The study introduces a high-throughput method called paired-end mapping (PEM) to identify structural variations (SVs) in the human genome. PEM combines the rescue and capture of 3-kb DNA fragments, massive 454 sequencing, and computational mapping to detect SVs of 3 kb or larger. Using PEM, researchers identified over 1,297 SV events in two individuals, including 1,175 SV indels and 122 inversions. These SVs were distributed throughout the genome, with hotspots such as regions at 22q11.2 and 7q11 containing multiple SVs. The study found that many SVs affect gene function, including those that remove exons, fuse genes, or alter gene copy number. SVs were validated using various methods, including PCR, array-CGH, fiber-FISH, and comparison with the Celera assembly. The results suggest that SVs are more common than previously thought and may have significant impacts on phenotypic variation and genetic disease. The study also identified mechanisms of SV formation, including nonhomologous end-joining (NHEJ), retrotransposition, and nonallelic homologous recombination (NAHR). Overall, PEM provides a cost-effective method for detecting SVs and improving genome assemblies, highlighting the importance of incorporating SV detection into human genome-sequencing projects.The study introduces a high-throughput method called paired-end mapping (PEM) to identify structural variations (SVs) in the human genome. PEM combines the rescue and capture of 3-kb DNA fragments, massive 454 sequencing, and computational mapping to detect SVs of 3 kb or larger. Using PEM, researchers identified over 1,297 SV events in two individuals, including 1,175 SV indels and 122 inversions. These SVs were distributed throughout the genome, with hotspots such as regions at 22q11.2 and 7q11 containing multiple SVs. The study found that many SVs affect gene function, including those that remove exons, fuse genes, or alter gene copy number. SVs were validated using various methods, including PCR, array-CGH, fiber-FISH, and comparison with the Celera assembly. The results suggest that SVs are more common than previously thought and may have significant impacts on phenotypic variation and genetic disease. The study also identified mechanisms of SV formation, including nonhomologous end-joining (NHEJ), retrotransposition, and nonallelic homologous recombination (NAHR). Overall, PEM provides a cost-effective method for detecting SVs and improving genome assemblies, highlighting the importance of incorporating SV detection into human genome-sequencing projects.