张锋
博士 教授 博士生导师
复旦大学 生命科学学院
一直致力于人类基因组拷贝数变异(Copy Number Variation, CNV)及其致出生缺陷、不孕不育等疾病的基础和转化研究。
个性化签名
- 姓名:张锋
- 目前身份:在职研究人员
- 担任导师情况:博士生导师
- 学位:博士
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学术头衔:
博士生导师
- 职称:高级-教授
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学科领域:
医学遗传学
- 研究兴趣:一直致力于人类基因组拷贝数变异(Copy Number Variation, CNV)及其致出生缺陷、不孕不育等疾病的基础和转化研究。
张锋,复旦大学附属妇产科医院、生殖与发育研究院教授、博士生导师。上海市女性生殖内分泌相关疾病重点实验室副主任。复旦大学生命科学学院、遗传工程国家重点实验室双聘PI。任中国遗传学会青年委员会副主任委员、中国优生科学协会基因诊断学分会常务委员。
一直致力于人类基因组拷贝数变异(Copy Number Variation, CNV)及其致出生缺陷、不孕不育等疾病的基础和转化研究。已在New England Journal of Medicine, Nature Genetics, AJHG等高影响力期刊上发表SCI论文和综述72篇,累计被引用2942次。
获奖情况:
第十五届中国青年科技奖,2019;
教育部高等学校自然科学一等奖(第一完成人),2018;
“转化医学奖励计划”转化医学创新奖,2018;
药明康德生命化学杰出成就奖,2015;
盖茨基金会“大挑战2015·青年科学家”,2015。
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157
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成果数
5
Nature Genetics,2009,41():849–853
2009年06月21日
We recently proposed a DNA replication–based mechanism of fork stalling and template switching (FoSTeS) to explain the complex genomic rearrangements associated with a dysmyelinating central nervous system disorder in humans1. The FoSTeS mechanism has been further generalized and molecular mechanistic details have been provided in the microhomology-mediated break-induced replication (MMBIR) model that may underlie many structural variations in genomes from all domains of life2. Here we provide evidence that human genomic rearrangements ranging in size from several megabases to a few hundred base pairs can be generated by FoSTeS/MMBIR. Furthermore, we show that FoSTeS/MMBIR-mediated rearrangements can occur mitotically and can result in duplication or triplication of individual genes or even rearrangements of single exons. The FoSTeS/MMBIR mechanism can explain both the gene duplication-divergence hypothesis3 and exon shuffling4, suggesting an important role in both genome and single-gene evolution.
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【期刊论文】Copy Number Variation in Human Health, Disease, and Evolution
Annual Review of Genomics and Human Genetics ,2009,10():451-481
2009年09月01日
Copy number variation (CNV) is a source of genetic diversity in humans. Numerous CNVs are being identified with various genome analysis platforms, including array comparative genomic hybridization (aCGH), single nucleotide polymorphism (SNP) genotyping platforms, and next-generation sequencing. CNV formation occurs by both recombination-based and replication-based mechanisms and de novo locus-specific mutation rates appear much higher for CNVs than for SNPs. By various molecular mechanisms, including gene dosage, gene disruption, gene fusion, position effects, etc., CNVs can cause Mendelian or sporadic traits, or be associated with complex diseases. However, CNV can also represent benign polymorphic variants. CNVs, especially gene duplication and exon shuffling, can be a predominant mechanism driving gene and genome evolution.
FoSTeS,, genomic disorder,, genomotype/, phenotype correlations,, MMBIR,, NAHR,, NHEJ
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Human Molecular Genetics,2013,22(4):749–756
2013年02月15日
Copy number variations (CNVs) in the human genome contribute significantly to disease. De novo CNV mutations arise via genomic rearrangements, which can occur in ‘trans’, i.e. via interchromosomal events, or in ‘cis’, i.e. via intrachromosomal events. However, what molecular mechanisms occur between chromosomes versus between or within chromatids has not been systematically investigated. We hypothesized that distinct CNV mutational mechanisms, based on their intrinsic properties, may occur in a biased intrachromosomal versus interchromosomal manner. Here, we studied 62 genomic duplications observed in association with sporadic Potocki–Lupski syndrome (PTLS), in which multiple mutational mechanisms appear to be operative. Intriguingly, more interchromosomal than intrachromosomal events were identified in recurrent PTLS duplications mediated by non-allelic homologous recombination, whereas the reciprocal distribution was found for replicative mechanisms and non-homologous end-joining, likely reflecting the differences in spacial proximity of homologous chromosomes during different mutational processes.
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Human Molecular Genetics,2015,24(6):1574–1583
2015年03月15日
Copy number variation (CNV) in the human genome is of vital importance to human health and evolution of our species. However, much of the molecular basis of CNV mutagenesis remains to be elucidated. Considering the DNA replication model of ‘fork stalling and template switching’ for CNV formation, we hypothesized that replication fork progression could be important for CNV mutagenesis. However, molecular assays of replication fork progression at the genome level are technically challenging. Instead, we conducted an estimation of DNA replication dynamics, as the statistic R, using the readily available data of replication timing. Small R-values can reflect ‘slowed’ replication, which could result from less fork initiation, reduced fork speed or fork barriers. We generated genome-wide profiles of R in the genomes of human, mouse and Drosophila. Intriguingly, the CNV breakpoints in all three genomes showed significantly biased distributions toward the genomic regions with small R-values, suggesting potential replication stress-induced CNV instability. Notably, among the human CNVs with distinct breakpoint junction characteristics, the homology-mediated and VNTR-mediated CNVs contribute the most to the correlation between CNV instability and the statistic R, consistent with the recent findings in the C. elegans and yeast genomes of repeat-induced DNA replication error and consequent CNV formation. The statistic R may reflect both replication stress and the effect of local genome architecture on fork progression. Our concordant observations suggest an important role for DNA replicative mechanisms in CNV mutagenesis and genome instability.
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【期刊论文】TBX6 Null Variants and a Common Hypomorphic Allele in Congenital Scoliosis
N Engl J Med,2015,372():341-350
2015年01月22日
Background Congenital scoliosis is a common type of vertebral malformation. Genetic susceptibility has been implicated in congenital scoliosis. Methods We evaluated 161 Han Chinese persons with sporadic congenital scoliosis, 166 Han Chinese controls, and 2 pedigrees, family members of which had a 16p11.2 deletion, using comparative genomic hybridization, quantitative polymerase-chain-reaction analysis, and DNA sequencing. We carried out tests of replication using an additional series of 76 Han Chinese persons with congenital scoliosis and a multicenter series of 42 persons with 16p11.2 deletions. Results We identified a total of 17 heterozygous TBX6 null mutations in the 161 persons with sporadic congenital scoliosis (11%); we did not observe any null mutations in TBX6 in 166 controls (P<3.8×10−6). These null alleles include copy-number variants (12 instances of a 16p11.2 deletion affecting TBX6) and single-nucleotide variants (1 nonsense and 4 frame-shift mutations). However, the discordant intrafamilial phenotypes of 16p11.2 deletion carriers suggest that heterozygous TBX6 null mutation is insufficient to cause congenital scoliosis. We went on to identify a common TBX6 haplotype as the second risk allele in all 17 carriers of TBX6 null mutations (P<1.1×10−6). Replication studies involving additional persons with congenital scoliosis who carried a deletion affecting TBX6 confirmed this compound inheritance model. In vitro functional assays suggested that the risk haplotype is a hypomorphic allele. Hemivertebrae are characteristic of TBX6-associated congenital scoliosis. Conclusions Compound inheritance of a rare null mutation and a hypomorphic allele of TBX6 accounted for up to 11% of congenital scoliosis cases in the series that we analyzed. (Funded by the National Basic Research Program of China and others.)
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