humans carry a small fraction of archaic ancestry across the genome, the legacy of gene flow from Neanderthals, Denisovans, and other hominids into the ancestors of modern humans. While the effects of Neanderthal ancestry on human fitness and health have been explored more thoroughly, there are fewer examples of adaptive introgression of Denisovan variants. Here, we study the gene MUC19, for which some modern humans carry a Denisovan-like haplotype. MUC19 is a mucin, a glycoprotein that forms gels with various biological functions, from lubrication to immunity. We find the diagnostic variants for the Denisovan-like MUC19 haplotype at high frequencies in admixed Latin American individuals among global population, and at highest frequency in 23 ancient Indigenous American individuals, all predating population admixture with Europeans and Africans. We find that some Neanderthals--Vindija and Chagyrskaya--carry the Denisovan-like MUC19 haplotype, and that it was likely introgressed into human populations through Neanderthal introgression rather than Denisovan introgression. Finally, we find that the Denisovan-like MUC19 haplotype carries a higher copy number of a 30 base-pair variable number tandem repeat relative to the Human-like haplotype, and that copy numbers of this repeat are exceedingly high in American populations. Our results suggest that the Denisovan-like MUC19 haplotype served as the raw genetic material for positive selection as American populations adapted to novel environments during their movement from Beringia into North and then South America.

The ancestry and geographical origins of St Helena's liberated Africans.

The island of St Helena played a crucial role in the suppression of the transatlantic slave trade. Strategically located in the middle of the South Atlantic, it served as a staging post for the Royal Navy and reception point for enslaved Africans who had been "liberated" from slave ships intercepted by the British. In total, St Helena received approximately 27,000 liberated Africans between 1840 and 1867. Written sources suggest that the majority of these individuals came from West Central Africa, but their precise origins are unknown. Here, we report the results of ancient DNA analyses that we conducted as part of a wider effort to commemorate St Helena's liberated Africans and to restore knowledge of their lives and experiences. We generated partial genomes (0.1-0.5×) for 20 individuals whose remains had been recovered during archaeological excavations on the island. We compared their genomes with genotype data for over 3,000 present-day individuals from 90 populations across sub-Saharan Africa and conclude that the individuals most likely originated from different source populations within the general area between northern Angola and Gabon. We also find that the majority (17/20) of the individuals were male, supporting a well-documented sex bias in the latter phase of the transatlantic slave trade. The study expands our understanding of St Helena's liberated African community and illustrates how ancient DNA analyses can be used to investigate the origins and identities of individuals whose lives were bound up in the story of slavery and its abolition.

Towards an ethical and legal framework in archeogenomics: A local case in the Atlantic coast of central Patagonia.

Ethical discussions around ancient DNA (aDNA) research predate the technological breakthroughs that led to the accelerated generation of ancient genomic data, revealing a long-due need to address these aspects in the field. Given the diverse conflicts that genomics has raised towards the communities associated with the Non-living Human Ancestors under study, it has been suggested that the ethical and legal implications of genetically studying present-day and ancient human populations should be considered case-by-case. Nevertheless, the discussions have focused on US and European perspectives. To contribute from a local and Latin American position to the problem, we present the history of consensus and disagreement of the relationships between scientists and Indigenous communities of the Atlantic coast of the central Argentinian Patagonia. We describe how these relationships resulted in the approval of a groundbreaking provincial law that acknowledges the Indigenous community's right to be involved in decision-making concerning their Ancestors. In addition, we emphasize how these established relationships allowed the development of aDNA studies. With this background, we address the main ethical concerns of genomic studies of Ancestors identified in the reference literature and commit to applying some of the recommendations suggested in those ethical guidelines. Then, we reflect on possible negative consequences of ongoing research and propose some suggestions based on personal experiences that will contribute to moving the ethical field towards a more contextualized science with a local perspective.

Clinical relevance of stem cells in lung cancer.

Lung cancer is the major cause of cancer-related deaths worldwide, it has one of the lowest 5-year survival rate, mainly because it is diagnosed in the late stage of the disease. Lung cancer is classified into two groups, small cell lung cancer (SCLC) and non-SCLC (NSCLC). In turn, NSCLC is categorized into three distinct cell subtypes: Adenocarcinoma, squamous cell carcinoma, and large cell carcinoma. NSCLC is the most common lung cancer, accounting for 85% of all lung cancers. Treatment for lung cancer is linked to the cell type and stage of the disease, involving chemotherapy, radiation therapy, and surgery. Despite improvements in therapeutic treatments, lung cancer patients show high rates of recurrence, metastasis, and resistance to chemotherapy. Lung stem cells (SCs) are undifferentiated cells capable of self-renewal and proliferation, are resistant to chemotherapy and radiotherapy and, due to their properties, could be involved in the development and progression of lung cancer. The presence of SCs in the lung tissue could be the reason why lung cancer is difficult to treat. The identification of lung cancer stem cells biomarkers is of interest for precision medicine using new therapeutic agents directed against these cell populations. In this review, we present the current knowledge on lung SCs and discuss their functional role in the initiation and progression of lung cancer, as well as their role in tumor resistance to chemotherapy.

A Glimpse into the Past: What Ancient Viral Genomes Reveal About Human History.

Humans have battled viruses for millennia. However, directly linking the symptomatology of disease outbreaks to specific viral pathogens was not possible until the twentieth century. With the advent of the genomic era and the development of advanced protocols for isolation, sequencing, and analysis of ancient nucleic acids from diverse human remains, the identification and characterization of ancient viruses became feasible. Recent studies have provided invaluable information about past epidemics and made it possible to examine assumptions and inferences on the origin and evolution of certain viral families. In parallel, the study of ancient viruses also uncovered their importance in the evolution of the human lineage and their key roles in shaping major events in human history. In this review, we describe the strategies used for the study of ancient viruses, along with their limitations, and provide a detailed account of what past viral infections have revealed about human history.

Demographic history and genetic structure in pre-Hispanic Central Mexico.

Aridoamerica and Mesoamerica are two distinct cultural areas in northern and central Mexico, respectively, that hosted numerous pre-Hispanic civilizations between 2500 BCE and 1521 CE. The division between these regions shifted southward because of severe droughts ~1100 years ago, which allegedly drove a population replacement in central Mexico by Aridoamerican peoples. In this study, we present shotgun genome-wide data from 12 individuals and 27 mitochondrial genomes from eight pre-Hispanic archaeological sites across Mexico, including two at the shifting border of Aridoamerica and Mesoamerica. We find population continuity that spans the climate change episode and a broad preservation of the genetic structure across present-day Mexico for the past 2300 years. Lastly, we identify a contribution to pre-Hispanic populations of northern and central Mexico from two ancient unsampled "ghost" populations.

Results of treatment with alemtuzumab in a Spanish cohort of patients with multiple sclerosis in the real world: The RealMS study.

Background: Alemtuzumab (ALZ) is a humanized monoclonal antibody approved for the treatment of patients with highly active relapsing-remitting multiple sclerosis (RRMS) administered in two annual courses. The objective of this study was to describe the effectiveness and safety data of ALZ and to report the health resource utilization in patients receiving this treatment. Methods: In this retrospective, non-interventional study, information was retrieved from patients' medical charts at one center in Spain. Included patients were ≥18 years old, and ALZ treatment was initiated between 1 March 2015 and 31 March 2019, according to routine clinical practice and local labeling. Results: Of 123 patients, 78% were women. The mean (standard deviation, SD) age of patients at diagnosis was 40.3 (9.1) years, and the mean time since diagnosis was 13.8 (7.3) years. Patients were previously treated with a median (interquartile range; IQR) number of two (2.0-3.0) disease-modifying treatments (DMTs). Patients were treated with ALZ for a mean (SD) of 29.7 (13.8) months. ALZ reduced the annualized relapse rate (ARR) (1.5 before vs. 0.05 after; p < 0.001) and improved the median EDSS (4.63 before vs. 4.00 after; p < 0.001). Most (90.2%) patients were relapse-free while receiving ALZ. The mean number of gadolinium-enhancing [Gd+] T1 lesions was reduced (1.7 before vs. 0.1 after; p < 0.001), and the mean number of T2 hyperintense lesions was maintained (35.7 before vs. 35.4 after; p = 0.392). A total of 27 (21.9%) patients reported 29 autoimmune diseases: hyperthyroidism (12), hypothyroidism (11), idiopathic thrombocytopenic purpura (ITP) (3), alopecia areata (1), chronic urticaria (1), and vitiligo (1). The mean number of health resources (outpatient visits, emergency room visits, hospital admissions, and tests performed in the hospital) used while patients were treated with ALZ progressively decreased from year 1 to year 4, except for a slight increase at year 2 of outpatient visits. Conclusion: The ReaLMS study provides real-world evidence that ALZ can promote clinical and magnetic resonance imaging disease remission, as well as disability improvement in patients with MS, despite several prior DMT failures. The ALZ safety profile was consistent with data available from clinical trials and other real-world studies. Healthcare resource use was reduced throughout the treatment period.

Web Geographic Information System: A Support Tool for the Study, Evaluation, and Monitoring of Foci of Malaria Transmission in Mexico.

Malaria is currently an endemic disease in Mexico. The country joined the WHO's E-25 initiative for the elimination of Plasmodium vivax to achieve elimination and certification within the established period. Having a Web-based information system was, therefore, deemed necessary to assist in the detection, investigation, and elimination of transmission in the foci, as well as for the timely treatment of malaria-positive cases. The "Information System for the Elimination of Malaria in Mexico" was designed, developed, and implemented with a geographic vision, which includes a Web tool to georeference homes and aquatic systems, a dashboard and an indicator evaluation card for monitoring activities, notification of probable cases, and vector control among other indicators. The implementation of the system was gradual in the seven states that are currently in the malaria elimination phase; subsequently, the system was implemented in non-transmission states. In 2020, the system implementation stage began; first, the basic data of more than 96,000 homes throughout the country were georeferenced, and then the primary data capture tools of 17 formats, 32 reports, and 2 geographic viewers were enabled for information queries. A total of 56 active foci have been identified in 406 localities as well as 71 residual foci in 320 localities. Recently, the Foci Manager was developed, which is a specific tool for the study, evaluation, and monitoring of active foci through a GIS, a dashboard, and a systematized evaluation certificate. Georeferencing tools decreased the cost of spatial data collection.

SUMO/deSUMOylation of the BRI1 brassinosteroid receptor modulates plant growth responses to temperature.

Brassinosteroids (BRs) are a class of steroid molecules perceived at the cell surface that act as plant hormones. The BR receptor BRASSINOSTEROID INSENSITIVE1 (BRI1) offers a model to understand receptor-mediated signaling in plants and the role of post-translational modifications. Here we identify SUMOylation as a new modification targeting BRI1 to regulate its activity. BRI1 is SUMOylated in planta on two lysine residues, and the levels of BRI1 SUMO conjugates are controlled by the Desi3a SUMO protease. Loss of Desi3a leads to hypersensitivity to BRs, indicating that Desi3a acts as a negative regulator of BR signaling. Besides, we demonstrate that BRI1 is deSUMOylated at elevated temperature by Desi3a, leading to increased BRI1 interaction with the negative regulator of BR signaling BIK1 and to enhanced BRI1 endocytosis. Loss of Desi3a or BIK1 results in increased response to temperature elevation, indicating that BRI1 deSUMOylation acts as a safety mechanism necessary to keep temperature responses in check. Altogether, our work establishes BRI1 deSUMOylation as a molecular crosstalk mechanism between temperature and BR signaling, allowing plants to translate environmental inputs into growth response.

The population genomic legacy of the second plague pandemic.

Human populations have been shaped by catastrophes that may have left long-lasting signatures in their genomes. One notable example is the second plague pandemic that entered Europe in ca. 1,347 CE and repeatedly returned for over 300 years, with typical village and town mortality estimated at 10%-40%.1 It is assumed that this high mortality affected the gene pools of these populations. First, local population crashes reduced genetic diversity. Second, a change in frequency is expected for sequence variants that may have affected survival or susceptibility to the etiologic agent (Yersinia pestis).2 Third, mass mortality might alter the local gene pools through its impact on subsequent migration patterns. We explored these factors using the Norwegian city of Trondheim as a model, by sequencing 54 genomes spanning three time periods: (1) prior to the plague striking Trondheim in 1,349 CE, (2) the 17th-19th century, and (3) the present. We find that the pandemic period shaped the gene pool by reducing long distance immigration, in particular from the British Isles, and inducing a bottleneck that reduced genetic diversity. Although we also observe an excess of large FST values at multiple loci in the genome, these are shaped by reference biases introduced by mapping our relatively low genome coverage degraded DNA to the reference genome. This implies that attempts to detect selection using ancient DNA (aDNA) datasets that vary by read length and depth of sequencing coverage may be particularly challenging until methods have been developed to account for the impact of differential reference bias on test statistics.

Skin Autoimmunity Secondary to Alemtuzumab in a Tertiary Care Spanish Hospital.

Background and Objectives: The most common adverse events (AEs) after alemtuzumab (ALZ) include adverse infusion reactions, infections, and autoimmune disorders. Skin AEs are common during infusion, but there are few reported cases of long-term skin autoimmune disease. Methods: A retrospective case series of patients developing long-term autoimmune skin disorders after ALZ administration in a tertiary care hospital. Results: Of 133 patients treated with ALZ, 8 patients (6.02%) developed 9 autoimmune cutaneous AEs, including 4 events of alopecia areata, 2 of vitiligo, 2 of chronic urticaria, and 1 of inflammatory atrichia. Three of them occurred between the first and the second infusion. Discussion: The lesions described are secondary to autoimmune disorders, probably related to immune dysregulation because of a differential lymphocyte repopulation after ALZ. Autoimmune cutaneous AEs may be frequent, and it would be recommended to monitor its appearance to treat them.

Role of thyroid hormones-induced oxidative stress on cardiovascular physiology.

Thyroid hormones (THs) play an essential role in the maintenance of cardiovascular homeostasis and are involved in the modulation of cardiac contractility, heart rate, diastolic function, systemic vascular resistance, and vasodilation. THs have actions on cardiovascular physiology through the activation or repression of target genes or the activation of intracellular signals through non-genomic mechanisms. Hyperthyroidism alters certain intracellular pathways involved in the preservation of the structure and functionality of the heart, causing relevant cardiovascular disorders. Reactive oxygen species (ROS) play an important role in the cardiovascular system, but the exacerbated increase in ROS caused by chronic hyperthyroidism together with regulation on the antioxidant system have been associated with the development of cardiovascular dysfunction. In this review, we analyze the role of THs-induced oxidative stress in the cellular and molecular changes that lead to cardiac dysfunction, as well as the effectiveness of antioxidant treatments in attenuating cardiac abnormalities developed during hyperthyroidism.

Regulation of the cellular redox state and the expression of DNA methyltransferase-1 in peripheral blood mononuclear cells from patients with Graves' disease.

BACKGROUND: Graves' disease is an autoimmune disorder characterised by excessive production of thyroid hormones, which induces increased cellular metabolism in most tissues and increased production of reactive oxygen species (ROS). The aim of this work was to analyse the effect of ROS on cell viability and the expression of catalase (CAT), glutathione peroxidase-1 (GPx-1), superoxide dismutase (SOD-1) and DNA methyltransferase-1 (DNMT-1) in peripheral blood mononuclear cells (PBMC) from patients with newly diagnosed Graves' disease or treated with methimazole. PATIENTS AND METHODS: For this study, women patients with newly diagnosed Graves' disease (n=18), treated with methimazole (n=6) and healthy subjects (n=15) were recruited. ROS were evaluated by flow cytometry, and the viability/apoptosis of PBMC was analysed by flow cytometry and fluorescence microscopy. Genomic expression of CAT, GPx-1, SOD-1 and DNMT-1 was quantified by real-time PCR. RESULTS: We found high levels of ROS and increased expression of CAT, GPx-1, SOD-1 and DNMT-1 in PBMC from patients with newly diagnosed Graves' disease. Methimazole treatment reversed these parameters. Cell viability was similar in all study groups. CONCLUSIONS: ROS induces the expression of CAT, GPx-1, and SOD-1. The activity of these enzymes may contribute to the protection of PBMC from the harmful effect of free radicals on cell viability. Increased expression of DNMT-1 may be associated with aberrant methylation patterns in immunoregulatory genes contributing to autoimmunity in Graves' disease.

Recommendations for Sustainable Ancient DNA Research in the Global South: Voices From a New Generation of Paleogenomicists.

Paleogenomics - the study of ancient genomes - has made significant contributions, especially to our understanding of the evolutionary history of humans. This knowledge influx has been a direct result of the coupling of next-generation sequencing with improved methods for DNA recovery and analysis of ancient samples. The appeal of ancient DNA studies in the popular media coupled with the trend for such work to be published in "high impact" journals has driven the amassing of ancestral human remains from global collections, often with limited to no engagement or involvement of local researchers and communities. This practice in the paleogenomics literature has led to limited representation of researchers from the Global South at the research design and subsequent stages. Additionally, Indigenous and descendant communities are often alienated from popular and academic narratives that both involve and impact them, sometimes adversely. While some countries have safeguards against 'helicopter science', such as federally regulated measures to protect their biocultural heritage, there is variable oversight in others with regard to sampling and exportation of human remains for destructive research, and differing requirements for accountability or consultation with local researchers and communities. These disparities reveal stark contrasts and gaps in regional policies that lend themselves to persistent colonial practices. While essential critiques and conversations in this sphere are taking place, these are primarily guided through the lens of US-based heritage legislation such as the Native American Graves and Protection Act (NAGPRA). In this article, we aim to expand the scope of ongoing conversations by taking into account diverse regional contexts and challenges drawing from our own research experiences in the field of paleogenomics. We emphasize that true collaborations involve knowledge sharing, capacity building, mutual respect, and equitable participation, all of which take time and the implementation of sustainable research methods; amass-and-publish strategy is simply incompatible with this ethos.