Dairying, diseases and the evolution of lactase persistence in Europe.

In European and many African, Middle Eastern and southern Asian populations, lactase persistence (LP) is the most strongly selected monogenic trait to have evolved over the past 10,000 years1. Although the selection of LP and the consumption of prehistoric milk must be linked, considerable uncertainty remains concerning their spatiotemporal configuration and specific interactions2,3. Here we provide detailed distributions of milk exploitation across Europe over the past 9,000 years using around 7,000 pottery fat residues from more than 550 archaeological sites. European milk use was widespread from the Neolithic period onwards but varied spatially and temporally in intensity. Notably, LP selection varying with levels of prehistoric milk exploitation is no better at explaining LP allele frequency trajectories than uniform selection since the Neolithic period. In the UK Biobank4,5 cohort of 500,000 contemporary Europeans, LP genotype was only weakly associated with milk consumption and did not show consistent associations with improved fitness or health indicators. This suggests that other reasons for the beneficial effects of LP should be considered for its rapid frequency increase. We propose that lactase non-persistent individuals consumed milk when it became available but, under conditions of famine and/or increased pathogen exposure, this was disadvantageous, driving LP selection in prehistoric Europe. Comparison of model likelihoods indicates that population fluctuations, settlement density and wild animal exploitation-proxies for these drivers-provide better explanations of LP selection than the extent of milk exploitation. These findings offer new perspectives on prehistoric milk exploitation and LP evolution.

DECIPHER: Supporting the interpretation and sharing of rare disease phenotype-linked variant data to advance diagnosis and research.

DECIPHER (https://www.deciphergenomics.org) is a free web platform for sharing anonymized phenotype-linked variant data from rare disease patients. Its dynamic interpretation interfaces contextualize genomic and phenotypic data to enable more informed variant interpretation, incorporating international standards for variant classification. DECIPHER supports almost all types of germline and mosaic variation in the nuclear and mitochondrial genome: sequence variants, short tandem repeats, copy-number variants, and large structural variants. Patient phenotypes are deposited using Human Phenotype Ontology (HPO) terms, supplemented by quantitative data, which is aggregated to derive gene-specific phenotypic summaries. It hosts data from >250 projects from ~40 countries, openly sharing >40,000 patient records containing >51,000 variants and >172,000 phenotype terms. The rich phenotype-linked variant data in DECIPHER drives rare disease research and diagnosis by enabling patient matching within DECIPHER and with other resources, and has been cited in >2,600 publications. In this study, we describe the types of data deposited to DECIPHER, the variant interpretation tools, and patient matching interfaces which make DECIPHER an invaluable rare disease resource.

Holocene fluctuations in human population demonstrate repeated links to food production and climate.

We consider the long-term relationship between human demography, food production, and Holocene climate via an archaeological radiocarbon date series of unprecedented sampling density and detail. There is striking consistency in the inferred human population dynamics across different regions of Britain and Ireland during the middle and later Holocene. Major cross-regional population downturns in population coincide with episodes of more abrupt change in North Atlantic climate and witness societal responses in food procurement as visible in directly dated plants and animals, often with moves toward hardier cereals, increased pastoralism, and/or gathered resources. For the Neolithic, this evidence questions existing models of wholly endogenous demographic boom-bust. For the wider Holocene, it demonstrates that climate-related disruptions have been quasi-periodic drivers of societal and subsistence change.

Facilitating collaboration in rare genetic disorders through effective matchmaking in DECIPHER.

DECIPHER (https://decipher.sanger.ac.uk) is a web-based platform for secure deposition, analysis, and sharing of plausibly pathogenic genomic variants from well-phenotyped patients suffering from genetic disorders. DECIPHER aids clinical interpretation of these rare sequence and copy-number variants by providing tools for variant analysis and identification of other patients exhibiting similar genotype-phenotype characteristics. DECIPHER also provides mechanisms to encourage collaboration among a global community of clinical centers and researchers, as well as exchange of information between clinicians and researchers within a consortium, to accelerate discovery and diagnosis. DECIPHER has contributed to matchmaking efforts by enabling the global clinical genetics community to identify many previously undiagnosed syndromes and new disease genes, and has facilitated the publication of over 700 peer-reviewed scientific publications since 2004. At the time of writing, DECIPHER contains anonymized data from ∼250 registered centers on more than 51,500 patients (∼18000 patients with consent for data sharing and ∼25000 anonymized records shared privately). In this paper, we describe salient features of the platform, with special emphasis on the tools and processes that aid interpretation, sharing, and effective matchmaking with other data held in the database and that make DECIPHER an invaluable clinical and research resource.

Advancing Treatments for Rare Renal Diseases: New Hopes and Opportunities to Address a High Unmet Need.

Introduction: The etiology of chronic kidney disease (CKD) is varied and complex. Diabetes and hypertension comprise 2/3 of cases and rare conditions, including inherited genetic diseases, comprise 1/3. We previously reported a 54% increase in clinical studies in CKD in the last 10 years. Hypothesizing a greater increase in rare renal disease studies, we undertook further analysis of metadata from Clinicaltrials.gov. Methods: CT.gov was searched for 49 conditions determined to be rare renal diseases posted between Jan-2003 and Dec-2022. Studies were divided into 2 time periods: P1 (2003-2012) and P2 (2013-2022) and analyzed by study type, phase, indication, primary endpoint, population, and funding. Results: Studies increased significantly in P2 versus P1 (123%, p < 0.001) with the greatest rise in observational studies (283%, p < 0.001). Interventional studies increased 93% (p < 0.01), with the greatest rise in early phases (205%, p < 0.001). The most frequent indications were LN, ADPKD, and IgA nephropathy; all increased 77-166% in P2 (p < 0.05 - p < 0.001). Proteinuria was the most frequent primary endpoint, which increased 63% (p = 0.054). Studies with pediatric populations increased 78% (p < 0.01). Most studies were nonindustry funded; however, industry-funded studies increased by 225% (p < 0.001). Conclusion: Clinical research in rare renal diseases has increased significantly in the last 10 years, particularly in glomerular diseases (GDs) and ADPKD. Proteinuria correlates with outcomes in GD, which explains the high percentage of studies with this primary endpoint. Rare renal diseases disproportionately affect children and the rise in studies with pediatric populations is encouraging. The rise in observational studies may signal an increased focus on understanding the natural course and pathophysiology of disease, which may lead to new potential therapeutic targets and future interventional studies. The increase in industry-funded studies suggests basic science is translating into industry-sponsored research.

Reconstructing the earliest known composite-tiled roofs from the Chinese Loess Plateau.

The origins of composite tiles, one of the oldest forms of roofing, are still unclear. This study is based on a set of over 5000 clay tile fragments excavated from a single context in the Qiaocun site on the Chinese Loess Plateau, dated to ~ 2400-2200 BCE (Early Longshan Period). By combining morphological measurement statistics, 3D modeling, computer-based simulations, and reference to historical and archaeological records, we reconstruct the earliest known composite-tile roofing techniques and demonstrate that tile production was under a low-level standardization, with manual control forming a key agent during the roofing process. The quantitative study of the composite roof tiles from Qiaocun was then placed in its archaeological context and compared with other sites on the Loess Plateau. It was found that tile-roofed buildings were, by necessity, community projects. Such structures served as nodes in larger social communication networks; additionally, their appearance was linked to intensified social complexity in public affairs during the Longshan Period. The invention of clay tiles was associated with the inception of thick rammed-earth walls which had sufficient strength to serve as load-bearing structures for heavy tiled roofs. The roof tiles excavated from Qiaocun site indicate that the Loess Plateau was a key center for the origin and spread of composite tiles and related roofing and construction methods, suggesting a Longshan-Western Zhou tradition of roofing techniques in East Asia.

Genetic Testing in Natural History Studies: A Review of the Regulatory and Legal Landscape.

BACKGROUND: Natural history (NH) studies, using observational methods, are common in rare and orphan diseases (80% of which have a genetic component). There is profound interest in identifying genetic mutations driving these diseases in these studies to support the formulation of targeted precision medicines. The global regulatory classification of NH studies with novel molecular biomarker collection has not been clearly delineated, presenting researchers with the challenge of determining how these studies are classified and regulated across multiple geographies. OBJECTIVE: The aim of this investigation was to conduct a review of regulations related to NH studies and genetic testing to elucidate regulatory pathways to inform clinical researchers in the field. METHODS: Regulatory provisions for NH studies and genetic testing were obtained from Pharmaceutical Product Development (PPD)'s propriety regulatory intelligence database and by surveying the company's country-specific regulatory experts. A literature search was conducted in the Google Scholar search engine and PubMed for supplementary information. RESULTS: Nineteen countries were evaluated; 37% classified NH studies with biomarker collection as noninterventional and 26% required regulatory approval (increasing to 47% when molecular biomarker testing was introduced). No regulatory provisions for genetic testing could be identified in 32% of countries, and 58% did not have binding requirements for genetic counseling. CONCLUSION: Lack of harmonization of regulations governing NH studies with molecular biomarker collection contributes to the operational complexity of conducting multinational studies in orphan and rare diseases. A set of harmonized international guidelines for these studies would improve efficiency, and this may be on the horizon with the recent adaption of International Conference on Harmonisation (ICH) guideline E18.

Nonlinear landscape and cultural response to sea-level rise.

Rising sea levels have been associated with human migration and behavioral shifts throughout prehistory, often with an emphasis on landscape submergence and consequent societal collapse. However, the assumption that future sea-level rise will drive similar adaptive responses is overly simplistic. While the change from land to sea represents a dramatic and permanent shift for preexisting human populations, the process of change is driven by a complex set of physical and cultural processes with long transitional phases of landscape and socioeconomic change. Here, we use reconstructions of prehistoric sea-level rise, paleogeographies, terrestrial landscape change, and human population dynamics to show how the gradual inundation of an island archipelago resulted in decidedly nonlinear landscape and cultural responses to rising sea levels. Interpretation of past and future responses to sea-level change requires a better understanding of local physical and societal contexts to assess plausible human response patterns in the future.

Surface chromium on Terracotta Army bronze weapons is neither an ancient anti-rust treatment nor the reason for their good preservation.

For forty years, there has been a widely held belief that over 2,000 years ago the Chinese Qin developed an advanced chromate conversion coating technology (CCC) to prevent metal corrosion. This belief was based on the detection of chromium traces on the surface of bronze weapons buried with the Chinese Terracotta Army, and the same weapons' very good preservation. We analysed weapons, lacquer and soils from the site, and conducted experimental replications of CCC and accelerated ageing. Our results show that surface chromium presence is correlated with artefact typology and uncorrelated with bronze preservation. Furthermore we show that the lacquer used to cover warriors and certain parts of weapons is rich in chromium, and we demonstrate that chromium on the metals is contamination from nearby lacquer after burial. The chromium anti-rust treatment theory should therefore be abandoned. The good metal preservation probably results from the moderately alkaline pH and very small particle size of the burial soil, in addition to bronze composition.

Ritual responses to drought: An examination of ritual expressions in Classic Maya written sources.

Planting and rain-beckoning rituals are an extremely common way in which past and present human communities have confronted the risk of drought across a range of environments worldwide. In tropical environments, such ceremonies are particularly salient despite widespread assumptions that water supplies are unproblematic in such regions. We demonstrate for the first time that two common but previously under-appreciated Maya rituals are likely planting and rain-beckoning rituals preferentially performed at certain times of the year in close step with the rainy season and the Maya agricultural cycle. We also argue for considerable historical continuity between these Classic Maya ceremonies and later Maya community rituals still performed in times of uncertain weather conditions up to the present day across Guatemala, Belize, and eastern Mexico. During the Terminal Classic period (AD 800-900), the changing role played by ancient Maya drought-related rituals fits into a wider rhetorical shift observed in Maya texts away from the more characteristic focus on royal births, enthronements, marriages, and wars towards greater emphasis on the correct perpetuation of key ceremonies, and we argue that such changes are consistent with palaeoclimatic evidence for a period of diminished precipitation and recurrent drought.

Modelling the Geographical Origin of Rice Cultivation in Asia Using the Rice Archaeological Database.

We have compiled an extensive database of archaeological evidence for rice across Asia, including 400 sites from mainland East Asia, Southeast Asia and South Asia. This dataset is used to compare several models for the geographical origins of rice cultivation and infer the most likely region(s) for its origins and subsequent outward diffusion. The approach is based on regression modelling wherein goodness of fit is obtained from power law quantile regressions of the archaeologically inferred age versus a least-cost distance from the putative origin(s). The Fast Marching method is used to estimate the least-cost distances based on simple geographical features. The origin region that best fits the archaeobotanical data is also compared to other hypothetical geographical origins derived from the literature, including from genetics, archaeology and historical linguistics. The model that best fits all available archaeological evidence is a dual origin model with two centres for the cultivation and dispersal of rice focused on the Middle Yangtze and the Lower Yangtze valleys.