M6P/IGF2R imprinting first appeared approximately 150 million years ago following the divergence of prototherian from therian mammals. Although M6P/IGF2R is clearly imprinted in opossums and rodents, its imprint status in humans remains ambiguous. It is also still unknown if M6P/IGF2R imprinting was an ancestral mammalian epigenotype or if it evolved convergently. We report herein that M6P/IGF2R is imprinted in Artiodactyla, as it is in Rodentia and Marsupialia, but that it is not imprinted in Scandentia, Dermoptera and Primates, including ringtail lemurs and humans. These results are most parsimonious with a single ancestral origin of M6P/IGF2R imprinting followed by a lineage-specific disappearance of M6P/IGF2R imprinting in Euarchonta. The absence of M6P/IGF2R imprinting in extant primates, due to its disappearance from the primate lineage over 75 million years ago, demonstrates that imprinting at this locus does not predispose to human disease. Moreover, the divergent evolution of M6P/IGF2R imprinting predicts that the success of in vitro embryo procedures such as cloning may be species dependent.

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Divergent evolution in M6P/IGF2R imprinting from the Jurassic to the Quaternary

The inactivation of one X chromosome in females is normally random with regard to which X is inactivated. However, exclusive or almost-exclusive inactivation of one X may be observed in association with some X-autosomal rearrangements, mutations of the XIST gene, certain X-linked diseases, and MZ twinning. In the present study, a methylation difference near a polymorphism in the X-linked androgen-receptor gene was used to investigate the possibility that nonrandom X inactivation is increases in fetuses and newborns that are associated with confined placental mosaicism (CPM) involving an autosomal trisomy. Extreme skewing was observed in 7 (58%) of 12 cases with a meiotic origin of the trisomy, but in none of 10 cases examined with a somatic origin of the trisomy, and in only 1 (4%) of 27 control adult females. In addition, an extremely skewed X-inactivation pattern was observed in 3 of 10 informative cases of female uniparental disomy (UPD) of chromosome 15. This may reflect the fact that a proportion of UPD cases arise by "rescue" of a chromosomally abnormal conceptus and are therefore associated with CPM. A skewed pattern of X inactivation in CPM cases is hypothesized to result from a reduction in the size of the early-embryonic cell pool, because of either poor early growth or subsequent selection against the trisomic cells. Since approximately 2% of pregnancies detected by chorionic villus sampling are associated with CPM, this is likely a significant contributor to both skewed X inactivation observed in the newborn population and the expression of recessive X-linked diseases in females.

https://www.cell.com/ajhg/pdf/S0002-9297(07)60237-7.pdf

Skewed X-Chromosome Inactivation Is Common in Fetuses or Newborns Associated with Confined Placental Mosaicism

Summary IntroductionThe inactivation of one Xchromosome in females isnormallyrandomwithregardtowhichXis inactivated.However, exclusive or almost-exclusive inactivation ofone Xmay be observed in association with some X-autosomal rearrangements, mutations ofthe XIST gene,certainX-linked diseases, andMZ twinning. Inthepres-ent study, a methylationdifference neara polymorphism in the X-linked androgen-receptor genewasusedto in-vestigate the possibility that nonrandomXinactivationis increases in fetuses andnewbornsthat are associatedwith confined placental mosaicism (CPM)involving anautosomal trisomy. Extreme skewing wasobservedin 7(58%) of 12 cases with a meiotic origin ofthe trisomy,butin noneof10cases examinedwithasomaticoriginof the trisomy, and in only 1 (4%) of27control adultfemales. In addition, an extremely skewed X-inactiva-tion pattern was observed in 3 of 10 informative casesoffemaleuniparental disomy (UPD)ofchromosome15.Thismayreflect thefact that aproportionofUPDcasesarise by "rescue" of a

Skewed X-Chromosome Inactivation IsCommoninFetuses orNewborns Associated withConfined Placental Mosaicism

https://aasldpubs.onlinelibrary.wiley.com/doi/pdf/10.1053/jhep.2002.32669

M6P/IGF2R tumor suppressor gene mutated in hepatocellular carcinomas in Japan

Amyotrophic lateral sclerosis (ALS: Lou Gehrig's Disease) is a lethal neurodegenerative disease of upper and lower motorneurons in the brain and spinal cord. We previously reported linkage of a gene for familial ALS (FALS) to human chromosome 21 using 4 restriction fragment length polymorphism DNA markers [Siddique et al.: N Engl J Med 324:1381-1384, 1991] and identified disease-associated mutations in the superoxide dismutase (SOD)-1 gene in some ALS families [Rosen et al.: Nature 362:59-62, 1993]. We report here the genetic linkage data that led us to examine the SOD-1 gene for mutations. We also report a new microsatellite DNA marker for D21S63, derived from the cosmid PW517 [VanKeuren et al.: Am J Hum Genet 38:793-804, 1986]. Ten microsatellite DNA markers, including the new marker D21S63, were used to reinvestigate linkage of FALS to chromosome 21. Genetic linkage analysis performed with 13 ALS families for these 10 DNA markers confirmed the presence of a FALS gene on chromosome 21. The highest total 2-point LOD score for all families was 4.33, obtained at a distance of 10 cM from the marker D21S223. For 5 ALS families linked to chromosome 21, a peak 2-point LOD score of 5.94 was obtained at the DNA marker D21S223. A multipoint score of 6.50 was obtained with the markers D21S213, D21S223, D21S167, and FALS for 5 chromosome 21-linked ALS families. The haplotypes of these families for the 10 DNA markers revealed recombination events that further refined the location of the FALS gene to a segment of approximately 5 megabases (Mb) between D21S213 and D21S219.(ABSTRACT TRUNCATED AT 250 WORDS)

J. Goto

Papers

Dinucleotide repeat polymorphism at the IGF2R locus.

Dinucleotide repeat polymorphism at the D21S65 locus.

Dinucleotide repeat polymorphism at the D21S219 locus which flanks the GARS-AIRS-GART gene

A PvuII RFLP at the HOX 1.4 homeobox locus (HOX1D).