REVIEWS Imprinted genes in mammals are those genes that are ex- pressed predominantly from one of the parental chromo- somes 1-3. Imprinted genes have important roles in devel- opment, and deregulation of imprinting (e.g. loss of imprinting; LOI) is implicated in a number of genetic dis- eases and cancers in humans4-6. One fascinating aspect of imprinting that is emerging is that imprinted genes tend to be clustered in the genome. While this might not be true for all of the imprinted genes, there are at least two major and one minor imprinted clusters in the mouse genome. The two major clusters each contain at least five imprinted genes. Interestingly, in humans the two clusters are associated with two of the major imprint- ing syndromes: the cluster on chromosome 15q11-13 is linked with Prader Willi and Angelman syndromes 7 (PWS and AS), and the one on chromosome 11p15.5 with the Beckwith-Wiedemann syndrome (BWS)~. Deregulation of imprinting in the dusters is iinplic~ted in both diseases. Clustering might occur for mechanistic reasons. Dif- ferent timing of DNA replication between homologues in imprinted regionsg.t0, and differences in meiotic recom- bination frequencies between male and female germ cells in the same regionslt, tz, both suggest a domain organiz- ation that is particular to the paternal and maternal homologue, respectively. Thus, it is possible that a gene can only be imprinted ff it resides in one of these domains (in the same way an X-linked gene becomes inactivated becanse it is on the X chromosome). Alternatively, or in addition, more local mechanistic interactions could occur between imprinted genes that are physically linked. For both major imprinted clusters there is evidence for such regional control, some of which comes from the elucidation of the molecular pathology of the imprinting syndromes and some from genetic experiments in the mouse. For the PWS/AS duster, the existence of an imprinting centre (IC), that potemially controls the epi- genotype of all the genes in the cluster, has been sug- gested from mutations in PWS and AS patients 13-~6. This centre is apparently required in cis in order to reset the imprints when chromosomes enter the germline vl-t6. While there is currently no direct evidence for such an IC for the other cluster (in the distal region of chromosome 7 in mouse and at 11p15.5 in humans; Fig. 1), there are experiments that reveal regional regulation as well. In the mouse, deletion of the maternal (active) copy of the HI9 Imprintingin clusters: lessons from Beckwith- Wiedemann syndrome WOLF ~ ( ~ u k ) EAMONN It. MAHElt (~,~Ngmp.mrc.ac.uk) lmprtated getw$ tt, mammals cambe clustered ht tbe genome. This raises imf~rtut questions about mecba~tic and fmgtioml ~bips betweea i~OrMted &etw$ in a chm~r. The tusuY~4ikegrowthfactor H (IGF2)ger, e is expressed ~/s ~rronded by expressed geae~ Loss of ~ of lGF2 is the most n~kctdar defea $oad tm tbe bumasfoetal (BWS~ Transgewic e x ~ in the mmtse establish that overexpressiom of lGF2 cas resldt M most of the symptoms of BW£ However, mtCMtim~t r a ~ or methflctiom defects M BWShave sofar bea fomul tmthree of the ltnked expressedgeme~ We prese~t a model where the patertud growth ~ IGF2is surromuled by multiple matmsal ~ssor~ wad .~.~ or a ~ t~ a~ o/these s~ssors ~ ~ B~ depe~i o~ which matenu~v expressed ger, e is ~mtated gene results in derepression of the maternal copy of IR[2 (Ref. 17), and deletion of the 1-119 enhancers abolishes H19 expression on the maternal or lgf2 expression on the oatemal chromosome t8. These observations have given rise to the enhancer competition model, whereby both genes compete for shared enhancers and this competition results in reciprocal imprinting 17. In the mouse, H19 deletion affects imprinting of lg/2 and lns2 (homologous to INS in humans) but appar- ently not of Mash2 or p57 raP2 (MGD designation Cdkn l~,, GDB designation CDKNIC), suggesting that H19 is not an IC for the whole cluster17. In BWS patients, region- ally altered epigenotypes (expression and DNA methyl- ation) have also been observed, with 1-119 and IGF2 both adopting a paternal epigenotype on the maternal CEN I I I I I BWSCR2 500 kb TEL m BWSCR1 /' ¢ ¢ ¢ ¢',,, NAP2 CDKNIC KCNA9 INS IGF2 H19 L23 Ftou~ 1. The imprinting duster on human chromtr, ome 11p15.5.The two breakpoint dusters (BWSCR1, 2) of translocalions associatedwith Beckwith-Wiedemann syndrome (BWS) are i,dicated. All translocationsin BWSCR1 identified to date appear to disrupt the KCNA9 (KvZQT) gene. The imprintedgenes that have been identified are shown underneath, and are flanked by two genes that are apparentlynot imprinted (NAP2and/23). An'ows show transcriptionalactivity.The imprinting statusof INS(insulin gene) is not clear yet. The broken line indicates that this region has not been preciselymapped, and in the mouse containsanother imprintedgene, Mash2. (No¢ drawn to ~ale.) "riG AUGUST 1997 VOL. 13 No. 8 ~ / n 1 4 t a c~ lgt-rT EL"ev~'rt ~ n c e lld. All aght" Tt~'~ed. Ol{~l'9525/97/$17.~ 330 PII: ~J 16~952~97)01Zf'~l-6