Conservation ofsyntenybetweenthegenome ofthepufferfish (Fugurubripes) andtheregion on humanchromosome14 (14q24.3) associated withfamilial Alzheimer disease (AD3locus)

Thegenome ofthepufferfish (Fugu rubripes) (400Mb)is-7.5times smaller thanthehumangenome, but ithasasimilar generepertoire tothat ofman.Ifregions ofthe twogenomes exhibited conservation ofgeneorder(i.e., were syntenic), itshould bepossible toreduce dramatically the effort required foridentification ofcandidate genes inhuman disease loci bysequencing syntenic regions ofthecompact Fugugenome. Wehavedemonstrated thatthree genes (dihy- drolipoamide succinyltransferase, S31iii125, andS20il5), whicharelinked toFOSinthefamilial Alzheimer disease locus (AD3)onhumanchromosome 14,havehomologues in theFugugenomeadjacent toFugucFOS.Therelative gene order ofcFOS,S31iii125, andS20i15 wasthesameinboth genomes, butinFuguthese three genes laywithin a12.4-kb region, compared to>600kbinthehumanAD3locus. These results demonstrate theconservation ofsynteny between the genomes ofFuguandmanandhighlight theutility ofthis approach forsequence-based identification ofgenes inhuman disease loci. Identification ofgenesingenomic lociassociated with humandiseases hasbeengreatly facilitated bythedevelop- mentoftechniques suchas"exontrapping" (1)andcDNA selection (2,3).Direct sequencing ofdisease loci hasalso beenshowntobeoneofthemosteffective methods ofgene detection, butitrequires significant sequencing capacity (4-6). TheFugurubripes genomeis7-to8-fold smaller than that ofhuman(-400Mbcompared to'3000 Mb),butitis believed tocontain asimilar complement ofgenes(7). Thus atypical cosmid clone ofgenomic DNA might beexpected tocontain seventoeight Fugugenes compared toonly one humangene.Therefore, sequencing regions oftheFugu genomesyntenic withhumandisease loci should accelerate theidentification ofcandidate genes. We haveusedthis approach tocharacterize a humanchromosomal region (14q24.3) associated withanautosomal dominant, early onset formofAlzheimer disease (AD3locus) (8). Theresults ofourinvestigations aredescribed herein.