Genome structure and cognitive map of Williams syndrome

Williams syndrome (WMS) is a most compelling model of human cognition, of h uman genome organization, and of evolution. Due to a deletion in chromosome band 7q11.23, subjects have cardiovascular, connective tissue, and neurode velopmental deficits. Given the striking peaks and valleys in neurocognitio n including deficits in visual-spatial and global processing, preserved lan guage and face processing, hypersociability, and heightened affect, the goa l of this work has been to identify the genes that are responsible, the cau se of the deletion, and its origin in primate evolution. To do this, we hav e generated an integrated physical, genetic, and transcriptional map of the WMS and flanking regions using multicolor metaphase and interphase fluores cence in situ hybridization (FISH) of bacterial artificial chromosomes (BAC s) and P1 artificial chromosomes (PACs), BAC end sequencing, PCR gene marke r and microsatellite, large-scale sequencing, cDNA library, and database an alyses. The results indicate the genomic organization of the WMS region as two nested duplicated regions flanking a largely single-copy region. There are at least two common deletion breakpoints, one in the centromeric and at least two in the telomeric repeated regions. Clones anchoring the unique t o the repeated regions are defined along with three new pseudogene families . Primate studies indicate an evolutionary hot spot for chromosomal inversi on in the WMS region. A cognitive phenotypic map of WMS is presented, which combines previous data with five further WMS subjects and three atypical W MS subjects with deletions; two larger (deleted for D7S489L) and one smalle r, deleted for genes telomeric to FZD9, through LIMK1, but not WSCR1 or tel omeric. The results establish regions and consequent gene candidates for WM S features including mental retardation, hypersociability, and facial featu res. The approach provides the basis for defining pathways linking genetic underpinnings with the neuroanatomical, functional, and behavioral conseque nces that result in human cognition.