Evidence has shown that differential transcriptomic profiles among human populations from diverse ancestries,supporting the role of genetic architecture in regulating gene expression alongside environmental stimuli.Ge...Evidence has shown that differential transcriptomic profiles among human populations from diverse ancestries,supporting the role of genetic architecture in regulating gene expression alongside environmental stimuli.Genetic variants that regulate gene expression,known as expression quantitative trait loci(eQTL),are primarily shaped by human migration history and evolutionary forces,likewise,regulation of gene expression in principle could have been influenced by these events.Therefore,a comprehensive understanding of how human evolution impacts eQTL offers important insights into how phenotypic diversity is shaped.Recent studies,however,suggest that eQTL is enriched in genes that are selectively constrained.Whether eQTL is minimally affected by selective pressures remains an open question and requires comprehensive investigations.In addition,such studies are primarily dominated by the major populations of European ancestry,leaving many marginalized populations underrepresented.These observations indicate there exists a fundamental knowledge gap in the role of genomics variation on phenotypic diversity,which potentially hinders precision medicine.This article aims to revisit the abundance of eQTL across diverse populations and provide an overview of their impact from the population and evolutionary genetics perspective,subsequently discuss their influence on phenomics,as well as challenges and opportunities in the applications to precision medicine.展开更多
Medical genetics is the newest cutting-edge discipline that focuses on solving medical problems using genetics knowledge and methods. In China, medical genetics research activities initiated from a poor inner basis bu...Medical genetics is the newest cutting-edge discipline that focuses on solving medical problems using genetics knowledge and methods. In China, medical genetics research activities initiated from a poor inner basis but a prosperous outer environment. During the 40 years of reform and opening-up policy,Chinese scientists contributed significantly in the field of medical genetics, garnering considerable attention worldwide. In this review, we highlight the significant findings and/or results discovered by Chinese scientists in monogenic diseases, complex diseases, cancer, genetic diagnosis, as well as gene manipulation and gene therapy. Due to these achievements, China is widely recognized to be at the forefront of medical genetics research and development. However, the significant progress and development that has been achieved could not have been accomplished without sufficient funding and a wellconstructed logistics network. The successful implementation of translational and precise medicine sourced from medical genetics will depend on an open ethics policy and intellectual property protection,along with strong support at the national industry level.展开更多
Individuals with congenital absence of the vas deferens(CAVD)may transmit cystic fibrosis(CF)-causing variants of the cystic fibrosis transmembrane conductance regulator(CFTR)gene to their offspring through assisted r...Individuals with congenital absence of the vas deferens(CAVD)may transmit cystic fibrosis(CF)-causing variants of the cystic fibrosis transmembrane conductance regulator(CFTR)gene to their offspring through assisted reproductive technology(ART).We aimed to delineate the spectrum and estimate the prevalence of CF-causing variants in Chinese individuals with CAVD through a cohort analysis and meta-analysis.CFTR was sequenced in 145 Chineseindividuals with CAVD.CFTR variants were classified as CF-causing or non-CF-causing variants regarding clinical significance.A comprehensive genotype analysis was performed in Chinese individuals with CAVD,incorporating previous studies and our study cohort.The prevalence of CF-causing variants was estimated through meta-analysis.In our cohort,56 differentCFTR variants were identified in 108(74.5%)patients.Twenty variants were categorized as CF-causing and were detected in 28(19.3%)patients.A comprehensive genotype analysis of 867 patients identified 174 differentCFTR variants.Sixty-four were classified as CF-causing variants,56.3%of which had not been previously reported in Chinese patients with CF.Meta-analysis showed that 14.8%(95%confidence interval[CI]:11.0%-18.9%)CAVD cases harbored one CF-causing variant,and 68.6%(95%CI:65.1%-72.0%)CAVD cases carried at least one CFTR variant.Our study underscores the urgent need for extensiveCFTR screening,including sequencing of whole exons and flanking regions and detection of large rearrangements and deep intronic CF-causing variants,in Chinese individuals with CAVDbefore undergoing ART.The established CF-causing variants spectrum may aid in the development of genetic counseling strategies and preimplantation diagnosis to prevent the birth of a child with CF.展开更多
Mitochondria play a key role in lipid metabolism,and mitochondrial DNA(mtDNA)mutations are thus considered to affect obesity susceptibility by altering oxidative phosphorylation and mitochondrial function.In this stud...Mitochondria play a key role in lipid metabolism,and mitochondrial DNA(mtDNA)mutations are thus considered to affect obesity susceptibility by altering oxidative phosphorylation and mitochondrial function.In this study,we investigate mtDNA variants that may affect obesity risk in 2877 Han Chinese individuals from 3 independent populations.The association analysis of 16 basal mtDNA haplogroups with body mass index,waist circumference,and waist-to-hip ratio reveals that only haplogroup M7 is significantly negatively correlated with all three adiposity-related anthropometric traits in the overall cohort,verified by the analysis of a single population,i.e.,the Zhengzhou population.Furthermore,subhaplogroup analysis suggests that M7b1a1 is the most likely haplogroup associated with a decreased obesity risk,and the variation T12811C(causing Y159H in ND5)harbored in M7b1a1 may be the most likely candidate for altering the mitochondrial function.Specifically,we find that proportionally more nonsynonymous mutations accumulate in M7b1a1 carriers,indicating that M7b1a1 is either under positive selection or subject to a relaxation of selective constraints.We also find that nuclear variants,especially in DACT2 and PIEZO1,may functionally interact with M7b1a1.展开更多
Shandong province,located in the Lower Yellow River,is one of the birthplaces of ancient Chinese civilization.However,the comprehensive genetic histories of this region have remained largely unknown until now due to a...Shandong province,located in the Lower Yellow River,is one of the birthplaces of ancient Chinese civilization.However,the comprehensive genetic histories of this region have remained largely unknown until now due to a lack of ancient human genomes.Here,we present 21 ancient genomes from Shandong dating from the Warring States period to the Northern Dynasties.Unlike the early Neolithic samples from Shandong,the historical samples are most closely related to post-Late Neolithic populations of the Middle Yellow River Basin,suggesting a population turnover in Shandong from the Neolithic Age to the Historical era.In addition,we detect a close genetic affinity between the historical samples in Shandong and present-day Han Chinese,showing long-term genetic stability in Han Chinese,at least since the Warring States period.展开更多
China's Northern and Southern Dynasties period(3rd–6th centuries AD)marked a significant era of ethnic integration in northern China.However,previous ancient DNA studies have primarily focused on northern ethnic ...China's Northern and Southern Dynasties period(3rd–6th centuries AD)marked a significant era of ethnic integration in northern China.However,previous ancient DNA studies have primarily focused on northern ethnic groups,with limited research on the genetic formation of the hereditary elite family,especially considering their abundant archaeological record and clear material identity.In this study,we obtain the ancient genome of a hereditary elite family,Gao Bin(高宾,503 AD–572 AD),at 0.6473-fold coverage with 475,132 single-nucleotide polymorphisms(SNPs)on the 1240k panel.His mitochondrial haplogroup belongs to Z4 and Y-haplogroup to O1a1a2b-F2444∗.The genetic profile of Gao Bin is most similar to that of the northern Han Chinese.He can be modeled as deriving all his ancestry from Late Neolithic to Iron Age Yellow River farmers without influence from Northeast Asia,Korea,or the Mongolian Plateau.Our study sheds light on the genetic formation of hereditary elite families in the context of the Southern and Northern Dynasties ethnic integration.展开更多
Facial morphology,a complex trait influenced by genetics,holds great significance in evolutionary research.However,due to limited fossil evidence,the facial characteristics of Neanderthals and Denisovans have remained...Facial morphology,a complex trait influenced by genetics,holds great significance in evolutionary research.However,due to limited fossil evidence,the facial characteristics of Neanderthals and Denisovans have remained largely unknown.In this study,we conduct a large-scale multi-ethnic meta-analysis of the genome-wide association study(GWAS),including 9674 East Asians and 10,115 Europeans,quantitatively assessing 78 facial traits using 3D facial images.We identify 71 genomic loci associated with facial features,including 21 novel loci.We develop a facial polygenic score(FPS)that enables the prediction of facial features based on genetic information.Interestingly,the distribution of FPSs among populations from diverse continental groups exhibits relevant correlations with observed facial features.Furthermore,we apply the FPS to predict the facial traits of seven Neanderthals and one Denisovan using ancient DNA and align predictions with the fossil records.Our results suggest that Neanderthals and Denisovans likely share similar facial features,such as a wider but shorter nose and a wider endocanthion distance.The decreased mouth width is characterized specifically in Denisovans.The integration of genomic data and facial trait analysis provides valuable insights into the evolutionary history and adaptive changes in human facial morphology.展开更多
Asthma is a common chronic inflammatory disorder that is more prevalent in children than in adults.China has seen an increasing prevalence of childhood asthma in recentdecades[1].Earlier studies have shown that air pa...Asthma is a common chronic inflammatory disorder that is more prevalent in children than in adults.China has seen an increasing prevalence of childhood asthma in recentdecades[1].Earlier studies have shown that air particulate matter (PM),particularly fine particulate matter(PM2.5)[2],is an important factor triggering childhood asthma. Since nationalPM2.5data were nota vailabl euntil 2013,展开更多
Microtus fortis is the only mammalian host that exhibits intrinsic resistance against Schistosoma japonicum infection.However,the underlying molecular mechanisms of this resistance are not yet known.Here,we perform th...Microtus fortis is the only mammalian host that exhibits intrinsic resistance against Schistosoma japonicum infection.However,the underlying molecular mechanisms of this resistance are not yet known.Here,we perform the first de novo genome assembly of M.fortis,comprehensive gene annotation analysis,and evolution analysis.Furthermore,we compare the recovery rate of schistosomes,pathological changes,and liver transcriptomes between M.fortis and mice at different time points after infection.We observe that the time and type of immune response in M.fortis are different from those in mice.M.fortis activates immune and inflammatory responses on the 10th day post infection,such as leukocyte extravasation,antibody activation,Fc-gamma receptor-mediated phagocytosis,and the interferon signaling cascade,which play important roles in preventing the development of schistosomes.In contrast,an intense immune response occurrs in mice at the late stages of infection and could not eliminate schistosomes.Infected mice suffer severe pathological injury and continuous decreases in cell cycle,lipid metabolism,and other functions.Our findings offer new insights into the intrinsic resistance mechanism of M.fortis against schistosome infection.The genome sequence also provides the basis for future studies of other important traits in M.fortis.展开更多
Understanding the micro-coevolution of the human gut microbiome with host genetics is challenging but essential in both evolutionary and medical studies.To gain insight into the interactions between host genetic varia...Understanding the micro-coevolution of the human gut microbiome with host genetics is challenging but essential in both evolutionary and medical studies.To gain insight into the interactions between host genetic variation and the gut microbiome,we analyzed both the human genome and gut microbiome collected from a cohort of 190 students in the same boarding college and representing 3 ethnic groups,Uyghur,Kazakh,and Han Chinese.We found that differences in gut microbiome were greater between genetically distinct ethnic groups than those genetically closely related ones in taxonomic composition,functional composition,enterotype stratification,and microbiome genetic differentiation.We also observed considerable correlations between host genetic variants and the abundance of a subset of gut microbial species.Notably,interactions between gut microbiome species and host genetic variants might have coordinated effects on specific human phenotypes.Bacteroides ovatus,previously reported to modulate intestinal immunity,is significantly correlated with the host genetic variant rs12899811(meta-P=5.55×10^(-5)),which regulates the VPS33B expression in the colon,acting as a tumor suppressor of colorectal cancer.These results advance our understanding of the micro-coevolution of the human gut microbiome and their interactive effects with host genetic variation on phenotypic diversity.展开更多
Animal models are increasingly gaining values by cross-comparisons of response or resistance to clinical agents used for patients.However,many disease mechanisms and drug effects generated from animal models are not t...Animal models are increasingly gaining values by cross-comparisons of response or resistance to clinical agents used for patients.However,many disease mechanisms and drug effects generated from animal models are not transferable to human.To address these issues,we developed SysFinder（http：//lifecenter.sgst.cn/SysFinder）,a platform for scientists to find appropriate animal models for translational research.SysFinder offers a ＂topic-centered＂ approach for systematic comparisons of human genes,whose functions are involved in a specific scientific topic,to the corresponding homologous genes of animal models.Scientific topic can be a certain disease,drug,gene function or biological pathway.SysFinder calculates multi-level similarity indexes to evaluate the similarities between human and animal models in specified scientific topics.Meanwhile,SysFinder offers species-specific information to investigate the differences in molecular mechanisms between humans and animal models.Furthermore,SysFinder provides a userfriendly platform for determination of short guide RNAs（sgRNAs） and homology arms to design a new animal model.Case studies illustrate the ability of SysFinder in helping experimental scientists.SysFinder is a useful platform for experimental scientists to carry out their research in the human molecular mechanisms.展开更多
Teratozoospermia with cephalic defects is one of the most severe types of sperm defects known to date.While several monogenic factors are linked to cephalic abnormalities,such as globozoospermia and macrozoospermia,th...Teratozoospermia with cephalic defects is one of the most severe types of sperm defects known to date.While several monogenic factors are linked to cephalic abnormalities,such as globozoospermia and macrozoospermia,the genetic cause of vacuolated spermatozoa remains inadequately described.Here,we analyzed whole-exome sequencing(WES)data for an individual from a consanguineous family with severely vacuolated spermatozoa.The analysis revealed a novel homozygous c.520A>G(p.Thr174Ala)variant in the archaelysin family metallopeptidase 2(AMZ2),a gene that encodes a zinc metalloprotease previously shown to be highly expressed in the testes and sperm.Multiple algorithms predicted this variant to be a damaging mutation.Consistent with an autosomal recessive mode of inheritance,this variant was inherited from heterozygous parental carriers.To investigate the potential pathogenicity of the identified variant,we compared the AMZ2 expression in sperm cells from the patient with the AMZ2 variant and from a healthy control.Immunoblot analysis revealed that the homozygous missense variant in AMZ2 abolished AMZ2 expression in the spermatozoa.Our findings reveal a candidate causative gene for vacuolated spermatozoa.展开更多
Climate has changed sufficiently over the last 150 years and forced out upper treeline advance at the most studied sites around the world.The rate of advance has been extremely variable–from tens to hundreds meters i...Climate has changed sufficiently over the last 150 years and forced out upper treeline advance at the most studied sites around the world.The rate of advance has been extremely variable–from tens to hundreds meters in altitude.This is because the degree at which tree frontal populations respond to climate change depends on the complex interaction of biological and physical factors.The resulting stand pattern is the consequence of the interaction between dispersal and survival functions.A few publications have addressed the question of how this pattern is generated.In order to understand how the spatial structure of tree stands was formed at the upper limit of their distribution in the Ural Mountains,we assessed the distance and direction of dispersal of offspring from maternal individuals.We found that in frontal Larix sibirica Ledeb.populations,‘effective’dispersal of offspring ranges from 3 to 758 m(with a median of 20–33 m in open forest and 219 m in single-tree tundra in the Polar Urals and 107 m in open forest in the Northern Urals).We revealed that most of the offspring effectively dispersed not only in the direction of the prevailing winds,but also in the opposite direction up the slope,and the distance can reach 500–760 m.The data obtained can be used to develop an individual-based model which is capable of simulating in detail the dynamics of tree stands at the upper limit of their growth and reliably predicting the future position and pattern of treeline ecotone as growth conditions continue to improve in the face of observed climate change.展开更多
Background:Tumor-derived exosomes are involved in tumor progression and immune invasion and might func-tion as promising noninvasive approaches for clinical management.However,there are few reports on exosom-based mar...Background:Tumor-derived exosomes are involved in tumor progression and immune invasion and might func-tion as promising noninvasive approaches for clinical management.However,there are few reports on exosom-based markers for predicting the progression and adjuvant therapy response rate among patients with clear cell renal cell carcinoma(ccRCC).Methods:The signatures differentially expressed in exosomes from tumor and normal tissues from ccRCC pa-tients were correspondingly deregulated in ccRCC tissues.We adopted a two-step strategy,including Lasso and bootstrapping,to construct a novel risk stratification system termed the TDERS(Tumor-Derived Exosome-Related Risk Score).During the testing and validation phases,we leveraged multiple external datasets containing over 2000 RCC cases from eight cohorts and one inhouse cohort to evaluate the accuracy of the TDERS.In addition,enrichment analysis,immune infiltration signatures,mutation landscape and therapy sensitivity between the high and low TDERS groups were compared.Finally,the impact of TDERS on the tumor microenvironment(TME)was also analysed in our single-cell datasets.Results:TDERS consisted of 12 mRNAs deregulated in both exosomes and tissues from patients with ccRCC.TDERS achieved satisfactory performance in both prognosis and immune checkpoint inhibitor(ICI)response across all ccRCC cohorts and other pathological types,since the average area under the curve(AUC)to predict 5-year overall survival(OS)was larger than 0.8 across the four cohorts.Patients in the TDERS high group were resistant to ICIs,while mercaptopurine might function as a promising agent for those patients.Patients with a high TDERS were characterized by coagulation and hypoxia,which induced hampered tumor antigen presentation and relative resistance to ICIs.In addition,single cells from 12 advanced samples validated this phenomenon since the interaction between dendritic cells and macrophages was limited.Finally,PLOD2,which is highly expressed in fibro-and epi-tissue,could be a potential therapeutic target for ccRCC patients since inhibiting PLOD2 altered the malignant phenotype of ccRCC in vitro.Conclusion:As a novel,non-invasive,and repeatable monitoring tool,the TDERS could work as a robust risk stratification system for patients with ccRCC and precisely inform treatment decisions about ICI therapy.展开更多
To the Editor:Psoriatic arthritis(PsA)affects up to 30%of patients with psoriasis,contributing to a decreased quality of life.PsA can involve a variety of clinical manifestations,including peripheral and axial arthrit...To the Editor:Psoriatic arthritis(PsA)affects up to 30%of patients with psoriasis,contributing to a decreased quality of life.PsA can involve a variety of clinical manifestations,including peripheral and axial arthritis,enthesitis,dactylitis,and nail disease.[1]Early intervention is important for preventing loss of function and permanent disability;however,the diagnosis of PsA is often delayed by an average of five years.[1]Therefore,it is important to identify biomarkers that can detect PsA in patients with psoriasis.展开更多
The human face harbors a rich tapestry of complex phenotypic information spanning genetic,environmental,and physiological dimensions.While facial images excel in diagnosing genetic diseases,their untapped potential fo...The human face harbors a rich tapestry of complex phenotypic information spanning genetic,environmental,and physiological dimensions.While facial images excel in diagnosing genetic diseases,their untapped potential for predicting metabolic health presents an intriguing prospect.Metabolic Syndrome(Met S),marked by a constellation of metabolic abnormalities,poses a significant risk for various chronic diseases.Utilizing Face-Wide Association Studies(Fa WAS)on a discovery cohort of 2,621 Chinese individuals and a replication cohort of 2,188 Chinese individuals,we investigated the associations between facial features and Met S and its related conditions.Our findings highlight half of our investigated facial features strongly correlated with Met S risk,such as a slender forehead,a broader and shorter jawline,and fuller features around the temples-eye-cheek region,with notable genetic correlations(0.55–0.58)and influences from environmental factors like age,urban residency,and educational level.The developed face-based prediction model demonstrated significant predictive robustness,achieving an AUC of up to 0.87 for Met S and 0.89 for obesity in external validations,surpassing traditional 2D imaging techniques.Our model also aids in identifying subtypes within healthy populations,with a 2.07 to 2.40-fold increased risk of developing different metabolic disorders within the next five years.This paves the way for precise risk stratification of individuals who are‘at risk'.Integrating 3D facial imaging for metabolic health predictions,our research introduces an innovative,non-invasive framework for health assessment and subtype identification,demonstrating high potential in personalized medicine and health monitoring.展开更多
Next-generation sequencing technologies have significantly accelerated the identification of disease-causing mutations and facilitated the emergence of personalized medicine(Genomes Project Consortium et al.,2015;Good...Next-generation sequencing technologies have significantly accelerated the identification of disease-causing mutations and facilitated the emergence of personalized medicine(Genomes Project Consortium et al.,2015;Goodwin et al.,2016;Sirugo et al.,2019).In comparison with whole-genome sequencing,whole-exome sequencing(WES),which covers the coding regions of the genome,offers a cost-efficacy balance.WES provides deeper sequencing depth(>100)and allows the more accurate detection of rare variants that are tailored for clinical applications(Lek et al.,2016).展开更多
RNase MRP RNA is the RNA subunit of the RNase mitochondrial RNA processing （MRP） enzyme complex that is involved in multiple cellular RNA processing events. Mutations on RNase MRP RNA gene （RMRP） cause a recessive...RNase MRP RNA is the RNA subunit of the RNase mitochondrial RNA processing （MRP） enzyme complex that is involved in multiple cellular RNA processing events. Mutations on RNase MRP RNA gene （RMRP） cause a recessively inherited developmental disorder, cartilage-hair hypoplasia （CHH）. The relationship of the genotype （RMRP mutation）, RNA processing deficiency of the RNase MRP complex, and the phenotype of CHH and other skeletal dysplasias is yet to be explored.展开更多
Petaloid toenail, or accessory nail of the fifth toe, is a physical trait characterized by the presence of an additional tiny toenail on the small toe. Since it can occasionally cause disfigurement and tenderness whil...Petaloid toenail, or accessory nail of the fifth toe, is a physical trait characterized by the presence of an additional tiny toenail on the small toe. Since it can occasionally cause disfigurement and tenderness while wearing tight shoes or walking, standard surgical matricectomy is often carried out to repair the petaloid toenail （Chi and Wang, 2004）. Chinese legends recorded petaloid toenails as a trait unique to Han Chinese （Gao, 2010）, but population- based studies are largely absent.展开更多
基金supported by the Ministry of Higher Education(MOHE)Malaysia through Fundamental Research Grant Scheme(FRGS)with project code:FRGS/1/2021/STG01/UCSI/01/.SX was funded by the National Natural Science Foundation of China(NSFC)grants 32030020 and 32288101funded by the NSFC grant 32270665.
文摘Evidence has shown that differential transcriptomic profiles among human populations from diverse ancestries,supporting the role of genetic architecture in regulating gene expression alongside environmental stimuli.Genetic variants that regulate gene expression,known as expression quantitative trait loci(eQTL),are primarily shaped by human migration history and evolutionary forces,likewise,regulation of gene expression in principle could have been influenced by these events.Therefore,a comprehensive understanding of how human evolution impacts eQTL offers important insights into how phenotypic diversity is shaped.Recent studies,however,suggest that eQTL is enriched in genes that are selectively constrained.Whether eQTL is minimally affected by selective pressures remains an open question and requires comprehensive investigations.In addition,such studies are primarily dominated by the major populations of European ancestry,leaving many marginalized populations underrepresented.These observations indicate there exists a fundamental knowledge gap in the role of genomics variation on phenotypic diversity,which potentially hinders precision medicine.This article aims to revisit the abundance of eQTL across diverse populations and provide an overview of their impact from the population and evolutionary genetics perspective,subsequently discuss their influence on phenomics,as well as challenges and opportunities in the applications to precision medicine.
基金supported by Ministry of Science and Technology Project (2017YFC1001302 and 2016YFC0906400)the Grant of Shanghai Brain-Intelligence Project from the Shanghai Science and Technology Committee (STCSM) (16JC1420500)Shanghai Jiao Tong University Medical Engineering Cross Research Foundation (YG2014MS07)
文摘Medical genetics is the newest cutting-edge discipline that focuses on solving medical problems using genetics knowledge and methods. In China, medical genetics research activities initiated from a poor inner basis but a prosperous outer environment. During the 40 years of reform and opening-up policy,Chinese scientists contributed significantly in the field of medical genetics, garnering considerable attention worldwide. In this review, we highlight the significant findings and/or results discovered by Chinese scientists in monogenic diseases, complex diseases, cancer, genetic diagnosis, as well as gene manipulation and gene therapy. Due to these achievements, China is widely recognized to be at the forefront of medical genetics research and development. However, the significant progress and development that has been achieved could not have been accomplished without sufficient funding and a wellconstructed logistics network. The successful implementation of translational and precise medicine sourced from medical genetics will depend on an open ethics policy and intellectual property protection,along with strong support at the national industry level.
基金supported by the National Natural Science Foundation of China(grant No.82171588)the Fundamental Research Funds for the Central Institutes(grant No.2023GJZD01).
文摘Individuals with congenital absence of the vas deferens(CAVD)may transmit cystic fibrosis(CF)-causing variants of the cystic fibrosis transmembrane conductance regulator(CFTR)gene to their offspring through assisted reproductive technology(ART).We aimed to delineate the spectrum and estimate the prevalence of CF-causing variants in Chinese individuals with CAVD through a cohort analysis and meta-analysis.CFTR was sequenced in 145 Chineseindividuals with CAVD.CFTR variants were classified as CF-causing or non-CF-causing variants regarding clinical significance.A comprehensive genotype analysis was performed in Chinese individuals with CAVD,incorporating previous studies and our study cohort.The prevalence of CF-causing variants was estimated through meta-analysis.In our cohort,56 differentCFTR variants were identified in 108(74.5%)patients.Twenty variants were categorized as CF-causing and were detected in 28(19.3%)patients.A comprehensive genotype analysis of 867 patients identified 174 differentCFTR variants.Sixty-four were classified as CF-causing variants,56.3%of which had not been previously reported in Chinese patients with CF.Meta-analysis showed that 14.8%(95%confidence interval[CI]:11.0%-18.9%)CAVD cases harbored one CF-causing variant,and 68.6%(95%CI:65.1%-72.0%)CAVD cases carried at least one CFTR variant.Our study underscores the urgent need for extensiveCFTR screening,including sequencing of whole exons and flanking regions and detection of large rearrangements and deep intronic CF-causing variants,in Chinese individuals with CAVDbefore undergoing ART.The established CF-causing variants spectrum may aid in the development of genetic counseling strategies and preimplantation diagnosis to prevent the birth of a child with CF.
基金supported by the National Natural Science Foundation of China(32270670,32288101,32271186,and 32200482)the National Basic Research Program of China(2015FY111700)the CAMS Innovation Fund for Medical Sciences(2019-I2M-5-066).
文摘Mitochondria play a key role in lipid metabolism,and mitochondrial DNA(mtDNA)mutations are thus considered to affect obesity susceptibility by altering oxidative phosphorylation and mitochondrial function.In this study,we investigate mtDNA variants that may affect obesity risk in 2877 Han Chinese individuals from 3 independent populations.The association analysis of 16 basal mtDNA haplogroups with body mass index,waist circumference,and waist-to-hip ratio reveals that only haplogroup M7 is significantly negatively correlated with all three adiposity-related anthropometric traits in the overall cohort,verified by the analysis of a single population,i.e.,the Zhengzhou population.Furthermore,subhaplogroup analysis suggests that M7b1a1 is the most likely haplogroup associated with a decreased obesity risk,and the variation T12811C(causing Y159H in ND5)harbored in M7b1a1 may be the most likely candidate for altering the mitochondrial function.Specifically,we find that proportionally more nonsynonymous mutations accumulate in M7b1a1 carriers,indicating that M7b1a1 is either under positive selection or subject to a relaxation of selective constraints.We also find that nuclear variants,especially in DACT2 and PIEZO1,may functionally interact with M7b1a1.
基金funded by the Shandong Province Humanities and Social Sciences Project“Sorting and Research on Human Bones of Han Dynasty Excavated from the Medical Center Cemetery in Linzi”granted to Zhigang Wu(2022-JCLS-12)the National Key Research and Development Program(2023YFC3303701-02)+5 种基金the National Natural Science Foundation of China(32270667)the Natural Science Foundation of Fujian Province of China(2023J06013)the Major Project of the National Social Science Foundation of China granted to Chuan-Chao Wang(21&ZD285)Open Research Fund of State Key Laboratory of Genetic Engineering at Fudan University(No.SKLGE-2310)Open Research Fund of Forensic Genetics Key Laboratory of the Ministry of Public Security(2023FGKFKT07)Major Special Project of Philosophy and Social Sciences Research of the Ministry of Education(2022JZDZ023).
文摘Shandong province,located in the Lower Yellow River,is one of the birthplaces of ancient Chinese civilization.However,the comprehensive genetic histories of this region have remained largely unknown until now due to a lack of ancient human genomes.Here,we present 21 ancient genomes from Shandong dating from the Warring States period to the Northern Dynasties.Unlike the early Neolithic samples from Shandong,the historical samples are most closely related to post-Late Neolithic populations of the Middle Yellow River Basin,suggesting a population turnover in Shandong from the Neolithic Age to the Historical era.In addition,we detect a close genetic affinity between the historical samples in Shandong and present-day Han Chinese,showing long-term genetic stability in Han Chinese,at least since the Warring States period.
基金funded by the National Natural Science Foundation of China(32070576,31801040,and 32270667)Lantai Young Scholars Program of Chinese History Institute(2022LTQN602)+11 种基金the National Social Science Fund of China(19VJX074 and 21CKG022)Priority Research Program of the Chinese Academy of Sciences:Pan-Third Pole Environment Study for a Green Silk Road(Pan-TPE)(XDA2004010101)the National Key Research and Development Program(2023YFC3303701-02)the Natural Science Foundation of Fujian Province of China(2023J06013)the Science and Technology Commission of Shanghai Municipality(18490750300)the National Key Research and Development Program(2020YFE0201600)Shanghai Municipal Science and Technology Major Project(2017SHZDZX01)the Major Project of National Social Science Foundation of China granted to C.C.W.(21&ZD285),S.W.(20&ZD212),and D.L.(21&ZD237)Major Special Project of Philosophy and Social Sciences Research of the Ministry of Education(2022JZDZ023)Open Research Fund of State Key Laboratory of Genetic Engineering at Fudan University(SKLGE-2310)Open Research Fund of Forensic Genetics Key Laboratory of the Ministry of Public Security(2023FGKFKT07)European Research Council(ERC)grant(ERC-2019-ADG-883700-TRAM).
文摘China's Northern and Southern Dynasties period(3rd–6th centuries AD)marked a significant era of ethnic integration in northern China.However,previous ancient DNA studies have primarily focused on northern ethnic groups,with limited research on the genetic formation of the hereditary elite family,especially considering their abundant archaeological record and clear material identity.In this study,we obtain the ancient genome of a hereditary elite family,Gao Bin(高宾,503 AD–572 AD),at 0.6473-fold coverage with 475,132 single-nucleotide polymorphisms(SNPs)on the 1240k panel.His mitochondrial haplogroup belongs to Z4 and Y-haplogroup to O1a1a2b-F2444∗.The genetic profile of Gao Bin is most similar to that of the northern Han Chinese.He can be modeled as deriving all his ancestry from Late Neolithic to Iron Age Yellow River farmers without influence from Northeast Asia,Korea,or the Mongolian Plateau.Our study sheds light on the genetic formation of hereditary elite families in the context of the Southern and Northern Dynasties ethnic integration.
基金funded by the following grants and contracts:Strategic Priority Research Program of the Chinese Academy of Sciences(XDB38020400 to S.W.)the National Natural Science Foundation of China(32325013 to S.W.,32271186 to J.T.,31900408 to M.Z.)+5 种基金the CAS Project for Young Scientists in Basic Research(YSBR-077 to S.W.)Shanghai Science and Technology Commission Excellent Academic Leaders Program(22XD1424700 to S.W.)CAMS Innovation Fund for Medical Sciences(2019-I2M-5-066 to L.J.and J.W.)Shanghai Municipal Science and Technology Major Project(2017SHZDZX01 to L.J.and S.W.)the National Science and Technology Basic Research Project(2015FY111700 to L.J.)the 111 Project(B13016 to L.J.).
文摘Facial morphology,a complex trait influenced by genetics,holds great significance in evolutionary research.However,due to limited fossil evidence,the facial characteristics of Neanderthals and Denisovans have remained largely unknown.In this study,we conduct a large-scale multi-ethnic meta-analysis of the genome-wide association study(GWAS),including 9674 East Asians and 10,115 Europeans,quantitatively assessing 78 facial traits using 3D facial images.We identify 71 genomic loci associated with facial features,including 21 novel loci.We develop a facial polygenic score(FPS)that enables the prediction of facial features based on genetic information.Interestingly,the distribution of FPSs among populations from diverse continental groups exhibits relevant correlations with observed facial features.Furthermore,we apply the FPS to predict the facial traits of seven Neanderthals and one Denisovan using ancient DNA and align predictions with the fossil records.Our results suggest that Neanderthals and Denisovans likely share similar facial features,such as a wider but shorter nose and a wider endocanthion distance.The decreased mouth width is characterized specifically in Denisovans.The integration of genomic data and facial trait analysis provides valuable insights into the evolutionary history and adaptive changes in human facial morphology.
基金supported by the Development Foundation of Shanghai Meteorological and Health Key Laboratory [QXJK201606]the Investigation of Science&Technology Basic Resources Program of China [2017FY101206]the General Program Foundation of Hebei Meteorological Bureau [17KY10]
文摘Asthma is a common chronic inflammatory disorder that is more prevalent in children than in adults.China has seen an increasing prevalence of childhood asthma in recentdecades[1].Earlier studies have shown that air particulate matter (PM),particularly fine particulate matter(PM2.5)[2],is an important factor triggering childhood asthma. Since nationalPM2.5data were nota vailabl euntil 2013,
基金This work was supported by the Key Project in the National Science&Technology Pillar Program from the Ministry of Science and Technology(2015BAI09B04)the National Natural Science Foundation of China(31872256,31472188)+2 种基金the National Key Research and Development Program of China(2017YFD0501306)the Science and Technology Service Network Initiative of Chinese Academy of Sciences(KFJ-STS-QYZD-126,ZDBS-SSW-DQC-02)CAS Youth Innovation Promotion Association,and SA-SIBS Scholarship Program.
文摘Microtus fortis is the only mammalian host that exhibits intrinsic resistance against Schistosoma japonicum infection.However,the underlying molecular mechanisms of this resistance are not yet known.Here,we perform the first de novo genome assembly of M.fortis,comprehensive gene annotation analysis,and evolution analysis.Furthermore,we compare the recovery rate of schistosomes,pathological changes,and liver transcriptomes between M.fortis and mice at different time points after infection.We observe that the time and type of immune response in M.fortis are different from those in mice.M.fortis activates immune and inflammatory responses on the 10th day post infection,such as leukocyte extravasation,antibody activation,Fc-gamma receptor-mediated phagocytosis,and the interferon signaling cascade,which play important roles in preventing the development of schistosomes.In contrast,an intense immune response occurrs in mice at the late stages of infection and could not eliminate schistosomes.Infected mice suffer severe pathological injury and continuous decreases in cell cycle,lipid metabolism,and other functions.Our findings offer new insights into the intrinsic resistance mechanism of M.fortis against schistosome infection.The genome sequence also provides the basis for future studies of other important traits in M.fortis.
基金the National Natural Science Foundation of China(NSFC)(31771388,32030020,31525014,32071465,31871334,31671374,91731303,31961130380,and 32041008)the Strategic Priority Research Program(XDPB17,XDB38000000)+2 种基金the Chinese Academy of Sciences,National Key Research and Development Program of China(2018YFC0910502,2016YFC0906403)the UK Royal Society-Newton Advanced Fellowship(NAF\R1\191094)the Shanghai Municipal Science and Technology Major Project(2017SHZDZX01).
文摘Understanding the micro-coevolution of the human gut microbiome with host genetics is challenging but essential in both evolutionary and medical studies.To gain insight into the interactions between host genetic variation and the gut microbiome,we analyzed both the human genome and gut microbiome collected from a cohort of 190 students in the same boarding college and representing 3 ethnic groups,Uyghur,Kazakh,and Han Chinese.We found that differences in gut microbiome were greater between genetically distinct ethnic groups than those genetically closely related ones in taxonomic composition,functional composition,enterotype stratification,and microbiome genetic differentiation.We also observed considerable correlations between host genetic variants and the abundance of a subset of gut microbial species.Notably,interactions between gut microbiome species and host genetic variants might have coordinated effects on specific human phenotypes.Bacteroides ovatus,previously reported to modulate intestinal immunity,is significantly correlated with the host genetic variant rs12899811(meta-P=5.55×10^(-5)),which regulates the VPS33B expression in the colon,acting as a tumor suppressor of colorectal cancer.These results advance our understanding of the micro-coevolution of the human gut microbiome and their interactive effects with host genetic variation on phenotypic diversity.
基金supported by the National High Technology Research and Development Program of China(No.2015AA020104)the National Key Research and Development Program on Precision Medicine(No.2016YFC0901700)+6 种基金the National Basic Research Program of China(Nos.2011CB910204,2011CB510102,and 2010CB529200)the National Key Technology Support Program (No.2013BA1101B09)the National Key Scientific Instrument and Equipment Development Project(No.2012YQ03026108)the National Grand Program on Key Infectious Diseases(No. 2015ZX10004801)the Medical-Engineering Cross Project of Shanghai Jiao Tong University(No.YG2016MS33)the Youth Innovation Promotion Association CASthe National Institutes of Health grants(Nos.R01HL117491 and R01HL129778 to Y.E.C)
文摘Animal models are increasingly gaining values by cross-comparisons of response or resistance to clinical agents used for patients.However,many disease mechanisms and drug effects generated from animal models are not transferable to human.To address these issues,we developed SysFinder（http：//lifecenter.sgst.cn/SysFinder）,a platform for scientists to find appropriate animal models for translational research.SysFinder offers a ＂topic-centered＂ approach for systematic comparisons of human genes,whose functions are involved in a specific scientific topic,to the corresponding homologous genes of animal models.Scientific topic can be a certain disease,drug,gene function or biological pathway.SysFinder calculates multi-level similarity indexes to evaluate the similarities between human and animal models in specified scientific topics.Meanwhile,SysFinder offers species-specific information to investigate the differences in molecular mechanisms between humans and animal models.Furthermore,SysFinder provides a userfriendly platform for determination of short guide RNAs（sgRNAs） and homology arms to design a new animal model.Case studies illustrate the ability of SysFinder in helping experimental scientists.SysFinder is a useful platform for experimental scientists to carry out their research in the human molecular mechanisms.
基金This study was supported by the National Natural Science Foundation of China(No.32200485)the University Synergy Innovation Program of Anhui Province(GXXT-2021-071)Shanghai Municipal Science and Technology Major Project(No.2017SHZDZX01).
文摘Teratozoospermia with cephalic defects is one of the most severe types of sperm defects known to date.While several monogenic factors are linked to cephalic abnormalities,such as globozoospermia and macrozoospermia,the genetic cause of vacuolated spermatozoa remains inadequately described.Here,we analyzed whole-exome sequencing(WES)data for an individual from a consanguineous family with severely vacuolated spermatozoa.The analysis revealed a novel homozygous c.520A>G(p.Thr174Ala)variant in the archaelysin family metallopeptidase 2(AMZ2),a gene that encodes a zinc metalloprotease previously shown to be highly expressed in the testes and sperm.Multiple algorithms predicted this variant to be a damaging mutation.Consistent with an autosomal recessive mode of inheritance,this variant was inherited from heterozygous parental carriers.To investigate the potential pathogenicity of the identified variant,we compared the AMZ2 expression in sperm cells from the patient with the AMZ2 variant and from a healthy control.Immunoblot analysis revealed that the homozygous missense variant in AMZ2 abolished AMZ2 expression in the spermatozoa.Our findings reveal a candidate causative gene for vacuolated spermatozoa.
基金supported by the Russian Center for Scientific Information under grant RFBR–21–54–12016 for the sampling and treating of collected materialsby the Russian Scientific Foundation under grant RSF-24–14-00206 for data analysis and preparation of the manuscript.
文摘Climate has changed sufficiently over the last 150 years and forced out upper treeline advance at the most studied sites around the world.The rate of advance has been extremely variable–from tens to hundreds meters in altitude.This is because the degree at which tree frontal populations respond to climate change depends on the complex interaction of biological and physical factors.The resulting stand pattern is the consequence of the interaction between dispersal and survival functions.A few publications have addressed the question of how this pattern is generated.In order to understand how the spatial structure of tree stands was formed at the upper limit of their distribution in the Ural Mountains,we assessed the distance and direction of dispersal of offspring from maternal individuals.We found that in frontal Larix sibirica Ledeb.populations,‘effective’dispersal of offspring ranges from 3 to 758 m(with a median of 20–33 m in open forest and 219 m in single-tree tundra in the Polar Urals and 107 m in open forest in the Northern Urals).We revealed that most of the offspring effectively dispersed not only in the direction of the prevailing winds,but also in the opposite direction up the slope,and the distance can reach 500–760 m.The data obtained can be used to develop an individual-based model which is capable of simulating in detail the dynamics of tree stands at the upper limit of their growth and reliably predicting the future position and pattern of treeline ecotone as growth conditions continue to improve in the face of observed climate change.
基金funded by grants from the National Natural Science Foundation of China(grant numbers:82002664,81872074,81772740,82173345 and 82373154)the Hanghai Jiading District Health Commission Scientific Research Project Youth Fund(grant num-ber:2020-QN-02)the Meng Chao Talent Training Plan-Youth Re-search Talent Training Program of Eastern Hepatobiliary Surgery Hos-pital and the Foundation for Distinguished Youths of Jiangsu Province(grant number:BK20200006).
文摘Background:Tumor-derived exosomes are involved in tumor progression and immune invasion and might func-tion as promising noninvasive approaches for clinical management.However,there are few reports on exosom-based markers for predicting the progression and adjuvant therapy response rate among patients with clear cell renal cell carcinoma(ccRCC).Methods:The signatures differentially expressed in exosomes from tumor and normal tissues from ccRCC pa-tients were correspondingly deregulated in ccRCC tissues.We adopted a two-step strategy,including Lasso and bootstrapping,to construct a novel risk stratification system termed the TDERS(Tumor-Derived Exosome-Related Risk Score).During the testing and validation phases,we leveraged multiple external datasets containing over 2000 RCC cases from eight cohorts and one inhouse cohort to evaluate the accuracy of the TDERS.In addition,enrichment analysis,immune infiltration signatures,mutation landscape and therapy sensitivity between the high and low TDERS groups were compared.Finally,the impact of TDERS on the tumor microenvironment(TME)was also analysed in our single-cell datasets.Results:TDERS consisted of 12 mRNAs deregulated in both exosomes and tissues from patients with ccRCC.TDERS achieved satisfactory performance in both prognosis and immune checkpoint inhibitor(ICI)response across all ccRCC cohorts and other pathological types,since the average area under the curve(AUC)to predict 5-year overall survival(OS)was larger than 0.8 across the four cohorts.Patients in the TDERS high group were resistant to ICIs,while mercaptopurine might function as a promising agent for those patients.Patients with a high TDERS were characterized by coagulation and hypoxia,which induced hampered tumor antigen presentation and relative resistance to ICIs.In addition,single cells from 12 advanced samples validated this phenomenon since the interaction between dendritic cells and macrophages was limited.Finally,PLOD2,which is highly expressed in fibro-and epi-tissue,could be a potential therapeutic target for ccRCC patients since inhibiting PLOD2 altered the malignant phenotype of ccRCC in vitro.Conclusion:As a novel,non-invasive,and repeatable monitoring tool,the TDERS could work as a robust risk stratification system for patients with ccRCC and precisely inform treatment decisions about ICI therapy.
基金funded by the National Key Research and Development Program of China(No.2023YFC2508100)the National Natural Science Foundation of China(Nos.81773322,82173420,81673054,81673073,and 81974471)+4 种基金the Shanghai Municipal Commission of Health and Family Planning(No.2023ZZ02018)the Shanghai Municipal Key Clinical Specialty(No.shslczdzk01002)the Natural Science Foundation of Shanghai(No.20ZR1440100)the Key Project in Basic Research Advocated by Shanghai Science and Technology Commission(No.13JC1402300)the Clinical Research Plan of SHDC(Nos.SHDC2020CR6022,SHDC2020CR1014B,SHDC22022302,and SHDC2024CRI052).
文摘To the Editor:Psoriatic arthritis(PsA)affects up to 30%of patients with psoriasis,contributing to a decreased quality of life.PsA can involve a variety of clinical manifestations,including peripheral and axial arthritis,enthesitis,dactylitis,and nail disease.[1]Early intervention is important for preventing loss of function and permanent disability;however,the diagnosis of PsA is often delayed by an average of five years.[1]Therefore,it is important to identify biomarkers that can detect PsA in patients with psoriasis.
基金supported by the National Key R&D Program of China(2024YFC3405800 to S.W.)the Strategic Priority Research Program of the Chinese Academy of Sciences(XDB38020400 to S.W.)+9 种基金CAS Youth Innovation Promotion Association(2020276 to Q.P.)CAS Young Team Program for Stable Support of Basic Research(YSBR-077 to S.W.)CAS Interdisciplinary Innovation Team to S.W.,Shanghai Municipal Science and Technology Major Project(2017SHZDZX01 to S.W.,L.J.,J.W.,J.T.,and Q.P.)Shanghai Science and Technology Innovation Action Project(24JS2810300 to S.W.)the National Natural Science Foundation of China(32325013,92249302 to S.W.,32471216 to Q.P.,32271186 to J.T.)the National Key Research and Development Project(2018YFC0910403 to S.W.)Ministry of Science and Technology of the People’s Republic of China(2015FY111700 to L.J.)Shanghai Science and Technology Commission Excellent Academic Leaders Program(22XD1424700 to S.W.)111 Project(B13016 to L.J.)CAMS Innovation Fund for Medical Science(2019-I2M-5-066 to J.W.and L.J.)。
文摘The human face harbors a rich tapestry of complex phenotypic information spanning genetic,environmental,and physiological dimensions.While facial images excel in diagnosing genetic diseases,their untapped potential for predicting metabolic health presents an intriguing prospect.Metabolic Syndrome(Met S),marked by a constellation of metabolic abnormalities,poses a significant risk for various chronic diseases.Utilizing Face-Wide Association Studies(Fa WAS)on a discovery cohort of 2,621 Chinese individuals and a replication cohort of 2,188 Chinese individuals,we investigated the associations between facial features and Met S and its related conditions.Our findings highlight half of our investigated facial features strongly correlated with Met S risk,such as a slender forehead,a broader and shorter jawline,and fuller features around the temples-eye-cheek region,with notable genetic correlations(0.55–0.58)and influences from environmental factors like age,urban residency,and educational level.The developed face-based prediction model demonstrated significant predictive robustness,achieving an AUC of up to 0.87 for Met S and 0.89 for obesity in external validations,surpassing traditional 2D imaging techniques.Our model also aids in identifying subtypes within healthy populations,with a 2.07 to 2.40-fold increased risk of developing different metabolic disorders within the next five years.This paves the way for precise risk stratification of individuals who are‘at risk'.Integrating 3D facial imaging for metabolic health predictions,our research introduces an innovative,non-invasive framework for health assessment and subtype identification,demonstrating high potential in personalized medicine and health monitoring.
基金Shanghai Municipal Science and Technology Major Project(2017SHZDZX01)CAMS Innovation Fund for Medical Sciences(2019-I2M-5-066)+1 种基金the National Basic Research Program of China(2015FY111700)This work was also supported by the Postdoctoral Science Foundation of China(2018M640333 and 2019M651354).
文摘Next-generation sequencing technologies have significantly accelerated the identification of disease-causing mutations and facilitated the emergence of personalized medicine(Genomes Project Consortium et al.,2015;Goodwin et al.,2016;Sirugo et al.,2019).In comparison with whole-genome sequencing,whole-exome sequencing(WES),which covers the coding regions of the genome,offers a cost-efficacy balance.WES provides deeper sequencing depth(>100)and allows the more accurate detection of rare variants that are tailored for clinical applications(Lek et al.,2016).
文摘RNase MRP RNA is the RNA subunit of the RNase mitochondrial RNA processing （MRP） enzyme complex that is involved in multiple cellular RNA processing events. Mutations on RNase MRP RNA gene （RMRP） cause a recessively inherited developmental disorder, cartilage-hair hypoplasia （CHH）. The relationship of the genotype （RMRP mutation）, RNA processing deficiency of the RNase MRP complex, and the phenotype of CHH and other skeletal dysplasias is yet to be explored.
基金supported by the National Natural Science Foundation of China(Nos.31322030,91331108 to S.W.31222030 to H.L.+10 种基金30890034,31271338 to L.J.91331204,31171218 to S.X.31260263 to Y.G.)the National Basic Research Program(No.2015FY111700 to L.J.)the Ministry of Education(No.113022A toH.L.)the Chinese Academy of Sciences(No.XDB13040100 to S.X.)the National Program for Top-notch Young Innovative Talents of The“Wanren Jihua”Project to S.X.the National Thousand Young Talents Award to S.W.the Shanghai Shuguang Project(No.14SG05)to H.L.the Max Planck-CAS Paul Gerson Unna Independent Research Group Leadership Award to S.W.the open projects from the State Key Laboratory of Genetic Engineering,Fudan University to S.W.
文摘Petaloid toenail, or accessory nail of the fifth toe, is a physical trait characterized by the presence of an additional tiny toenail on the small toe. Since it can occasionally cause disfigurement and tenderness while wearing tight shoes or walking, standard surgical matricectomy is often carried out to repair the petaloid toenail （Chi and Wang, 2004）. Chinese legends recorded petaloid toenails as a trait unique to Han Chinese （Gao, 2010）, but population- based studies are largely absent.
