Human leukocyte antigen(HLA)genes in the major histocompatibility complex(MHC)region are crucial for immunity and are associated with numerous diseases and phenotypes.The MHC region’s complexity and high genetic dive...Human leukocyte antigen(HLA)genes in the major histocompatibility complex(MHC)region are crucial for immunity and are associated with numerous diseases and phenotypes.The MHC region’s complexity and high genetic diversity make it challenging to analyze using short-read sequencing(SRS)technology.We sequence the MHC region of 100 Han Chinese individuals using both long-read sequencing(LRS)and SRS platforms at approximately 30X coverage to study genetic alterations and their potential functional impacts.LRS provides significantly greater coverage of the MHC region and eight classical HLA genes,particularly at the HLA-DRB1 locus,compared with SRS.We detect 78,249 single nucleotide polymorphisms(SNPs)using LRS,with 26.0%undetectable by SRS.Based on SNP and inferred HLA allele types,we construct an LRS-based MHC reference panel for the Han Chinese,containing approximately 2.6 times more genetic variants than the SRS-based Han-MHC reference panel.A phenome-wide association study assessing 26,024 phenotypes across 15 categories identifies significant associations for 7,879 independent variants(including 809 LRS-specific SNPs)with 409 phenotypes in nine categories.This analysis reveals 24 unreported HLA allele associations in the bioelectric and cellular categories.The conditional analysis identifies 530 independent signals across the 409 phenotypes,including 28 previously unreported signals of eight classical HLA genes associated with 33 phenotypes.Of the top-associated SNPs,191 are detected by LRS only.Fine-mapping identifies 126 independent candidate causal SNPs for three immune-related cellular phenotypes,with 17 detected exclusively by LRS.Our study reveals previously unreported variants and their functional impacts in the MHC region,enhancing our understanding of genetic diversity and its potential biological implications in the Han Chinese population.展开更多
Neurodegenerative diseases cause great medical and economic burdens for both patients and society;however, the complex molecular mechanisms thereof are not yet well understood. With the development of high-coverage se...Neurodegenerative diseases cause great medical and economic burdens for both patients and society;however, the complex molecular mechanisms thereof are not yet well understood. With the development of high-coverage sequencing technology, researchers have started to notice that genomic repeat regions, previously neglected in search of disease culprits, are active contributors to multiple neurodegenerative diseases. In this review, we describe the association between repeat element variants and multiple degenerative diseases through genome-wide association studies and targeted sequencing. We discuss the identification of disease-relevant repeat element variants, further powered by the advancement of long-read sequencing technologies and their related tools, and summarize recent findings in the molecular mechanisms of repeat element variants in brain degeneration, such as those causing transcriptional silencing or RNA-mediated gain of toxic function. Furthermore, we describe how in silico predictions using innovative computational models, such as deep learning language models, could enhance and accelerate our understanding of the functional impact of repeat element variants. Finally, we discuss future directions to advance current findings for a better understanding of neurodegenerative diseases and the clinical applications of genomic repeat elements.展开更多
为提升远程电表数据采集系统的覆盖能力与终端续航性能,设计并实现一套机器类通信长期演进(Long Term Evolution for Machines,LTE-M)技术的远程抄表系统。通过构建模块化架构、优化通信协议与部署策略,有效解决传统通用分组无线服务(Ge...为提升远程电表数据采集系统的覆盖能力与终端续航性能,设计并实现一套机器类通信长期演进(Long Term Evolution for Machines,LTE-M)技术的远程抄表系统。通过构建模块化架构、优化通信协议与部署策略,有效解决传统通用分组无线服务(General Packet Radio Service,GPRS)技术与远距离无线电(Long Range Radio,LoRa)方案在信号盲区多、功耗高、传输延迟大等方面的问题。实际运行结果显示,系统通信成功率达99.2%,日均上报延迟控制在3.5 min以内,终端续航时间超过10年。展开更多
基金supported by the National Natural Science Foundation of China(32370686)the National Key Research and Development Program of China(2021YFC2500202)+2 种基金the 111 Project(B13016)Shanghai Municipal Science and Technology(2017SHZDZX01)supported by the Human Phenome Data Center at Fudan University.
文摘Human leukocyte antigen(HLA)genes in the major histocompatibility complex(MHC)region are crucial for immunity and are associated with numerous diseases and phenotypes.The MHC region’s complexity and high genetic diversity make it challenging to analyze using short-read sequencing(SRS)technology.We sequence the MHC region of 100 Han Chinese individuals using both long-read sequencing(LRS)and SRS platforms at approximately 30X coverage to study genetic alterations and their potential functional impacts.LRS provides significantly greater coverage of the MHC region and eight classical HLA genes,particularly at the HLA-DRB1 locus,compared with SRS.We detect 78,249 single nucleotide polymorphisms(SNPs)using LRS,with 26.0%undetectable by SRS.Based on SNP and inferred HLA allele types,we construct an LRS-based MHC reference panel for the Han Chinese,containing approximately 2.6 times more genetic variants than the SRS-based Han-MHC reference panel.A phenome-wide association study assessing 26,024 phenotypes across 15 categories identifies significant associations for 7,879 independent variants(including 809 LRS-specific SNPs)with 409 phenotypes in nine categories.This analysis reveals 24 unreported HLA allele associations in the bioelectric and cellular categories.The conditional analysis identifies 530 independent signals across the 409 phenotypes,including 28 previously unreported signals of eight classical HLA genes associated with 33 phenotypes.Of the top-associated SNPs,191 are detected by LRS only.Fine-mapping identifies 126 independent candidate causal SNPs for three immune-related cellular phenotypes,with 17 detected exclusively by LRS.Our study reveals previously unreported variants and their functional impacts in the MHC region,enhancing our understanding of genetic diversity and its potential biological implications in the Han Chinese population.
基金supported by the National Natural Science Foundation of China, No.61932008Natural Science Foundation of Shanghai, No.21ZR1403200 (both to JC)。
文摘Neurodegenerative diseases cause great medical and economic burdens for both patients and society;however, the complex molecular mechanisms thereof are not yet well understood. With the development of high-coverage sequencing technology, researchers have started to notice that genomic repeat regions, previously neglected in search of disease culprits, are active contributors to multiple neurodegenerative diseases. In this review, we describe the association between repeat element variants and multiple degenerative diseases through genome-wide association studies and targeted sequencing. We discuss the identification of disease-relevant repeat element variants, further powered by the advancement of long-read sequencing technologies and their related tools, and summarize recent findings in the molecular mechanisms of repeat element variants in brain degeneration, such as those causing transcriptional silencing or RNA-mediated gain of toxic function. Furthermore, we describe how in silico predictions using innovative computational models, such as deep learning language models, could enhance and accelerate our understanding of the functional impact of repeat element variants. Finally, we discuss future directions to advance current findings for a better understanding of neurodegenerative diseases and the clinical applications of genomic repeat elements.
文摘为提升远程电表数据采集系统的覆盖能力与终端续航性能,设计并实现一套机器类通信长期演进(Long Term Evolution for Machines,LTE-M)技术的远程抄表系统。通过构建模块化架构、优化通信协议与部署策略,有效解决传统通用分组无线服务(General Packet Radio Service,GPRS)技术与远距离无线电(Long Range Radio,LoRa)方案在信号盲区多、功耗高、传输延迟大等方面的问题。实际运行结果显示,系统通信成功率达99.2%,日均上报延迟控制在3.5 min以内,终端续航时间超过10年。
