Compounds that form reversible covalent bonds with lysine amino-acid residues in proteins have high potential for drug discovery. A chemical group has been reported that prolongs the time for which... Show moreCompounds that form reversible covalent bonds with lysine amino-acid residues in proteins have high potential for drug discovery. A chemical group has been reported that prolongs the time for which such compounds bind to their targets. Show less
Brown, A.L.; Wilkins, O.G.; Keuss, M.J.; Hill, S.E.; Zanovello, M.; Lee, W.C.; ... ; NYGC ALS Consortium 2022
Risk variants for ALS and FTD in the synaptic gene UNC13A increase the expression of an UNC13A cryptic exon in neurons with TDP-43 depletion.Variants of UNC13A, a critical gene for synapse function... Show moreRisk variants for ALS and FTD in the synaptic gene UNC13A increase the expression of an UNC13A cryptic exon in neurons with TDP-43 depletion.Variants of UNC13A, a critical gene for synapse function, increase the risk of amyotrophic lateral sclerosis and frontotemporal dementia(1-3), two related neurodegenerative diseases defined by mislocalization of the RNA-binding protein TDP-43(4,5). Here we show that TDP-43 depletion induces robust inclusion of a cryptic exon in UNC13A, resulting in nonsense-mediated decay and loss of UNC13A protein. Two common intronic UNC13A polymorphisms strongly associated with amyotrophic lateral sclerosis and frontotemporal dementia risk overlap with TDP-43 binding sites. These polymorphisms potentiate cryptic exon inclusion, both in cultured cells and in brains and spinal cords from patients with these conditions. Our findings, which demonstrate a genetic link between loss of nuclear TDP-43 function and disease, reveal the mechanism by which UNC13A variants exacerbate the effects of decreased TDP-43 function. They further provide a promising therapeutic target for TDP-43 proteinopathies. Show less
In conventional superconductors, the phase transition into a zero-resistance and perfectly diamagnetic state is accompanied by a jump in the specific heat and the opening of a spectral gap(1). In... Show moreIn conventional superconductors, the phase transition into a zero-resistance and perfectly diamagnetic state is accompanied by a jump in the specific heat and the opening of a spectral gap(1). In the high-transition-temperature (high-T-c) cuprates, although the transport, magnetic and thermodynamic signatures of T-c have been known since the 1980s(2), the spectroscopic singularity associated with the transition remains unknown. Here we resolve this long-standing puzzle with a high-precision angle-resolved photoemission spectroscopy (ARPES) study on overdoped (Bi,Pb)(2)Sr2CaCu2O8+delta (Bi2212). We first probe the momentum-resolved electronic specific heat via spectroscopy and reproduce the specific heat peak at T-c, completing the missing link for a holistic description of superconductivity. Then, by studying the full momentum, energy and temperature evolution of the spectra, we reveal that this thermodynamic anomaly arises from the singular growth of in-gap spectral intensity across T-c. Furthermore, we observe that the temperature evolution of in-gap intensity is highly anisotropic in the momentum space, and the gap itself obeys both the d-wave functional form and particle-hole symmetry. These findings support the scenario that the superconducting transition is driven by phase fluctuations. They also serve as an anchor point for understanding the Fermi arc and pseudogap phenomena in underdoped cuprates. Show less
Cuciti, V.; de Gasperin, F.; Brüggen, M.; Vazza, F.; Brunetti, G.; Shimwell, T.W.; ... ; Tasse, C. 2022
Common single-nucleotide polymorphisms (SNPs) are predicted to collectively explain 40-50% of phenotypic variation in human height, but identifying the specific variants and associated regions... Show moreCommon single-nucleotide polymorphisms (SNPs) are predicted to collectively explain 40-50% of phenotypic variation in human height, but identifying the specific variants and associated regions requires huge sample sizes1. Here, using data from a genome-wide association study of 5.4 million individuals of diverse ancestries, we show that 12,111 independent SNPs that are significantly associated with height account for nearly all of the common SNP-based heritability. These SNPs are clustered within 7,209 non-overlapping genomic segments with a mean size of around 90 kb, covering about 21% of the genome. The density of independent associations varies across the genome and the regions of increased density are enriched for biologically relevant genes. In out-of-sample estimation and prediction, the 12,111 SNPs (or all SNPs in the HapMap 3 panel2) account for 40% (45%) of phenotypic variance in populations of European ancestry but only around 10-20% (14-24%) in populations of other ancestries. Effect sizes, associated regions and gene prioritization are similar across ancestries, indicating that reduced prediction accuracy is likely to be explained by linkage disequilibrium and differences in allele frequency within associated regions. Finally, we show that the relevant biological pathways are detectable with smaller sample sizes than are needed to implicate causal genes and variants. Overall, this study provides a comprehensive map of specific genomic regions that contain the vast majority of common height-associated variants. Although this map is saturated for populations of European ancestry, further research is needed to achieve equivalent saturation in other ancestries. Show less
Evershed, R.P.; Davey Smith, G.; Roffet-Salque, M.; et al. 2022
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. Alth... Show moreIn 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. Show less
Patterson, N.; Isakov, M.; Booth, T.; Buster, L.; Fischer, C.E.; Olalde, I.; ... ; Reich, D. 2021
Present-day people from England and Wales have more ancestry derived from early European farmers (EEF) than did people of the Early Bronze Age(1). To understand this, here we generated genome-wide... Show morePresent-day people from England and Wales have more ancestry derived from early European farmers (EEF) than did people of the Early Bronze Age(1). To understand this, here we generated genome-wide data from 793 individuals, increasing data from the Middle to the Late Bronze Age and Iron Age in Britain by 12-fold, and western and central Europe by 3.5-fold. Between 1000 and 875 bc, EEF ancestry increased in southern Britain (England and Wales) but not northern Britain (Scotland) due to incorporation of migrants who arrived at this time and over previous centuries, and who were genetically most similar to ancient individuals from France. These migrants contributed about half the ancestry of people of England and Wales from the Iron Age, thereby creating a plausible vector for the spread of early Celtic languages into Britain. These patterns are part of a broader trend of EEF ancestry becoming more similar across central and western Europe in the Middle to the Late Bronze Age, coincident with archaeological evidence of intensified cultural exchange(2-6). There was comparatively less gene flow from continental Europe during the Iron Age, and the independent genetic trajectory in Britain is also reflected in the rise of the allele conferring lactase persistence to approximately 50% by this time compared to approximately 7% in central Europe where it rose rapidly in frequency only a millennium later. This suggests that dairy products were used in qualitatively different ways in Britain and in central Europe over this period. Show less
Patterson, N.; Isakov, M.; Booth, T.; Büster, L.; Fischer, C.; Olalde, I.; ... ; Reich, D. 2021
Present-day people from England and Wales harbour more ancestry derived from Early European Farmers (EEF) than people of the Early Bronze Age1. To understand this, we generated genome-wide data... Show morePresent-day people from England and Wales harbour more ancestry derived from Early European Farmers (EEF) than people of the Early Bronze Age1. To understand this, we generated genome-wide data from 793 individuals, increasing data from the Middle to Late Bronze and Iron Age in Britain by 12-fold, and Western and Central Europe by 3.5-fold. Between 1000 and 875 BC, EEF ancestry increased in southern Britain (England and Wales) but not northern Britain (Scotland) due to incorporation of migrants who arrived at this time and over previous centuries, and who were genetically most similar to ancient individuals from France. These migrants contributed about half the ancestry of Iron Age people of England and Wales, thereby creating a plausible vector for the spread of early Celtic languages into Britain. These patterns are part of a broader trend of EEF ancestry becoming more similar across central and western Europe in the Middle to Late Bronze Age, coincident with archaeological evidence of intensified cultural exchange2-6. There was comparatively less gene flow from continental Europe during the Iron Age, and Britain's independent genetic trajectory is also reflected in the rise of the allele conferring lactase persistence to ~50% by this time compared to ~7% in central Europe where it rose rapidly in frequency only a millennium later. This suggests that dairy products were used in qualitatively different ways in Britain and in central Europe over this period. Show less
Increased blood lipid levels are heritable risk factors of cardiovascular disease with varied prevalence worldwide owing to different dietary patterns and medication use(1). Despite advances in... Show moreIncreased blood lipid levels are heritable risk factors of cardiovascular disease with varied prevalence worldwide owing to different dietary patterns and medication use(1). Despite advances in prevention and treatment, in particular through reducing low-density lipoprotein cholesterol levels(2), heart disease remains the leading cause of death worldwide(3). Genome-wideassociation studies (GWAS) of blood lipid levels have led to important biological and clinical insights, as well as new drug targets, for cardiovascular disease. However, most previous GWAS(4-23) have been conducted in European ancestry populations and may have missed genetic variants that contribute to lipid-level variation in other ancestry groups. These include differences in allele frequencies, effect sizes and linkage-disequilibrium patterns(24). Here we conduct a multi-ancestry, genome-wide genetic discovery meta-analysis of lipid levels in approximately 1.65 million individuals, including 350,000 of non-European ancestries. We quantify the gain in studying non-European ancestries and provide evidence to support the expansion of recruitment of additional ancestries, even with relatively small sample sizes. We find that increasing diversity rather than studying additional individuals of European ancestry results in substantial improvements in fine-mapping functional variants and portability of polygenic prediction (evaluated in approximately 295,000 individuals from 7 ancestry groupings). Modest gains in the number of discovered loci and ancestry-specific variants were also achieved. As GWAS expand emphasis beyond the identification of genes and fundamental biology towards the use of genetic variants for preventive and precision medicine(25), we anticipate that increased diversity of participants will lead to more accurate and equitable(26) application of polygenic scores in clinical practice. Show less
We are a group of archaeologists, anthropologists, curators and geneticists representing diverse global communities and 31 countries. All of us met in a virtual workshop dedicated to ethics in... Show moreWe are a group of archaeologists, anthropologists, curators and geneticists representing diverse global communities and 31 countries. All of us met in a virtual workshop dedicated to ethics in ancient DNA research held in November 2020. There was widespread agreement that globally applicable ethical guidelines are needed, but that recent recommendations grounded in discussion about research on human remains from North America are not always generalizable worldwide. Here we propose the following globally applicable guidelines, taking into consideration diverse contexts. These hold that: (1) researchers must ensure that all regulations were followed in the places where they work and from which the human remains derived; (2) researchers must prepare a detailed plan prior to beginning any study; (3) researchers must minimize damage to human remains; (4) researchers must ensure that data are made available following publication to allow critical re-examination of scientific findings; and (5) researchers must engage with other stakeholders from the beginning of a study and ensure respect and sensitivity to stakeholder perspectives. We commit to adhering to these guidelines and expect they will promote a high ethical standard in DNA research on human remains going forward.In this Perspective, a group representing a range of stakeholders makes the case for a set of five proposed globally applicable ethical guidelines for ancient human DNA research. Show less
Librado, P.; Khan, N.; Fages, A.; Kusliy, M.A.; Suchan, T.; Tonasso-Calviere, L.; ... ; Orlando, L. 2021
Analysis of 273 ancient horse genomes reveals that modern domestic horses originated in the Western Eurasian steppes, especially the lower Volga-Don region.Domestication of horses fundamentally... Show moreAnalysis of 273 ancient horse genomes reveals that modern domestic horses originated in the Western Eurasian steppes, especially the lower Volga-Don region.Domestication of horses fundamentally transformed long-range mobility and warfare(1). However, modern domesticated breeds do not descend from the earliest domestic horse lineage associated with archaeological evidence of bridling, milking and corralling(2-4) at Botai, Central Asia around 3500 bc(3). Other longstanding candidate regions for horse domestication, such as Iberia(5) and Anatolia(6), have also recently been challenged. Thus, the genetic, geographic and temporal origins of modern domestic horses have remained unknown. Here we pinpoint the Western Eurasian steppes, especially the lower Volga-Don region, as the homeland of modern domestic horses. Furthermore, we map the population changes accompanying domestication from 273 ancient horse genomes. This reveals that modern domestic horses ultimately replaced almost all other local populations as they expanded rapidly across Eurasia from about 2000 bc, synchronously with equestrian material culture, including Sintashta spoke-wheeled chariots. We find that equestrianism involved strong selection for critical locomotor and behavioural adaptations at the GSDMC and ZFPM1 genes. Our results reject the commonly held association(7) between horseback riding and the massive expansion of Yamnaya steppe pastoralists into Europe around 3000 bc(8,9) driving the spread of Indo-European languages(10). This contrasts with the scenario in Asia where Indo-Iranian languages, chariots and horses spread together, following the early second millennium bc Sintashta culture(11,12). Show less
Nous sommes un groupe d'archéologues, d’anthropologues, de conservateurs et de généticiens de différentes origines et représentant 31 pays. Nous nous sommes rencontrés en novembre 2020 lors d'une... Show moreNous sommes un groupe d'archéologues, d’anthropologues, de conservateurs et de généticiens de différentes origines et représentant 31 pays. Nous nous sommes rencontrés en novembre 2020 lors d'une table ronde en ligne dédiée à l'éthique de la recherche d’ADN ancien. Nous avons alors convenu de la nécessité de lignes directrices éthiques applicables à l'échelle mondiale. Les recommandations publiées récemment et développées dans le cadre de recherches d’ADN sur des vestiges humains d’Amérique du Nord ne s’avèrent pas généralisables à d’autres régions du monde. Suite à l’analyse de divers contextes, nous proposons ici des lignes directrices que nous pensons être applicables partout dans le monde. Ces lignes directrices sont les suivantes : 1) les chercheurs doivent s'assurer que les règlements s’appliquant dans les lieux où ils travaillent ainsi que dans les lieux d’où proviennent les vestiges humains sont bien respectés ; 2) les chercheurs doivent préparer un programme de recherche détaillé avant de commencer toute étude ; 3) les chercheurs doivent minimiser les dommages causés aux vestiges humains ; 4) les chercheurs doivent s'assurer que les données seront disponibles après la publication pour permettre un réexamen critique des résultats scientifiques; et 5) les chercheurs doivent échanger avec toutes les parties impliquées dès le début de l’étude et respecter leurs points de vue. Nous nous engageons à respecter ces directives et nous souhaitons qu’elles contribuent au renforcement de la pratique éthique de notre champ de recherche. Show less
The primary motor cortex (M1) is essential for voluntary fine-motor control and is functionally conserved across mammals(1). Here, using high-throughput transcriptomic and epigenomic profiling of... Show moreThe primary motor cortex (M1) is essential for voluntary fine-motor control and is functionally conserved across mammals(1). Here, using high-throughput transcriptomic and epigenomic profiling of more than 450,000 single nuclei in humans, marmoset monkeys and mice, we demonstrate a broadly conserved cellular makeup of this region, with similarities that mirror evolutionary distance and are consistent between the transcriptome and epigenome. The core conserved molecular identities of neuronal and non-neuronal cell types allow us to generate a cross-species consensus classification of cell types, and to infer conserved properties of cell types across species. Despite the overall conservation, however, many species-dependent specializations are apparent, including differences in cell-type proportions, gene expression, DNA methylation and chromatin state. Few cell-type marker genes are conserved across species, revealing a short list of candidate genes and regulatory mechanisms that are responsible for conserved features of homologous cell types, such as the GABAergic chandelier cells. This consensus transcriptomic classification allows us to use patch-seq (a combination of whole-cell patch-clamp recordings, RNA sequencing and morphological characterization) to identify corticospinal Betz cells from layer 5 in non-human primates and humans, and to characterize their highly specialized physiology and anatomy. These findings highlight the robust molecular underpinnings of cell-type diversity in M1 across mammals, and point to the genes and regulatory pathways responsible for the functional identity of cell types and their species-specific adaptations. Show less
Ruth, K.S.; Day, F.R.; Hussain, J.; Martinez-Marchal, A.; Aiken, C.E.; Azad, A.; ... ; 23 Me Res Team 2021
Reproductive longevity is essential for fertility and influences healthy ageing in women(1,2), but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here... Show moreReproductive longevity is essential for fertility and influences healthy ageing in women(1,2), but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause in approximately 200,000 women of European ancestry. These common alleles were associated with clinical extremes of age at natural menopause; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations(3). The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease. Show less
Ayres, J.; Berben, M.; Culo, M.; Hsu, Y.T.; Heumen, E. van; Huang, Y.; ... ; Hussey, N.E. 2021
Strange metals possess highly unconventional electrical properties, such as a linear-in-temperature resistivity(1-6), an inverse Hall angle that varies as temperature squared(7-9) and a linear-in... Show moreStrange metals possess highly unconventional electrical properties, such as a linear-in-temperature resistivity(1-6), an inverse Hall angle that varies as temperature squared(7-9) and a linear-in-field magnetoresistance(10-13). Identifying the origin of these collective anomalies has proved fundamentally challenging, even in materials such as the hole-doped cuprates that possess a simple bandstructure. The prevailing consensus is that strange metallicity in the cuprates is tied to a quantum critical point at a doping p* inside the superconducting dome(14,15). Here we study the high-field in-plane magnetoresistance of two superconducting cuprate families at doping levels beyond p*. At all dopings, the magnetoresistance exhibits quadrature scaling and becomes linear at high values of the ratio of the field and the temperature, indicating that the strange-metal regime extends well beyond p*. Moreover, the magnitude of the magnetoresistance is found to be much larger than predicted by conventional theory and is insensitive to both impurity scattering and magnetic field orientation. These observations, coupled with analysis of the zero-field and Hall resistivities, suggest that despite having a single band, the cuprate strange-metal region hosts two charge sectors, one containing coherent quasiparticles, the other scale-invariant 'Planckian' dissipators.Measurements of high-field magnetotransport in overdoped cuprates indicate that the strange-metal regime exists beyond the critical doping, and that it has both coherent and incoherent contributions. Show less
The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to... Show moreThe genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-19(1,2), host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases(3-7). They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease. Show less
E3 ligases are typically classified by hallmark domains such as RING and RBR, which are thought to specify unique catalytic mechanisms of ubiquitin transfer to recruited substrates(1,2). However,... Show moreE3 ligases are typically classified by hallmark domains such as RING and RBR, which are thought to specify unique catalytic mechanisms of ubiquitin transfer to recruited substrates(1,2). However, rather than functioning individually, many neddylated cullin-RING E3 ligases (CRLs) and RBR-type E3 ligases in the ARIH family-which together account for nearly half of all ubiquitin ligases in humans-form E3-E3 super-assemblies(3-7). Here, by studying CRLs in the SKP1-CUL1-F-box (SCF) family, we show how neddylated SCF ligases and ARIH1 (an RBR-type E3 ligase) co-evolved to ubiquitylate diverse substrates presented on various F-box proteins. We developed activity-based chemical probes that enabled cryo-electron microscopy visualization of steps in E3-E3 ubiquitylation, initiating with ubiquitin linked to the E2 enzyme UBE2L3, then transferred to the catalytic cysteine of ARIH1, and culminating in ubiquitin linkage to a substrate bound to the SCF E3 ligase. The E3-E3 mechanism places the ubiquitin-linked active site of ARIH1 adjacent to substrates bound to F-box proteins (for example, substrates with folded structures or limited length) that are incompatible with previously described conventional RING E3-only mechanisms. The versatile E3-E3 super-assembly may therefore underlie widespread ubiquitylation. Show less
Lungfishes belong to lobe-fined fish (Sarcopterygii) that, in the Devonian period, 'conquered' the land and ultimately gave rise to all land vertebrates, including humans(1-3). Here we determine... Show moreLungfishes belong to lobe-fined fish (Sarcopterygii) that, in the Devonian period, 'conquered' the land and ultimately gave rise to all land vertebrates, including humans(1-3). Here we determine the chromosome-quality genome of the Australian lungfish (Neoceratodus forsteri), which is known to have the largest genome of any animal. The vast size of this genome, which is about 14x larger than that of humans, is attributable mostly to huge intergenic regions and introns with high repeat content (around 90%), the components of which resemble those of tetrapods (comprising mainly long interspersed nuclear elements) more than they do those of ray-finned fish. The lungfish genome continues to expand independently (its transposable elements are still active), through mechanisms different to those of the enormous genomes of salamanders. The 17 fully assembled lungfish macrochromosomes maintain synteny to other vertebrate chromosomes, and all microchromosomes maintain conserved ancient homology with the ancestral vertebrate karyotype. Our phylogenomic analyses confirm previous reports that lungfish occupy a key evolutionary position as the closest living relatives to tetrapods(4,5), underscoring the importance of lungfish for understanding innovations associated with terrestrialization. Lungfish preadaptations to living on land include the gain of limb-like expression in developmental genes such as hoxc13 and sall1 in their lobed fins. Increased rates of evolution and the duplication of genes associated with obligate air-breathing, such as lung surfactants and the expansion of odorant receptor gene families (which encode proteins involved in detecting airborne odours), contribute to the tetrapod-like biology of lungfishes. These findings advance our understanding of this major transition during vertebrate evolution. Show less
Fudamoto, Y.; Oesch, P.A.; Schouws, S.; Stefanon, M.; Smit, R.; Bouwens, R.J.; ... ; White, C. 2021
