NIPBL, Cohesin and Related Structural Birth Defects

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In the last three years there has been considerable progress in understanding the nature and pattern of single nucleotide variation within the human species. By contrast, a comprehensive understanding of human structural variation which includes deletion, insertion and inversion polymorphisms lags far behind. The structure, frequency and phenotypic impact of most of these events are not known. Recent studies, however, suggest that genome structural variation is common in the normal population, alters structure and copy number of genes and is associated with human disease/disease susceptibility factors. This program project develops a systematic approach to characterize common structural variation within the human genome. The specific aims of this proposal are 1) to identify all inversions, deletions and insertions (> 6 kb in size) in nine human samples using an end-sequence-pair mapping strategy; 2) to sequence the structure of each of these (n=~2000 variants) including breakpoints; and 3) to develop genotyping assays to assess their frequency in the human population. It is a collaborative effort which brings together expertise in genome sequencing, clone characterization and structural variation. The results of this work will generate the first high quality reference set of sequenced structural variants, provide insight into the molecular mechanisms underlying these events, and develop the genotyping platforms that will be needed to assess the phenotypic consequences in terms of human disease and adaptation.