Four genes, including the related and ancient NIPA1 and NIPA2 genes within the Prader-Willi/Angelman syndromes deletion region, have undergone evolutionary transposition mediated by HERC2- or adjacent duplicons.  

Jing-Hua Chai¹, Devin P. Locke², Evan E. Eichler², and Robert D. Nicholls¹. ¹Center for Neurobiology and Behavior, Department of Psychiatry, University of Pennsylvania, Philadelphia, PA; ²Department of Genetics, Case Western Reserve University, Cleveland, OH. 

Prader-Willi and Angelman syndromes (PWS and AS) typically result from an ~4 Mb deletion of human chromosome 15q11-13, with clustered breakpoints at either of two proximal (BP1 and BP2) and one distal (BP3) site. HERC2 and other duplicons map to these BP regions, with the 2 Mb PWS/AS imprinted domain just distal of BP2. Previously, the presence of genes and their imprinted status has not been examined between BP1 and BP2. We have identified two novel genes, NIPA1 and NIPA2, in this region in human and their orthologs in mouse chromosome 7C and in Fugu. NIPA1 and NIPA2 each encode putative polypeptides with 9 transmembrane domains, suggesting function as receptors or as transporters. Phylogenetic analyses for NIPA1 in 3 vertebrate species and for NIPA2 in 8 vertebrate, invertebrate and plant species shows that NIPA1 and NIPA2 are highly conserved, indicating they play important roles in multicellular organisms, and suggesting that NIPA1 evolved by duplication from an ancestral NIPA2 gene at least 450 million years ago (mya). Both NIPA1 and NIPA2 are expressed in cells derived from normal individuals, PWS and AS patients, as well as corresponding mouse models, indicating they are non-imprinted genes. By northern analysis, NIPA2 is expressed in all tissues in human and mouse, and two alternatively polyadenylated transcripts are found for NIPA1 with the longer mRNA highly expressed in brain. Intriguingly, phylogenetic studies indicate that a 4-gene cassette between BP1 and BP2 in human, including NIPA1 and NIPA2 as well as two other non-imprinted genes, is conserved and adjacent to the Herc2 gene in mouse and Fugu. These observations suggest a model in which duplications of the HERC2 gene in primates (> 15-20 mya) first flank the 4-gene cassette, with subsequent transposition of these 4 unique genes by a HERC2- or adjacent duplicon mediated process to form the BP1-BP2 region. It will be important to assess the degree of polymorphism in which deletions or duplications of BP1-BP2 occur within the population, and whether the hemizygous or homozygous loss or duplication of the four genes between BP1 and BP2 in PWS (and AS) subjects with class I or II deletions contributes to the phenotype.

July 2002