Structural Variation in the Human Genome and its Role in Disease

Corresponding author: James R. Lupski
Board Certified Clinical Geneticist and Clinical Molecular Geneticist
Texas Children's Hospital

1. INTRODUCTION

Copy-Number Variation

• CNVs of 1–50 kb in size have been under-ascertained because there has not been an accurate molecular method available to study these smaller rearrangements on a genome-wide scale in different populations. #这是2010年的综述，如今情况待继续看文献。
• CNVs can be inherited or sporadic; large de novo CNVs are thought more likely to be disease causative.
• public databases：Find DGV Variants，DECIPHER

Low-Copy Repeats (segmental duplications) 低拷贝重复序列

DNA fragments >1 kb in size and of >90% DNA sequence identity

• LCRs longer than 10kb and of over ∼97% sequence identity can lead to local genomic instability

2. MECHANISMS FOR FORMATION OF CNVs

Nonallelic Homologous Recombination (NAHR) 非等位同源重组

基因组上同一位点的DNA序列能够与其同源序列发生重组，即等位同源重组（AHR），而对于基因组上的重复序列来说，它们的同源序列不再是一一对应的；除了同一位点的同源序列以外，不同位点上的重复序列也可能具有高度同源性， 从而发生非等位的同源重组。

Nonhomologous End Joining (NHEJ) 非同源末端连接

In NHEJ,double strand breaks are detected; then both broken DNA ends are bridged, modified, and finally ligated. Incontrast to NAHR, NHEJ does not require LCRs or minimal efficient processing segments to mediate the recombination but may also be stimulated by genome architecture. 真核生物细胞在不依赖DNA同源性的情况下，而为了避免DNA或染色体断裂的滞留，避免因此造成的DNA降解或对生命力的影响，强行将两个DNA断端彼此连接在一起的一种特殊的DNA双链断裂修复机制。NHEJ的作用机制决定了它不是一种忠实的DNA双链断裂修复手段。除引发彼此毫不相干的DNA断端的连接，导致包括移位（移位) 等在内的染色体之间的重排改变之外，就是对本来彼此连接的DNA断端的处理也会造成少数核苷酸残基的缺失突变。

Replication-Error Mechanisms —— fork stalling and template switching (FoSTeS) 复制叉停顿和模板转换

In this model, the DNA replication fork stalls; the lagging strand disengages from the original template and an neals to another replication fork in physical proximity,by virtue of microhomology at the 3' end, “priming” or reinitiating DNA synthesis. DNA复制叉停滞的时候，滞后链可以从模板上脱落，通过微同源序列转到临近复制叉上开始重新合成DNA。

3. HOW CNVs CONVEY PHENOTYPES

• altering the copy number of a gene (or genes) sensitive to a dosage effect
• unmaskingofrecessivemutationsorfunctionalpolymorphisms of the remaining allele when a deletion occurs
• effects of transvection (基因转应作用 communication between alleles on homologous chromosomes), by deleting regulatory elements required for communication between alleles or simply by disrupting a coding sequence

4. HIGH-THROUGHPUT METHODS FOR ANALYSIS OF GENOMIC DISORDERS

• 旧方法：fluorescence in situ hybridization (荧光原位杂交 FISH),，pulsed-field gel electrophoresis (脉冲凝胶电泳 PFGE),，multiplex ligation-dependent probe amplification (MLPA) ，comparative genomic hybridization (比较基因组杂交 CGH)
• 新方法：SNP arrays

5.CLINICAL CONSEQUENCES OF CNVs

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6. COMPLEX TRAITS

• Autism
• Schizophrenia
• Parkinson Disease
• Alzheimer Disease
• Epilepsy
• Pancreatitis
• Developmental Delay/Mental Retardation
• Susceptibility to Other Diseases：HIV infection, Crohn disease, glomerulonephritis, psoriasis, systemic lupus erythematosus, emphysema, and many other human diseases