γ -actin （ACTG1） gene is a cytoplasmic nonmuscle actin gene, which encodes a major cytoskeletal protein in the sensory hair cells of the cochlea. Mutations in ACTG1 were found to cause autosomal dominant, progressi...γ -actin （ACTG1） gene is a cytoplasmic nonmuscle actin gene, which encodes a major cytoskeletal protein in the sensory hair cells of the cochlea. Mutations in ACTG1 were found to cause autosomal dominant, progressive, sensorineural hearing loss linked to the DFNA 20/26 locus on chromosome 17q25.3 in European and American families, respectively. In this study, a novel missense mutation （c.364A〉G; p.I122V） co-segregated with the affected individuals in the family and did not exist in the unaffected family members and 150 unrelated normal controls. The alteration of residue Ile122 was predicted to damage its interaction with actin-binding proteins, which may cause disruption of hair cell organization and function. These findings strongly suggested that the I122V mutation in ACTG1 caused autosomal dominant non-syndromic hearing impairment in a Chinese family and expanded the spectrum of ACTG1 mutations causing hearing loss.展开更多
Objective ：To study the gene mutations of homeobox transcription factor （CSX/NKX2.5） associated with a Chinese family with secundum atrial septal defect （ASD）. Methods ：Polymerase chain reaction and DNA sequenci...Objective ：To study the gene mutations of homeobox transcription factor （CSX/NKX2.5） associated with a Chinese family with secundum atrial septal defect （ASD）. Methods ：Polymerase chain reaction and DNA sequencing were used to check all the members in the family with ASD, and single strand conformation polymorphism analysis （SSCP） was used to check 126 normal control people for detecting the mutations of CSX/NKX2.5 gene. Results： Three mutations, G270A（Glu32Lys ）, G378A （Glu68Lys）andG390A （Glu72Lys）were identified in CSX/NKX2.5 gene of ASD patients. However, the other members in the family with ASD and the control did not have such gene mutations. Conclusion：These mutations of CSX/NKX2.5 gene, which were identified in a Chinese family, may be one of the secundum ASD etiologic causes .展开更多
Mollusc shell matrix proteins （SMPs） are important functional components embedded in the shell and play a role in shell formation. A SMP （Pif177） was identified previously from the nacreous layer of the Japanese p...Mollusc shell matrix proteins （SMPs） are important functional components embedded in the shell and play a role in shell formation. A SMP （Pif177） was identified previously from the nacreous layer of the Japanese pearl oyster Pinctadafucata, and its cleavage products （named pfPif97 and pfPif80 proteins） were found to bind to the chitin framework and induce aragonite crystal formation and orient the c axis. In this study, a homologue of pfPif177 was cloned from the mantle of the Pacific oyster Crassostrea gigas, containing the homologue of pfPif97 only and not pfPif80. This finding hints at the large divergence in gene structure between the two species. This homologue （cgPif97） shares characteristics with pfPif97, and suggests that the biological functions of these two proteins may be similar. The expression pattern of cgPif97 in different tissues and development stages in- dicates that it may play an important role in shell formation of the adult oyster. The morphology of the inner shell surface was af- fected by injected siRNA of cgPif97 and the calcite laths of the shell became thinner and narrower when the siRNA dose in- creased, suggesting that the cgPip7 gene plays an important role in calcite shell formation in C. gigas. In conclusion, we found evidence that the Pif177 gene evolved very fast but still retains a similar function among species [Current Zoology 59 （1）： 109-115, 2013].展开更多
Complex structural variants(CSVs) are genomic alterations that have more than two breakpoints and are considered as the simultaneous occurrence of simple structural variants.However,detecting the compounded mutational...Complex structural variants(CSVs) are genomic alterations that have more than two breakpoints and are considered as the simultaneous occurrence of simple structural variants.However,detecting the compounded mutational signals of CSVs is challenging through a commonly used model-match strategy.As a result,there has been limited progress for CSV discovery compared with simple structural variants.Here,we systematically analyzed the multi-breakpoint connection feature of CSVs,and proposed Mako,utilizing a bottom-up guided model-free strategy,to detect CSVs from paired-end short-read sequencing.Specifically,we implemented a graph-based pattern growth approach,where the graph depicts potential breakpoint connections,and pattern growth enables CSV detection without pre-defined models.Comprehensive evaluations on both simulated and real datasets revealed that Mako outperformed other algorithms.Notably,validation rates of CSVs on real data based on experimental and computational validations as well as manual inspections are around 70%,where the medians of experimental and computational breakpoint shift are 13 bp and 26 bp,respectively.Moreover,the Mako CSV subgraph effectively characterized the breakpoint connections of a CSV event and uncovered a total of 15 CSV types,including two novel types of adjacent segment swap and tandem dispersed duplication.Further analysis of these CSVs also revealed the impact of sequence homology on the formation of CSVs.Mako is publicly available at https://github.com/xjtu-omics/Mako.展开更多
Cereal genes are classified into two distinct classes according to the guanine-cytosine （GC） content at the third codon sites （GC3）. Natural selection and mutation bias have been proposed to affect the GC content....Cereal genes are classified into two distinct classes according to the guanine-cytosine （GC） content at the third codon sites （GC3）. Natural selection and mutation bias have been proposed to affect the GC content. However, there has been controversy about the cause of GC variation. Here, we characterized the GC content of 1 092 paralogs and other single-copy genes in the duplicated chromosomal regions of the rice genome （ssp. indica） and classified the paralogs into GC3-rich and GC3-poor groups. By referring to out-group sequences from Arabidopsis and maize, we confirmed that the average synonymous substitution rate of the GC3-rich genes is significantly lower than that of the GC3-poor genes. Furthermore, we explored the other possible factors corresponding to the GC variation including the length of coding sequences, the number of exons in each gene, the number of genes in each family, the location of genes on chromosomes and the protein functions. Consequently, we propose that natural selection rather than mutation bias was the primary cause of the GC variation.展开更多
We aimed to develop a whole-genome sequencing(WGS)-based copy number variant(CNV)calling algorithm with the potential of replacing chromosomal microarray assay(CMA)for clinical diagnosis.JAX-CNV is thus developed for ...We aimed to develop a whole-genome sequencing(WGS)-based copy number variant(CNV)calling algorithm with the potential of replacing chromosomal microarray assay(CMA)for clinical diagnosis.JAX-CNV is thus developed for CNV detection from WGS data.The performance of this CNV calling algorithm was evaluated in a blinded manner on 31 samples and compared to the 112 CNVs reported by clinically validated CMAs for these 31 samples.The result showed that JAX-CNV recalled 100%of these CNVs.Besides,JAX-CNV identified an average of 30 CNVs per individual,representing an approximately seven-fold increase compared to calls of clinically validated CMAs.Experimental validation of 24 randomly selected CNVs showed one false positive,i.e.,a false discovery rate(FDR)of 4.17%.A robustness test on lowercoverage data revealed a 100%sensitivity for CNVs larger than 300 kb(the current threshold for College of American Pathologists)down to 10×coverage.For CNVs larger than 50 kb,sensitivities were 100%for coverages deeper than 20×,97%for 15×,and 95%for 10×.We developed a WGS-based CNV pipeline,including this newly developed CNV caller JAX-CNV,and found it capable of detecting CMA-reported CNVs at a sensitivity of 100%with about a FDR of 4%.We propose that JAX-CNV could be further examined in a multi-institutional study to justify the transition of first-tier genetic testing from CMAs to WGS.JAX-CNV is available at https://github.com/TheJacksonLaboratory/JAX-CNV.展开更多
基金the National Natural Science Foundation of China (No. 30670736 and 30500168)the Department of Science and Technology of Jiangsu Province (No. BS2006533).
文摘γ -actin （ACTG1） gene is a cytoplasmic nonmuscle actin gene, which encodes a major cytoskeletal protein in the sensory hair cells of the cochlea. Mutations in ACTG1 were found to cause autosomal dominant, progressive, sensorineural hearing loss linked to the DFNA 20/26 locus on chromosome 17q25.3 in European and American families, respectively. In this study, a novel missense mutation （c.364A〉G; p.I122V） co-segregated with the affected individuals in the family and did not exist in the unaffected family members and 150 unrelated normal controls. The alteration of residue Ile122 was predicted to damage its interaction with actin-binding proteins, which may cause disruption of hair cell organization and function. These findings strongly suggested that the I122V mutation in ACTG1 caused autosomal dominant non-syndromic hearing impairment in a Chinese family and expanded the spectrum of ACTG1 mutations causing hearing loss.
文摘Objective ：To study the gene mutations of homeobox transcription factor （CSX/NKX2.5） associated with a Chinese family with secundum atrial septal defect （ASD）. Methods ：Polymerase chain reaction and DNA sequencing were used to check all the members in the family with ASD, and single strand conformation polymorphism analysis （SSCP） was used to check 126 normal control people for detecting the mutations of CSX/NKX2.5 gene. Results： Three mutations, G270A（Glu32Lys ）, G378A （Glu68Lys）andG390A （Glu72Lys）were identified in CSX/NKX2.5 gene of ASD patients. However, the other members in the family with ASD and the control did not have such gene mutations. Conclusion：These mutations of CSX/NKX2.5 gene, which were identified in a Chinese family, may be one of the secundum ASD etiologic causes .
文摘Mollusc shell matrix proteins （SMPs） are important functional components embedded in the shell and play a role in shell formation. A SMP （Pif177） was identified previously from the nacreous layer of the Japanese pearl oyster Pinctadafucata, and its cleavage products （named pfPif97 and pfPif80 proteins） were found to bind to the chitin framework and induce aragonite crystal formation and orient the c axis. In this study, a homologue of pfPif177 was cloned from the mantle of the Pacific oyster Crassostrea gigas, containing the homologue of pfPif97 only and not pfPif80. This finding hints at the large divergence in gene structure between the two species. This homologue （cgPif97） shares characteristics with pfPif97, and suggests that the biological functions of these two proteins may be similar. The expression pattern of cgPif97 in different tissues and development stages in- dicates that it may play an important role in shell formation of the adult oyster. The morphology of the inner shell surface was af- fected by injected siRNA of cgPif97 and the calcite laths of the shell became thinner and narrower when the siRNA dose in- creased, suggesting that the cgPip7 gene plays an important role in calcite shell formation in C. gigas. In conclusion, we found evidence that the Pif177 gene evolved very fast but still retains a similar function among species [Current Zoology 59 （1）： 109-115, 2013].
基金supported by the National Key R&D Program of China(Grant Nos.2018YFC0910400 and 2017YFC0907500)the National Science Foundation of China(Grant Nos.31671372,61702406,and 31701739)+3 种基金the Fundamental Research Funds for the Central Universitiesthe World-Class Universities(Disciplines)the Characteristic Development Guidance Funds for the Central Universitiesthe Shanghai Municipal Science and Technology Major Project(Grant No.2017SHZDZX01)。
文摘Complex structural variants(CSVs) are genomic alterations that have more than two breakpoints and are considered as the simultaneous occurrence of simple structural variants.However,detecting the compounded mutational signals of CSVs is challenging through a commonly used model-match strategy.As a result,there has been limited progress for CSV discovery compared with simple structural variants.Here,we systematically analyzed the multi-breakpoint connection feature of CSVs,and proposed Mako,utilizing a bottom-up guided model-free strategy,to detect CSVs from paired-end short-read sequencing.Specifically,we implemented a graph-based pattern growth approach,where the graph depicts potential breakpoint connections,and pattern growth enables CSV detection without pre-defined models.Comprehensive evaluations on both simulated and real datasets revealed that Mako outperformed other algorithms.Notably,validation rates of CSVs on real data based on experimental and computational validations as well as manual inspections are around 70%,where the medians of experimental and computational breakpoint shift are 13 bp and 26 bp,respectively.Moreover,the Mako CSV subgraph effectively characterized the breakpoint connections of a CSV event and uncovered a total of 15 CSV types,including two novel types of adjacent segment swap and tandem dispersed duplication.Further analysis of these CSVs also revealed the impact of sequence homology on the formation of CSVs.Mako is publicly available at https://github.com/xjtu-omics/Mako.
基金the State Key Basic Research and Development Plan of China(2003CB715900)the National Natural Science Foundation of China(90408015,30121003 and 30430030).
文摘Cereal genes are classified into two distinct classes according to the guanine-cytosine （GC） content at the third codon sites （GC3）. Natural selection and mutation bias have been proposed to affect the GC content. However, there has been controversy about the cause of GC variation. Here, we characterized the GC content of 1 092 paralogs and other single-copy genes in the duplicated chromosomal regions of the rice genome （ssp. indica） and classified the paralogs into GC3-rich and GC3-poor groups. By referring to out-group sequences from Arabidopsis and maize, we confirmed that the average synonymous substitution rate of the GC3-rich genes is significantly lower than that of the GC3-poor genes. Furthermore, we explored the other possible factors corresponding to the GC variation including the length of coding sequences, the number of exons in each gene, the number of genes in each family, the location of genes on chromosomes and the protein functions. Consequently, we propose that natural selection rather than mutation bias was the primary cause of the GC variation.
基金supported in part by the operational funds from The First Affiliated Hospital of Xi’an Jiaotong University, Chinasupported by the National Institutes of Health, USA (Grant Nos. U24AG041689 and U54AG052427)+5 种基金supported by the National Natural Science Foundation of China (Grant Nos. 61702406 and 31671372)the National Science and Technology Major Project of China (Grant No. 2018ZX10302205)the National Key R&D Program of China (Grant Nos. 2018YFC0910400 and 2017YFC0907500)the General Financial Grant from the China Postdoctoral Science Foundation (Grant No. 2017M623178)supported in part by the Ewha Womans University Research, South Korea (Grant No. 2018-2019)supported in part by the Connecticut Bio-Innovative Fund, USA
文摘We aimed to develop a whole-genome sequencing(WGS)-based copy number variant(CNV)calling algorithm with the potential of replacing chromosomal microarray assay(CMA)for clinical diagnosis.JAX-CNV is thus developed for CNV detection from WGS data.The performance of this CNV calling algorithm was evaluated in a blinded manner on 31 samples and compared to the 112 CNVs reported by clinically validated CMAs for these 31 samples.The result showed that JAX-CNV recalled 100%of these CNVs.Besides,JAX-CNV identified an average of 30 CNVs per individual,representing an approximately seven-fold increase compared to calls of clinically validated CMAs.Experimental validation of 24 randomly selected CNVs showed one false positive,i.e.,a false discovery rate(FDR)of 4.17%.A robustness test on lowercoverage data revealed a 100%sensitivity for CNVs larger than 300 kb(the current threshold for College of American Pathologists)down to 10×coverage.For CNVs larger than 50 kb,sensitivities were 100%for coverages deeper than 20×,97%for 15×,and 95%for 10×.We developed a WGS-based CNV pipeline,including this newly developed CNV caller JAX-CNV,and found it capable of detecting CMA-reported CNVs at a sensitivity of 100%with about a FDR of 4%.We propose that JAX-CNV could be further examined in a multi-institutional study to justify the transition of first-tier genetic testing from CMAs to WGS.JAX-CNV is available at https://github.com/TheJacksonLaboratory/JAX-CNV.
