Understanding genetic variant functionality is essential for advancing animal genomics and precision breeding.However,the lack of comprehensive functional genomic annotations in animals limits the effectiveness of mos...Understanding genetic variant functionality is essential for advancing animal genomics and precision breeding.However,the lack of comprehensive functional genomic annotations in animals limits the effectiveness of most variant function assessment methods.In this study,we gather 1030 raw epigenomic datasets from 10 animal species and systematically annotate 7 types of key regulatory regions,creating a comprehensive functional annotation map of animal genomic variants.Our findings demonstrate that integrating variants with regulatory annotations can identify tissues and cell types underlying economic traits,underscoring the utility of these annotations in functional variant discovery.Using our functional annotations,we rank the functional potential of genetic variants and classify over 127 million candidate variants into 5 functional confidence categories,with high-confidence variants significantly enriched in eQTLs and trait-associated SNPs.Incorporating these variants into genomic prediction models can improve estimated breeding value accuracy,demonstrating their practical utility in breeding programs.To facilitate the use of our results,we develop the Integrated Functional Mutation(IFmut:http://www.ifmutants.com:8212)platform,enabling researchers to explore regulatory annotations and assess the functional potential of animal variants efficiently.Our study provides a robust framework for functional genomic annotations in farm animals,enhancing variant function assessment and breeding precision.展开更多
Anti-PD-1/PD-L1 immune checkpoint blockade(ICB)therapy has revolutionized clinical cancer treatment,while abnormal PD-L1 or HLA-l expression in patients can significantly impact the therapeutic efficacy.Somatic mutati...Anti-PD-1/PD-L1 immune checkpoint blockade(ICB)therapy has revolutionized clinical cancer treatment,while abnormal PD-L1 or HLA-l expression in patients can significantly impact the therapeutic efficacy.Somatic mutations in cancer cells that modulate these critical regulators are closely associated with tumor progression and ICB response.However,a systematic interpretation of cancer immune-related mutations is stll lacking.Here,we harnessed the ABEmax system to establish a large-scale sgRNA library encompassing approximately 820,000 sgRNAs that target all feasible serine/threonine/tyrosine residues across the human genome,which systematically unveiled thousands of novel mutations that decrease or augment PD-L1 or HLA-I expression.Beyond residues associated with phosphorylation events,our screens also identified functional mutations that affect mRNA or protein stability,DNA binding capacity,protein-protein interactions,and enzymatic catalytic activity,leading to either gene inactivation or activation.Notably,we uncovered certain mutations that concurrently modulate PD-L1 and HLA-I expression,represented by the clinically relevant mutation SETD2_Y1666.We demonstrated that this mutation induces consistent phenotypic effects across multiple cancer cell lines and enhances the efficacy of immunotherapy in different tumor models.Our findings provide an unprecedented resource of functional residues that regulate cancer immunosurveillance,offering valuable guidance for clinical diagnosis,ICB therapy,and the development of innovative drugs for cancer treatment.展开更多
Congenital heart disease(CHD)is the mnost comman birth defect,with 34%of cases attrib utedto genetic variants.NOTCH1,a multi-domain transmembrane protein,regulates heart developmert bycontrolling the differantiation a...Congenital heart disease(CHD)is the mnost comman birth defect,with 34%of cases attrib utedto genetic variants.NOTCH1,a multi-domain transmembrane protein,regulates heart developmert bycontrolling the differantiation and migration of myocardial mesoderm cells,and different variants are presentin differnt types of CHD.In this review,we aim to provide a detailed description of NOTCH1 structuraldomains and their functions,highlighting NOTCH1 variants in CHD and the molecular mechanisms throughwhich they contribute to CHD occurrence,NOTCH1 has two main domains,the NOTCH extracellulardomain(NBCD)and the NOTCH intracellular domain(NICD).NECD facilitates ligand binding and NICDformation,while the NICD functions as a transcrip tion factor,forming complexes with co-factors in thenucleus to initiate gene transcription.Amnong the NOTCH1 variants associated with CHD occurrence,most are loss-of-function variants.Moreover,most of the variants are located in theEGF-like domain.Themolecular mechanism behind the NOTCH1 variant-associated CHD occurrence appears to be either due to aloss-of-function or missense variant.In the loss-of-function mutations,NOTCH1 haploinsufficiency is notedand directly reduces theNICD production,causing CHD ocaurrence.In the less common case of missensevariant,only a mild NOTCH1 malfuncticn is observed,but insufficient to directly lead to CHD occurrence.However,when a missense variant is combined with a risk factor,such as exposure to an environmentaltoxin,the cumulative effect can lead to CHD.Understanding the genetic and molecular mechanisms linkingNOTCH1 variants to CHD is crucial for improving clinical management and patient quality of life.展开更多
Body weight is a polygenic trait with intricate inheritance patterns.Functional genomics enriched with multi-layer annotations offers essential resources for exploring the genetic architecture of complex traits.In thi...Body weight is a polygenic trait with intricate inheritance patterns.Functional genomics enriched with multi-layer annotations offers essential resources for exploring the genetic architecture of complex traits.In this study,we conducted an extensive characterization of regulatory variants associated with body weight-related traits in cattle using multi-omics analysis.First,we identified seven candidate genes by integrating selective sweep analysis and multiple genome-wide association study(GWAS)strategies using imputed whole-genome sequencing data from a population of 1577 individuals.Subsequently,we uncovered 3340 eGenes(genes whose expression levels are associated with genetic variants)across 227 muscle samples.Transcriptome-wide association studies(TWASs)further revealed a total of 532 distinct candidate genes associated with body weight-related traits.Colocalization analyses unveiled 44 genes shared between expression quantitative trait loci(eQTLs)and GWAS signals.Moreover,a comprehensive analysis by integrating GWAS,selective sweep,eQTL,TWAS,epigenomic profiling,and molecular validation highlighted a positively selected genomic region on Bos taurus autosome 6(BTA6).This locus harbors pleiotropic genes(LAP3,MED28,and NCAPG)and a prioritized functional variant involved in the complex regulation of body weight.Additionally,convergent evolution analysis and phenome-wide association studies underscored the conservation of this locus across species.Our study provides a comprehensive understanding of the genetic regulation of body weight through multi-omics analysis in cattle.Our findings contribute to unraveling the genetic mechanisms governing weight-related traits and shed valuable light on the genetic improvement of farm animals.展开更多
基金supported by the National Natural Science Foundation of China(32341051)the grant from Department of Agriculture and Rural Affairs of Hubei Province(HBZY2023B006-02)+2 种基金the National Funding(2023ZD04050)the National Natural Science Foundation of China Outstanding Youth(32125035)the National Key R&D Young Scientists Project(2022YFD1302000).
文摘Understanding genetic variant functionality is essential for advancing animal genomics and precision breeding.However,the lack of comprehensive functional genomic annotations in animals limits the effectiveness of most variant function assessment methods.In this study,we gather 1030 raw epigenomic datasets from 10 animal species and systematically annotate 7 types of key regulatory regions,creating a comprehensive functional annotation map of animal genomic variants.Our findings demonstrate that integrating variants with regulatory annotations can identify tissues and cell types underlying economic traits,underscoring the utility of these annotations in functional variant discovery.Using our functional annotations,we rank the functional potential of genetic variants and classify over 127 million candidate variants into 5 functional confidence categories,with high-confidence variants significantly enriched in eQTLs and trait-associated SNPs.Incorporating these variants into genomic prediction models can improve estimated breeding value accuracy,demonstrating their practical utility in breeding programs.To facilitate the use of our results,we develop the Integrated Functional Mutation(IFmut:http://www.ifmutants.com:8212)platform,enabling researchers to explore regulatory annotations and assess the functional potential of animal variants efficiently.Our study provides a robust framework for functional genomic annotations in farm animals,enhancing variant function assessment and breeding precision.
基金supported by funds from Changping Laboratory,the National Natural Science Foundation of China(NSFC 31930016)Beijing Advanced Innovation Center for Genomics at Peking University,and the Peking-Tsinghua Center for Life Sciences(to W.W.)+2 种基金Additional support was provided by the China Postdoctoral Science Foundation(2020M670031,to Y.L2020M670053,to Y-S.L.)the Taishan Scholarship(tsqn202312362,to Y-S.L.).
文摘Anti-PD-1/PD-L1 immune checkpoint blockade(ICB)therapy has revolutionized clinical cancer treatment,while abnormal PD-L1 or HLA-l expression in patients can significantly impact the therapeutic efficacy.Somatic mutations in cancer cells that modulate these critical regulators are closely associated with tumor progression and ICB response.However,a systematic interpretation of cancer immune-related mutations is stll lacking.Here,we harnessed the ABEmax system to establish a large-scale sgRNA library encompassing approximately 820,000 sgRNAs that target all feasible serine/threonine/tyrosine residues across the human genome,which systematically unveiled thousands of novel mutations that decrease or augment PD-L1 or HLA-I expression.Beyond residues associated with phosphorylation events,our screens also identified functional mutations that affect mRNA or protein stability,DNA binding capacity,protein-protein interactions,and enzymatic catalytic activity,leading to either gene inactivation or activation.Notably,we uncovered certain mutations that concurrently modulate PD-L1 and HLA-I expression,represented by the clinically relevant mutation SETD2_Y1666.We demonstrated that this mutation induces consistent phenotypic effects across multiple cancer cell lines and enhances the efficacy of immunotherapy in different tumor models.Our findings provide an unprecedented resource of functional residues that regulate cancer immunosurveillance,offering valuable guidance for clinical diagnosis,ICB therapy,and the development of innovative drugs for cancer treatment.
基金the National Natural Science Foundation of China,GrantNos.82100321 and 82370353.
文摘Congenital heart disease(CHD)is the mnost comman birth defect,with 34%of cases attrib utedto genetic variants.NOTCH1,a multi-domain transmembrane protein,regulates heart developmert bycontrolling the differantiation and migration of myocardial mesoderm cells,and different variants are presentin differnt types of CHD.In this review,we aim to provide a detailed description of NOTCH1 structuraldomains and their functions,highlighting NOTCH1 variants in CHD and the molecular mechanisms throughwhich they contribute to CHD occurrence,NOTCH1 has two main domains,the NOTCH extracellulardomain(NBCD)and the NOTCH intracellular domain(NICD).NECD facilitates ligand binding and NICDformation,while the NICD functions as a transcrip tion factor,forming complexes with co-factors in thenucleus to initiate gene transcription.Amnong the NOTCH1 variants associated with CHD occurrence,most are loss-of-function variants.Moreover,most of the variants are located in theEGF-like domain.Themolecular mechanism behind the NOTCH1 variant-associated CHD occurrence appears to be either due to aloss-of-function or missense variant.In the loss-of-function mutations,NOTCH1 haploinsufficiency is notedand directly reduces theNICD production,causing CHD ocaurrence.In the less common case of missensevariant,only a mild NOTCH1 malfuncticn is observed,but insufficient to directly lead to CHD occurrence.However,when a missense variant is combined with a risk factor,such as exposure to an environmentaltoxin,the cumulative effect can lead to CHD.Understanding the genetic and molecular mechanisms linkingNOTCH1 variants to CHD is crucial for improving clinical management and patient quality of life.
基金supported by the National Key R&D Program of China(Grant No.2022YFF1000600)the National Natural Science Foundation of China(Grant No.31972554)+4 种基金supported by the Agricultural Science and Technology Innovation Program of the Chinese Academy of Agricultural Sciences(Grant Nos.ASTIP-IAS-TS-16 and ASTIP-IAS03)the National Beef Cattle Industrial Technology System(Grant No.CARS-37)supported in part by the Agriculture and Food Research Initiative(AFRI)(Grant Nos.2019-67015-29321 and 2021-67015-33409)from the United States Department of Agriculture(USDA)National Institute of Food and Agriculture(NIFA)Animal Genome and Reproduction ProgramsLingyang Xu was supported by the Elite Youth Scientists Program of the Chinese Academy of Agricultural Sciences.
文摘Body weight is a polygenic trait with intricate inheritance patterns.Functional genomics enriched with multi-layer annotations offers essential resources for exploring the genetic architecture of complex traits.In this study,we conducted an extensive characterization of regulatory variants associated with body weight-related traits in cattle using multi-omics analysis.First,we identified seven candidate genes by integrating selective sweep analysis and multiple genome-wide association study(GWAS)strategies using imputed whole-genome sequencing data from a population of 1577 individuals.Subsequently,we uncovered 3340 eGenes(genes whose expression levels are associated with genetic variants)across 227 muscle samples.Transcriptome-wide association studies(TWASs)further revealed a total of 532 distinct candidate genes associated with body weight-related traits.Colocalization analyses unveiled 44 genes shared between expression quantitative trait loci(eQTLs)and GWAS signals.Moreover,a comprehensive analysis by integrating GWAS,selective sweep,eQTL,TWAS,epigenomic profiling,and molecular validation highlighted a positively selected genomic region on Bos taurus autosome 6(BTA6).This locus harbors pleiotropic genes(LAP3,MED28,and NCAPG)and a prioritized functional variant involved in the complex regulation of body weight.Additionally,convergent evolution analysis and phenome-wide association studies underscored the conservation of this locus across species.Our study provides a comprehensive understanding of the genetic regulation of body weight through multi-omics analysis in cattle.Our findings contribute to unraveling the genetic mechanisms governing weight-related traits and shed valuable light on the genetic improvement of farm animals.
