Genomic disorders: genome architecture results in susceptibility to DNA rearrangements causing common human traits.

STANKIEWICZ P; INOUE K; BI W; WALZ K; PARK SS; KUROTAKI N; SHAW CJ; FONSECA P; YAN J; LEE JA; KHAJAVI M; LUPSKI JR

Cold Spring Harb Symp Quant Biol

Cold Spring Harbor Laboratory Press

Año: 2003

0091-7451

The beginnings of molecular medicine can perhaps betraced to Pauling?s work that recognized sickle cell anemiaas a molecular disease, or to Sanger?s demonstrationof a specific amino acid sequence for insulin. During thefour to five decades that followed these discoveries, andthat of the chemical basis of the gene, molecular medicineinvestigations have focused on genes (genocentric)?how mutations specifically alter DNA and how thesechanges affect the structure, function, and expression ofencoded proteins. Recently, however, advances in theHuman Genome Project and completion of the genomesfor several model organisms have enabled investigatorsto view genetic information in the context of the entiregenome. As a result, we recognize that the mechanismsfor some genetic diseases are best understood at the genomiclevel. Human diseases recognized to result fromDNA rearrangements involving unstable genomic regionshave been termed genomic disorders (Lupski1998). These rearrangements are not random events butrather reflect genome architecture consisting of regionspecificlow-copy repeats (LCRs), which contribute tothe susceptibility to DNA rearrangements. LCRs constituteat least 5?10% of the sequenced genome, perhaps>20% of some autosomal regions, and comprise 30?45%of the Y chromosome. These LCRs, also termed segmentalduplications or duplicons, usually span ~10?400 kb ofgenomic DNA and share >95?97% sequence identity(Bailey et al. 2001; Cheung et al. 2001; Eichler 2001;Lander et al. 2001; Hurles and Jobling 2003). By stimulatingand mediating nonallelic homologous recombination(NAHR), LCRs are responsible for genome instabilityand can lead to DNA rearrangements associated withseveral genomic disorders.