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Appendix: Imprinted Genes and Regions in Mouse and Human

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Appendix: Imprinted Genes and Regions in Mouse and Human Appendix: Imprinted Genes and Regions in Mouse and Human Colin V. Beechey 1 The Mouse Imprinting Map and Human Homologous Regions 1.1 Introduction The imprinting maps (Figs. 1-7) illustrate regions of the mouse genome that have been screened for developmental anomalies that could be attributable to imprinting (imprinting effects, reviewed in Cattanach and Beechey 1997). The maps also include chromosomes 9,14,18 and 19 that contain imprinted genes but which have not shown clear imprinting effects in genetic tests. The map is a modified version of an earlier imprinting map (ref. 7: Cattanach and Beechey 1997), that was updated annually in Mouse Genome and is now available on the WWW (http://www.mgu.har.mrc.ac.uk). It is based on mouse genetic studies (Cattanach and Beechey 1997) in which Robertsonian (Rb) and reciprocal (T) translocations have been used to generate mice with uniparental disomies and uniparental duplications (partial disomies) of whole or selected chromosome regions respectively (see Sect. 1.2 Methodology). These mice have been screened for abnormal phenotypes (imprinting effects) and autosomal chromosome regions where such effects have been found are illustrated on both the G-banded and genetic maps. The imprinting effects discovered so far are diverse (Cattanach and Beechey 1997). They include early embryonic lethalities, late foetal lethalities, neonatal abnormalities often with inviability, growth effects and more subtle effects upon postnatal development such as those shown by the mouse model of Angelman syndrome (Cattanach et al. 1997). The chromosomal location of the 28 currently known autosomal im­ printed genes are shown in bold and the repressed parental allele indicated. The majority of imprinted genes locate to regions associated with imprinting phenotypes, the exceptions being Rasgrfl on Chr 9, Htr2a on Chr 14, Insl on Chr 19, and possibly Impact on Chr 18. Fifteen imprinted genes are located in two domains in central and distal Chr 7. Recent evidence suggests that other Medical Research Council, Mammalian Genetics Unit, Harwell, Didcot, Oxfordshire OXll ORD, UK 304 C.V. Beechey Key to mouse imprinting maps MatDp = Maternal duplication PatDp = Paternal duplication established imprinting regions with phenotype untested or not investigated for post-natal effects • lgf2 etc = imprinted gene, maternally repressed Mash2 etc .,. = imprinted gene, paternally repressed p etc = positions in eM of phenotypic marker loci and imprinted genes T26H, =chromosome anomalies that define imprinting regions (see text) Rb9Lub, Dei56H, ls1Ct etc Fig. 1. Key to mouse imprinting map domains may be located on proximal Chr 11 (Cattanach et al. 1998) and distal Chr 2 (Kikyo et al. 1997; Williamson et al. 1998). The breakpoints of chromo­ some anomalies that currently define each imprinting region are illustrated, and their positions shown, on both the genetic and G-banded maps. The locations of imprinted genes and marker loci on the genetic map are taken from The mouse genome database (MGD 1998). Other chromosome anomalies such as deletions, (Del) and insertions (Is), that have been used to define or investigate imprinting regions are also identified, as are human homologues (Lyon et al. 1997) for mouse chromosome regions with imprinting effects or imprinted genes. 1.2 Methodology 1.2.1 Uniparental Disomies Mice with both copies of a specific chromosome inherited from the same parent, or uniparental disomies, can be generated by intercrossing heterozygotes for Robertsonian translocations (nonhomologous chromo- Appendix: Imprinted Genes and Regions in Mouse and Human 305 Human Chr 2 homologous region MatDp PatDp phenotype 7 2 A 3 8 11 1.2 1.32 c 3 67 ::::: !:> 1 3 2 E 'dec reasoid ... 89 a 20q cerebellar ~Nnat ~ . 4... folding • 2 1 F neo.:nata!' · · · · · · ·· .. 3 ... behaviour<< 1 2 G 20q 3 ..... ~~~ .l~!~~!i!~ ••.• 'i 2 1 3 H . ~ .... Human Chr6 homologous region MatDp PatDp ................ !',s;g 7q early embryonic ~':fsl' lethality · · · · .. · .. ·· .... ':is· Lc ~6Ad Fig. 2-7. Linkage and G-banded maps of mouse chromosomes 2, 6, 7, 9, 11, 12, 14, 17, 18, and 19. Regions that show developmental abnormalities (imprinting effects) with maternal or paternal duplication (MapDp or PatDp) are shown on Chrs 2, 6, 7, 11, 12, 17, 18, and 19. Chromosomes 9, 14 and 19 have not shown clear imprinting effects in genetic tests but contain imprinted genes. The breakpoints of chromosome anomalies that define imprinting regions are shown on both the linkage and G-banded maps. Human homologies to mouse imprinted regions are shown on the left 306 C.V. Beechey Human Chr7 hOI')10iogous MatDp PatDp reg1on .............. ~............ 19q neonatal 19p lethality 2 A 11p " """"28..:.. p • post-natal ~!nf'Pn • lethality :::; g : 3 8 15q Prader-WIIII .... J~~7 : ~~~~~~~?? .. .:' w:.3. · 44 c 2 D E 3 2 F 4 11p Human MatDp PatDp Chr9 homologous region 3q 50 asgrll 3p Fig. 2-7. Continued Appendix: Imprinted Genes and Regions in Mouse and Human 307 Human Chr 11 horl!ologous reg1on 22-- 7p 2p 2 3.1 16p ~ 9 wa2 3.2 A 5q ~ 3.3 1 2 1. 1 32 "' 1.3 8 c 0 E 2 Human Chr12 horl!ologous reg1on MatDp PatDp 11 1.2 1.3 2 A .L ..... 2 1 8 .... ~ .... I-----___,.,52H 2 c e1r1y embryonic : e1rly embryonic 14q lelh•lity : leth•lity 2 0 t-------10ei7SH ... 3 .... E 0r------T31H F .... 2 ... Fig. 2-7. Continued 308 C.V. Beechey Human Chr14 homologous MatDp PatDp region 2 A B 2 c 0 3 13q 41 Hlr2B ~ 2.1 2.3 E 4 Fig. 2-7. Continued Human Chr17 homologous region MatDp PatDp 4 2 A 32 Tme ;_T .. 6q neonatal: lethality ; \ B c ~post-natal "~· growth« \2 2 E ........... Fig. 2-7. Continued Appendix: Imprinted Genes and Regions in Mouse and Human 309 -------------------------- Human Chr18 homologous region MatDp PatDp Rb9Lub 10p 18q No post-natal effects lmp~ct No post-natal effects 11p but possible foetal but possible foetal 8q, Sq growth retardation? growth retardation? /T50H- ~T18H- 31 sytp Fig. 2- 7. Co ntinued Human Chr19 homologous regions MatDp PaiD 10q Fig. 2- 7. Continued somes fused at the centromere). The simplest system utilizes intercrosses between heterozygotes for a single Robertsonian translocation, preferably with a high rate of nondisjunction, one parent in the cross being homozygous for a suitable marker gene on one of the translocation chromosomes (Fig. 8). Nondisjunction during gamete formation in both parents leads to gametes that are disomic or nullisomic for one or other of the chromosomes involved in the translocation. These unbalanced gametes can usually complement each other to form chromosomally balanced viable zygotes with maternal (MatDi) or paternal disomy (PatDi). These can be recognized according to which parent was homozygous for the marker gene, and their phenotype studied for any imprinting effects. The frequency of each type of disomy among the total 310 C. V. Beechey Production of uniparental disomies FEMALE MALE r-------113 1 lD 13 1 ..... meiosis X :-. ........ vt I· ,. I vt 11 11 11 11 "'"-di*""'~ ~ . -........ complementation of unbalanced gametes / to give balanced zygotes ""' Mat ~- ..~\!) ... ._ Pat Mat 13 ;; lD zygotes 11 •11 11 '" l" I· 11 . MatDi.11 PatDi.11 phenotypically + phenotypically vt Fig. 8. Diagram of single Robertsonian system for generating uniparental disomies. The example presented illustrates how, as a result of meiotic nondisjunction in both parents heterozygous for a single (11:13) Robertsonian translocation, offspring with paternal disomy (PatDi) and maternal disomy (MatDi) for Chr 11 can be generated. If one parent, in this example the male, is homozygous for the visible Chr 11 marker gene vt and the female parent is homozygous normal, then PatDi offspring will show the vt phenotype. Offspring with maternal disomy (MatDi) are phenotypically wild type ( +) like their normal sibs (not shown) but they can be detected in the reciprocal cross in which the female parent is homozygous for vt. Chr 13 uniparental disomies (not shown) are also generated but without Chr 13 marker genes these cannot be identified. Offspring with unbalanced chromosome complements, e.g., trisomy or monosomy for Chrs II and 13 are also generated (not shown) but die prenatally Appendix: Imprinted Genes and Regions in Mouse and Human 311 progeny can reach about 5% but is commonly lower. Chromosomally unbal­ anced zygotes, such as monosomies and trisomies, are also generated but these usually die before birth. A more efficient system (not shown) uses intercrosses between double heterozygotes for two Robertsonian translocations sharing a common arm (monobrachial homology) with one parent homozygous for a marker gene on the shared chromosome. In such crosses higher frequencies of nondisjunction are found than with single Robertsonian heterozygotes, allowing up to 10% of uniparental disomies to be recovered. Litter sizes can be severely reduced, however, due to the high frequencies of chromosomally unbalanced zygotes produced. 1.2.2 Uniparental Duplications (Partial Disomies) Mice with uniparental inheritance of only parts of specific chromosomes, rather than whole chromosomes, can be generated by intercrossing heterozygotes for reciprocal translocations (reciprocal exchange of segments between nonhomologous chromosomes; see Figs. 9 and 10). Unbalanced gam­ etes with duplications and/or deficiencies of chromosome regions are pro­ duced and, as with the Robertsonian system, these can usually complement each other to form chromosomally balanced zygotes. Marker genes on one or both of the chromosomes concerned allows mice with paternal (PatDp) or maternal duplication (MatDp) to be recognized, and their phenotype studied for imprinting effects. This system for the production of PatDp and MatDp mice has two compli­ cating factors, however. The first is that regions proximal and distal to the translocation breakpoints have to be considered separately. Recovery of mice with duplication of distal regions (Fig. 9) is dependent upon the common adjacent -1 meiotic segregation of gametes, giving a recovery rate of PatDp and MatDp offspring of around 16%.
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