The emergence of animal phyla, each with their unique body plan, was a rapid event in the history of animal life, yet its genomic underpinnings are still poorly understood. Here we investigate at the genomic, regulatory...The emergence of animal phyla, each with their unique body plan, was a rapid event in the history of animal life, yet its genomic underpinnings are still poorly understood. Here we investigate at the genomic, regulatory and cellular levels, the origin of one of the most distinctive animal phyla, the chaetognaths, whose organismal characteristics have historically complicated their phylogenetic placement. We show that these characteristics are reflected at the cell-type level by the expression of genes that originated in the chaetognath lineage, contributing to adaptation to planktonic life at the sensory and structural levels. Similarly to other members of gnathiferans (which also include rotifers and several other microscopic phyla), chaetognaths have undergone accelerated genomic evolution with gene loss and chromosomal fusions. Furthermore, they secondarily duplicated thousands of genes, without evidence for a whole-genome duplication, yielding, for instance, tandemly expanded Hox genes, as well as many phylum-specific genes. We also detected repeat-rich highly methylated neocentromeres and a simplified DNA methylation toolkit that is involved in mobile element repression rather than transcriptional control. Consistent with fossil evidence, our observations suggest that chaetognaths emerged after a phase of morphological simplification through a reinvention of organ systems paralleled by massive genomic reorganization, explaining the uniqueness of their body plan.
The aridity index is widely used to indicate water availability on land. Balancing climatic water supply (precipitation, P) against demand (potential evapotranspiration, PET), it is often expressed as the P/PET ratio or...The aridity index is widely used to indicate water availability on land. Balancing climatic water supply (precipitation, P) against demand (potential evapotranspiration, PET), it is often expressed as the P/PET ratio or humidity index. Water also flows laterally by rivers and groundwater, from hills to valleys and from mountains to plains, subsidizing the receiving lowlands. Here, we show that this lateral subsidy reduces aridity in the receiving lowlands. We first estimate monthly subsidies (Qlat) by surface and groundwater at 30″ global grids with a global hydrology model. We then calculate the conventional global humidity index (GHI) as P/PET and a new GHI including Qlat as (P + Qlat)/PET. Termed GHI_topo, the latter reflects land topography, higher in hydrologically convergent lowlands. It also exhibits a delayed and dampened seasonality (relative to P) owing to delayed and diffused Qlat arrival at the receiving lowlands. Such spatiotemporal features of Qlat, arising from both the climate and the terrain, make GHI_topo a more realistic indicator of local water availability in downgradient societies and ecosystems, enabling life in arid locations and times. Global land area with GHI_topo ≥ 1 (supply meets or exceeds demand) is 33% greater than GHI ≥ 1 and far higher in arid and season-arid climates.
As tissue-resident macrophages of the central nervous system parenchyma, microglia perform diverse essential functions during homeostasis and perturbations. They primarily interact with neurons by means of synaptic engul...As tissue-resident macrophages of the central nervous system parenchyma, microglia perform diverse essential functions during homeostasis and perturbations. They primarily interact with neurons by means of synaptic engulfment and through the rapid elimination of apoptotic cells and non-functional synapses. Here, by combining unbiased lipidomics and high-resolution spatial lipid imaging, deep single-cell transcriptome analysis and novel cell-type-specific mutants, we identified a previously unknown mode of microglial interaction with neurons. During homeostasis, microglia deliver the lysosomal enzyme β-hexosaminidase to neurons for the degradation of the ganglioside GM2 that is integral to maintaining cell membrane organization and function. Absence of Hexb, encoding the β subunit of β-hexosaminidase, in both mice and patients with neurodegenerative Sandhoff disease leads to a massive accumulation of GM2 derivatives in a characteristic spatiotemporal manner. In mice, neuronal GM2 gangliosides subsequently engage the macrophage galactose-type lectin 2 receptor on microglia through N-acetylgalactosamine residues, leading to lethal neurodegeneration. Notably, replacement of microglia with peripherally derived microglia-like cells is able to break this degenerative cycle and fully restore central nervous system homeostasis. Our results reveal a mode of bidirectional microglia-neuron communication centred around GM2 ganglioside turnover, identify a microgliopathy and offer therapeutic avenues for these maladies.
Van Nuland ME, Averill C, Stewart JD
… +23 more, Prylutskyi O, Corrales A, van Galen LG, Manley BF, Qin C, Lauber T, Mikryukov V, Dulia O, Furci G, Marín C, Sheldrake M, Weedon JT, Peay KG, Cornwallis CK, Větrovský T, Kohout P, Baldrian P, Tedersoo L, West SA, Crowther TW, Kiers ET, SPUN Mapping Consortium, van den Hoogen J
Mycorrhizal fungi are ecosystem engineers that sustain plant life and help regulate Earth's biogeochemical cycles. However, in contrast to plants and animals, the global distribution of mycorrhizal fungal biodiversity is...Mycorrhizal fungi are ecosystem engineers that sustain plant life and help regulate Earth's biogeochemical cycles. However, in contrast to plants and animals, the global distribution of mycorrhizal fungal biodiversity is largely unknown, which limits our ability to monitor and protect key underground ecosystems. Here we trained machine-learning algorithms on a global dataset of 25,000 geolocated soil samples comprising >2.8 billion fungal DNA sequences. We predicted arbuscular mycorrhizal and ectomycorrhizal fungal richness and rarity across terrestrial ecosystems. On the basis of these predictions, we generated high-resolution, global-scale maps and identified key reservoirs of highly diverse and endemic mycorrhizal communities. Intersecting protected areas with mycorrhizal hotspots indicated that less than 10% of predicted mycorrhizal richness hotspots currently exist in protected areas. Our results describe a largely hidden component of Earth's underground ecosystems and can help identify conservation priorities, set monitoring benchmarks and create specific restoration plans and land-management strategies.
Our knowledge of biogeographic patterns and processes in the deep sea has been limited by the lack of integrated datasets that cover its vast extent. Here we analyse a new global dataset of genomic DNA sequences, spannin...Our knowledge of biogeographic patterns and processes in the deep sea has been limited by the lack of integrated datasets that cover its vast extent. Here we analyse a new global dataset of genomic DNA sequences, spanning an entire taxonomic class of benthic invertebrates (Ophiuroidea), to obtain a broad understanding of phylogenetic divergence and biotic movement across all oceans, from coastal margins down to the abyssal plains. We show that regional faunas on the continental shelf are phylogenetically divergent, particularly at temperate and tropical latitudes. By contrast, assemblages in the deep sea are much more connected. Many temperate deep-sea lineages have achieved distribution ranges across the planet, including over the Quaternary period. A close relationship exists between deep-sea faunas of the northern Atlantic and, on the opposite side of the globe, southern Australia. Bathymetric interchange is not only reliant on vertical migration through isothermal polar waters but also occurs across the thermal depth gradients of tropical regions. The connected nature of deep-sea life should be an important consideration in marine conservation assessments.
Logsdon GA, Ebert P, Audano PA
… +65 more, Loftus M, Porubsky D, Ebler J, Yilmaz F, Hallast P, Prodanov T, Yoo D, Paisie CA, Harvey WT, Zhao X, Martino GV, Henglin M, Munson KM, Rabbani K, Chin CS, Gu B, Ashraf H, Scholz S, Austine-Orimoloye O, Balachandran P, Bonder MJ, Cheng H, Chong Z, Crabtree J, Gerstein M, Guethlein LA, Hasenfeld P, Hickey G, Hoekzema K, Hunt SE, Jensen M, Jiang Y, Koren S, Kwon Y, Li C, Li H, Li J, Norman PJ, Oshima KK, Paten B, Phillippy AM, Pollock NR, Rausch T, Rautiainen M, Song Y, Söylev A, Sulovari A, Surapaneni L, Tsapalou V, Zhou W, Zhou Y, Zhu Q, Zody MC, Mills RE, Devine SE, Shi X, Talkowski ME, Chaisson MJP, Dilthey AT, Konkel MK, Korbel JO, Lee C, Beck CR, Eichler EE, Marschall T
Diverse sets of complete human genomes are required to construct a pangenome reference and to understand the extent of complex structural variation. Here we sequence 65 diverse human genomes and build 130 haplotype-resol...Diverse sets of complete human genomes are required to construct a pangenome reference and to understand the extent of complex structural variation. Here we sequence 65 diverse human genomes and build 130 haplotype-resolved assemblies (median continuity of 130 Mb), closing 92% of all previous assembly gaps and reaching telomere-to-telomere status for 39% of the chromosomes. We highlight complete sequence continuity of complex loci, including the major histocompatibility complex (MHC), SMN1/SMN2, NBPF8 and AMY1/AMY2, and fully resolve 1,852 complex structural variants. In addition, we completely assemble and validate 1,246 human centromeres. We find up to 30-fold variation in α-satellite higher-order repeat array length and characterize the pattern of mobile element insertions into α-satellite higher-order repeat arrays. Although most centromeres predict a single site of kinetochore attachment, epigenetic analysis suggests the presence of two hypomethylated regions for 7% of centromeres. Combining our data with the draft pangenome reference significantly enhances genotyping accuracy from short-read data, enabling whole-genome inference to a median quality value of 45. Using this approach, 26,115 structural variants per individual are detected, substantially increasing the number of structural variants now amenable to downstream disease association studies.
Genomic structural variants (SVs) contribute substantially to genetic diversity and human diseases, yet remain under-characterized in population-scale cohorts. Here we conducted long-read sequencing in 1,019 humans to co...Genomic structural variants (SVs) contribute substantially to genetic diversity and human diseases, yet remain under-characterized in population-scale cohorts. Here we conducted long-read sequencing in 1,019 humans to construct an intermediate-coverage resource covering 26 populations from the 1000 Genomes Project. Integrating linear and graph genome-based analyses, we uncover over 100,000 sequence-resolved biallelic SVs and we genotype 300,000 multiallelic variable number of tandem repeats, advancing SV characterization over short-read-based population-scale surveys. We characterize deletions, duplications, insertions and inversions in distinct populations. Long interspersed nuclear element-1 (L1) and SINE-VNTR-Alu (SVA) retrotransposition activities mediate the transduction of unique sequence stretches in 5' or 3', depending on source mobile element class and locus. SV breakpoint analyses point to a spectrum of homology-mediated processes contributing to SV formation and recurrent deletion events. Our open-access resource underscores the value of long-read sequencing in advancing SV characterization and enables guiding variant prioritization in patient genomes.
The metabolic activity of soil microbiomes has a central role in global nutrient cycles. Understanding how soil metabolic activity responds to climate-driven environmental perturbations is a key challenge. However, the e...The metabolic activity of soil microbiomes has a central role in global nutrient cycles. Understanding how soil metabolic activity responds to climate-driven environmental perturbations is a key challenge. However, the ecological, spatial and chemical complexity of soils impedes understanding how these communities respond to perturbations. Here we address this complexity by combining dynamic measurements of respiratory nitrate metabolism with modelling to reveal functional regimes that define soil responses to environmental change. Measurements across more than 1,500 soil microcosms subjected to pH perturbations reveal regimes in which distinct mechanisms govern metabolite dynamics. A minimal model with two parameters, biomass activity and growth-limiting nutrient availability, predicts nitrate utilization dynamics across soils and pH perturbations. Parameter shifts under perturbation reveal three functional regimes, each linked to distinct mechanisms: (1) an acidic regime marked by cell death and suppressed metabolism; (2) a nutrient-limited regime in which dominant taxa exploit matrix-released nutrients; and (3) a resurgent growth regime driven by exponential growth of rare taxa in nutrient-rich conditions. We validated these model-derived mechanisms with nutrient measurements, amendment experiments, sequencing and isolate studies. Additional experiments and meta-analyses suggest that functional regimes are widespread in pH-perturbed soils.
Research into the palaeobiology of extinct taxa through ancient DNA and proteomics has been mostly limited to Plio-Pleistocene fossils, due to molecular breakdown over time, which is exacerbated in tropical settings. Her...Research into the palaeobiology of extinct taxa through ancient DNA and proteomics has been mostly limited to Plio-Pleistocene fossils, due to molecular breakdown over time, which is exacerbated in tropical settings. Here we sample small proteomes from the interior enamel of fossils at palaeontological sites from the Pleistocene to the Oligocene in the Turkana Basin, Kenya, which has produced a rich record of Cenozoic mammalian evolution. Through a mass-spectrometry-based proteomic workflow, and using criteria to locate diagenetiforms derived from enamel, we recover fragments of enamelin, ameloblastin, matrix metalloprotease-20 and dentin matrix acidic phosphoprotein 1 from an Early Miocene rhinocerotid and several proboscideans collected from the sites of Buluk (16 million years ago; Ma) and Loperot (18 Ma). Diagenetiform counts decline in progressively older fossils, and we observe variability in Early Miocene preservation across sites. Phylogenetic analyses reveal the contribution of these sequences to the systematic placement of extinct taxa, although we caution that this approach must account for sparse fragments, uncertainty in fragment identification and possible sequence diagenesis. We identify likely modifications that support the ancient age of these proteins, and some of the oldest examples of advanced glycation end-products yet known. The discovery of protein sequences within dense enamel tissues in one of the persistently warmest regions on Earth promises the discovery of much older proteomes that will aid in the study of the palaeobiology and evolutionary relationships of extinct taxa.
Wang X, Huang H, Jiang S
… +16 more, Kang J, Li D, Wang K, Xie S, Tong C, Liu C, Hu G, Li H, Li C, Yang L, Ding Y, Li ST, Wang F, Lohmann JU, Liang Z, Gu X
Cell functions across eukaryotes are driven by specific gene expression programs, which are dependent on chromatin structure. Here we report a single-cell multi-omics atlas of rice, one of the world's major crops. By sim...Cell functions across eukaryotes are driven by specific gene expression programs, which are dependent on chromatin structure. Here we report a single-cell multi-omics atlas of rice, one of the world's major crops. By simultaneously profiling chromatin accessibility and RNA expression in 116,564 cells from eight organs, we identified cell-type-specific gene regulatory networks and described novel cell states, such as a 'transitional state' in floral meristems. On the basis of our network analyses, we uncovered the function of the cell-type-specific regulatory hubs RSR1, F3H and LTPL120 during rice development. Our analysis revealed correlations between cell type and agronomic traits, as well as conserved and divergent cell-type functions during evolution. In summary, this study not only offers a unique single-cell multi-omics resource for a major crop but also advances our understanding of cell-type functions and the underlying molecular programs in rice.
The North Eurasian forest and forest-steppe zones have sustained millennia of sociocultural connections among northern peoples, but much of their history is poorly understood. In particular, the genomic formation of popu...The North Eurasian forest and forest-steppe zones have sustained millennia of sociocultural connections among northern peoples, but much of their history is poorly understood. In particular, the genomic formation of populations that speak Uralic and Yeniseian languages today is unknown. Here, by generating genome-wide data for 180 ancient individuals spanning this region, we show that the Early-to-Mid-Holocene hunter-gatherers harboured a continuous gradient of ancestry from fully European-related in the Baltic, to fully East Asian-related in the Transbaikal. Contemporaneous groups in Northeast Siberia were off-gradient and descended from a population that was the primary source for Native Americans, which then mixed with populations of Inland East Asia and the Amur River Basin to produce two populations whose expansion coincided with the collapse of pre-Bronze Age population structure. Ancestry from the first population, Cis-Baikal Late Neolithic-Bronze Age (Cisbaikal_LNBA), is associated with Yeniseian-speaking groups and those that admixed with them, and ancestry from the second, Yakutia Late Neolithic-Bronze Age (Yakutia_LNBA), is associated with migrations of prehistoric Uralic speakers. We show that Yakutia_LNBA first dispersed westwards from the Lena River Basin around 4,000 years ago into the Altai-Sayan region and into West Siberian communities associated with Seima-Turbino metallurgy-a suite of advanced bronze casting techniques that expanded explosively from the Altai. The 16 Seima-Turbino period individuals were diverse in their ancestry, also harbouring DNA from Indo-Iranian-associated pastoralists and from a range of hunter-gatherer groups. Thus, both cultural transmission and migration were key to the Seima-Turbino phenomenon, which was involved in the initial spread of early Uralic-speaking communities.
Five years before the 2022 multi-country mpox outbreak, Nigeria and Cameroon reported their first cases in more than three decades. Whereas the outbreak in Nigeria is recognized as an ongoing human epidemic, the drivers...Five years before the 2022 multi-country mpox outbreak, Nigeria and Cameroon reported their first cases in more than three decades. Whereas the outbreak in Nigeria is recognized as an ongoing human epidemic, the drivers of the resurgence in Cameroon remain unclear. The rate of zoonoses remains uncertain in both countries, and gaps in genomic data obscure the timing and zoonotic and geographic origin of monkeypox virus (MPXV) emergence in humans. Here, to address these uncertainties, we sequenced 118 MPXV genomes isolated from cases in Nigeria and Cameroon between 2018 and 2023. We show that in contrast to cases in Nigeria, cases in Cameroon are the result of repeated zoonoses, with two distinct zoonotic lineages circulating across the Nigeria-Cameroon border. Our findings suggest that shared animal populations in the cross-border forest ecosystems drive the emergence and spread of the virus. Accordingly, we identify the closest zoonotic outgroup to the Nigerian human epidemic lineage (hMPXV-1) in a southern Nigerian border state. We estimate that the shared ancestor of the zoonotic outgroup and hMPXV-1 circulated in animals in southern Nigeria in late 2013. We find that hMPXV-1 emerged in humans in August 2014 in the southern Rivers State and circulated undetected for three years. Rivers State was the main source of viral spread during the human epidemic. Our study sheds light on the recent establishment of MPXV in the human population and highlights the risk of persistent zoonotic emergence of MPXV in the complex border regions of Cameroon and Nigeria.
He Y, Zhang X, Peng MS
… +49 more, Li YC, Liu K, Zhang Y, Mao L, Guo Y, Ma Y, Zhou B, Zheng W, Yue T, Liao Y, Liang SA, Chen L, Zhang W, Chen X, Tang B, Yang X, Ye K, Gao S, Lu Y, Wang Y, Wan S, Hao R, Wang X, Mao Y, Dai S, Gao Z, Yang LQ, Guo J, Li J, Liu C, Wang J, Sovannary T, Bunnath L, Kampuansai J, Inta A, Srikummool M, Kutanan W, Ho HQ, Pham KD, Singthong S, Sochampa S, Kyaing UW, Pongamornkul W, Morlaeku C, Rattanakrajangsri K, Consortium of Anthropological Research in Southeast Asia and Southwest China (CASEAC), Kong QP, Zhang YP, Su B
Mainland Southeast Asia (MSEA) has rich ethnic and cultural diversity with a population of nearly 300 million. However, people from MSEA are underrepresented in the current human genomic databases. Here we present the SE...Mainland Southeast Asia (MSEA) has rich ethnic and cultural diversity with a population of nearly 300 million. However, people from MSEA are underrepresented in the current human genomic databases. Here we present the SEA3K genome dataset (phase I), generated by deep short-read whole-genome sequencing of 3,023 individuals from 30 MSEA populations, and long-read whole-genome sequencing of 37 representative individuals. We identified 79.59 million small variants and 96,384 structural variants, among which 22.83 million small variants and 24,622 structural variants are unique to this dataset. We observed a high genetic heterogeneity across MSEA populations, reflected by the varied combinations of genetic components. We identified 44 genomic regions with strong signatures of Darwinian positive selection, covering 89 genes involved in varied physiological systems such as physical traits and immune response. Furthermore, we observed varied patterns of archaic Denisovan introgression in MSEA populations, supporting the proposal of at least two distinct instances of Denisovan admixture into modern humans in Asia. We also detected genomic regions that suggest adaptive archaic introgressions in MSEA populations. The large number of novel genomic variants in MSEA populations highlight the necessity of studying regional populations that can help answer key questions related to prehistory, genetic adaptation and complex diseases.
Industrial wastewater, petroleum pollution and plastic contamination are significant threats to global marine biosecurity because of their toxic, mutagenic and persistent nature. The use of microorganisms in bioremediati...Industrial wastewater, petroleum pollution and plastic contamination are significant threats to global marine biosecurity because of their toxic, mutagenic and persistent nature. The use of microorganisms in bioremediation has been constrained by the complexity of organic pollutants and limited tolerance to saline stress. In this study, we used synthetic biology to engineer Vibrio natriegens into a strain capable of bioremediating complex organic pollutants in saline wastewater and soils. The competence master regulator gene tfoX was inserted into chromosome 1 of the V. natriegens strain Vmax and overexpressed to enhance DNA uptake and integration. Degradation gene clusters were chemically synthesized and assembled in yeast. We developed a genome engineering method (iterative natural transformation based on Vmax with amplified tfoX effect) to transfer five gene clusters (43 kb total) into Vmax. The engineered strain has the ability to bioremediate five organic pollutants (biphenyl, phenol, naphthalene, dibenzofuran and toluene) covering a broad substrate range, from monocyclic to multicyclic compounds, in industrial wastewater samples from a chlor-alkali plant and a petroleum refinery.
Indigenous groups often encounter significant challenges when asserting ancestral claims and cultural affiliations based on oral histories, particularly in the USA where such narratives have historically been undervalued...Indigenous groups often encounter significant challenges when asserting ancestral claims and cultural affiliations based on oral histories, particularly in the USA where such narratives have historically been undervalued. Although ancient DNA offers a tool to complement traditional knowledge and address gaps in oral history, longstanding disregard for Indigenous sovereignty and beliefs has understandably led many Indigenous communities to distrust DNA studies. Earlier research often focused on repatriation claims, whereas more recent work has increasingly moved towards enhancing Tribal histories. Here we present a collaborative study initiated by a federally recognized Native American tribe, the sovereign nation of Picuris Pueblo in the Northern Rio Grande region of New Mexico, USA, to address gaps in traditional knowledge and further their understanding of their population history and ancestry. We generated genomes from 16 ancient Picuris individuals and 13 present-day members of Picuris Pueblo, providing genomic data spanning the last millennium. We show genetic continuity between ancient and present-day Picuris, and more broadly with Ancestral Puebloans from Pueblo Bonito in Chaco Canyon, 275 km to the west. This suggests a firm spatiotemporal link among these Puebloan populations of the North American Southwest. Furthermore, we see no evidence of population decline before European arrival, and no Athabascan ancestry in individuals predating 1500 CE, challenging earlier migration hypotheses. This work prioritizes Indigenous control of genetic data and brings together oral tradition, archaeology, ethnography and genetics.
Feng C, Chen B, Hofer J
… +44 more, Shi Y, Jiang M, Song B, Cheng H, Lu L, Wang L, Howard A, Bendahmane A, Fouchal A, Moreau C, Sawada C, LeSignor C, Zhang C, Vikeli E, Tsanakas G, Zhao H, Cheema J, Barclay JE, Hou J, Sayers L, Wingen L, Vigouroux M, Vickers M, Ambrose M, Dalmais M, Higuera-Poveda P, Li P, Yuan Q, Spanner R, Horler R, Wouters R, Chundakkad S, Wu T, Zhao X, Li X, Sun Y, Huang Z, Wu Z, Deng XW, Steuernagel B, Domoney C, Ellis N, Chayut N, Cheng S
Mendel studied in detail seven pairs of contrasting traits in pea (Pisum sativum), establishing the foundational principles of genetic inheritance. Here we investigate the genetic architecture that underlies these traits...Mendel studied in detail seven pairs of contrasting traits in pea (Pisum sativum), establishing the foundational principles of genetic inheritance. Here we investigate the genetic architecture that underlies these traits and uncover previously undescribed alleles for the four characterized Mendelian genes, including a rare revertant of Mendel's white-flowered a allele. Primarily, we focus on the three remaining uncharacterized traits and find that (1) an approximately 100-kb genomic deletion upstream of the Chlorophyll synthase (ChlG) gene disrupts chlorophyll biosynthesis through the generation of intergenic transcriptional fusion products, conferring the yellow pod phenotype of gp mutants; (2) a MYB gene with an upstream Ogre element insertion and a CLE peptide-encoding gene with an in-frame premature stop codon explain the v and p alleles, which disrupt secondary cell wall thickening and lignification, resulting in the parchmentless, edible-pod phenotype; and (3) a 5-bp exonic deletion in a CIK-like co-receptor kinase gene, in combination with a genetic modifier locus, is associated with the fasciated stem (fa) phenotype. Furthermore, we characterize genes and alleles associated with diverse agronomic traits, such as axil ring anthocyanin pigmentation, seed size and the 'semi-leafless' form. This study establishes a foundation for fundamental research, education in biology and genetics, and pea breeding practices.
The rapid advent of high-throughput omics technologies has created an exponential growth in biological data, often outpacing our ability to derive molecular insights. Large-language models have shown a way out of this da...The rapid advent of high-throughput omics technologies has created an exponential growth in biological data, often outpacing our ability to derive molecular insights. Large-language models have shown a way out of this data deluge in natural language processing by integrating massive datasets into a joint model with manifold downstream use cases. Here we envision developing multimodal foundation models, pretrained on diverse omics datasets, including genomics, transcriptomics, epigenomics, proteomics, metabolomics and spatial profiling. These models are expected to exhibit unprecedented potential for characterizing the molecular states of cells across a broad continuum, thereby facilitating the creation of holistic maps of cells, genes and tissues. Context-specific transfer learning of the foundation models can empower diverse applications from novel cell-type recognition, biomarker discovery and gene regulation inference, to in silico perturbations. This new paradigm could launch an era of artificial intelligence-empowered analyses, one that promises to unravel the intricate complexities of molecular cell biology, to support experimental design and, more broadly, to profoundly extend our understanding of life sciences.
Rosenberger FA, Mädler SC, Thorhauge KH
… +16 more, Steigerwald S, Fromme M, Lebedev M, Weiss CAM, Oeller M, Wahle M, Metousis A, Zwiebel M, Schmacke NA, Detlefsen S, Boor P, Fabián O, Fraňková S, Krag A, Strnad P, Mann M
Protein misfolding diseases, including α1-antitrypsin deficiency (AATD), pose substantial health challenges, with their cellular progression still poorly understood. We use spatial proteomics by mass spectrometry and mac...Protein misfolding diseases, including α1-antitrypsin deficiency (AATD), pose substantial health challenges, with their cellular progression still poorly understood. We use spatial proteomics by mass spectrometry and machine learning to map AATD in human liver tissue. Combining Deep Visual Proteomics (DVP) with single-cell analysis, we probe intact patient biopsies to resolve molecular events during hepatocyte stress in pseudotime across fibrosis stages. We achieve proteome depth of up to 4,300 proteins from one-third of a single cell in formalin-fixed, paraffin-embedded tissue. This dataset reveals a potentially clinically actionable peroxisomal upregulation that precedes the canonical unfolded protein response. Our single-cell proteomics data show α1-antitrypsin accumulation is largely cell-intrinsic, with minimal stress propagation between hepatocytes. We integrated proteomic data with artificial intelligence-guided image-based phenotyping across several disease stages, revealing a late-stage hepatocyte phenotype characterized by globular protein aggregates and distinct proteomic signatures, notably including elevated TNFSF10 (also known as TRAIL) amounts. This phenotype may represent a critical disease progression stage. Our study offers new insights into AATD pathogenesis and introduces a powerful methodology for high-resolution, in situ proteomic analysis of complex tissues. This approach holds potential to unravel molecular mechanisms in various protein misfolding disorders, setting a new standard for understanding disease progression at the single-cell level in human tissue.
Guo D, Li Y, Lu H
… +21 more, Zhao Y, Kurata N, Wei X, Wang A, Wang Y, Zhan Q, Fan D, Zhou C, Lu Y, Tian Q, Weng Q, Feng Q, Huang T, Zhang L, Gu Z, Wang C, Wang Z, Wang Z, Huang X, Zhao Q, Han B
Oryza rufipogon, the wild progenitor of Asian cultivated rice Oryza sativa, is an important resource for rice breeding. Here we present a wild-cultivated rice pangenome based on 145 chromosome-level assemblies, comprisin...Oryza rufipogon, the wild progenitor of Asian cultivated rice Oryza sativa, is an important resource for rice breeding. Here we present a wild-cultivated rice pangenome based on 145 chromosome-level assemblies, comprising 129 genetically diverse O. rufipogon accessions and 16 diverse varieties of O. sativa. This pangenome contains 3.87 Gb of sequences that are absent from the O. sativa ssp. japonica cv. Nipponbare reference genome. We captured alternate assemblies that include heterozygous information missing in the primary assemblies, and identified a total of 69,531 pan-genes, with 28,907 core genes and 13,728 wild-rice-specific genes. We observed a higher abundance and a significantly greater diversity of resistance-gene analogues in wild rice than in cultivars. Our analysis indicates that two cultivated subpopulations, intro-indica and basmati, were generated through gene flows among cultivars in South Asia. We also provide strong evidence to support the theory that the initial domestication of all Asian cultivated rice occurred only once. Furthermore, we captured 855,122 differentiated single-nucleotide polymorphisms and 13,853 differentiated presence-absence variations between indica and japonica, which could be traced to the divergence of their respective ancestors and the existence of a larger genetic bottleneck in japonica. This study provides reference resources for enhancing rice breeding, and enriches our understanding of the origins and domestication process of rice.
Potatoes were first brought to Europe in the sixteenth century. Two hundred years later, one of the species had become one of the most important food sources across the entire continent and, later, even the entire world....Potatoes were first brought to Europe in the sixteenth century. Two hundred years later, one of the species had become one of the most important food sources across the entire continent and, later, even the entire world. However, its highly heterozygous, autotetraploid genome has complicated its improvement since then. Here we present the pan-genome of European potatoes generated from phased genome assemblies of ten historical potato cultivars, which includes approximately 85% of all haplotypes segregating in Europe. Sequence diversity between the haplotypes was extremely high (for example, 20× higher than in humans), owing to numerous introgressions from wild potato species. By contrast, haplotype diversity was very low, in agreement with the population bottlenecks caused by domestication and transition to Europe. To illustrate a practical application of the pan-genome, we converted it into a haplotype graph and used it to generate phased, megabase-scale pseudo-genome assemblies of commercial potatoes (including the famous French fries potato 'Russet Burbank') using cost-efficient short reads only. In summary, we present a nearly complete pan-genome of autotetraploid European potato, we describe extraordinarily high sequence diversity in a domesticated crop, and we outline how this resource might be used to accelerate genomics-assisted breeding and research.