Transchromosomal mouse embryonic stem cell lines and chimeric mice that contain freely segregating segments of human chromosome 21

At least 8% of all human conceptions have major chromosome abnormalities an d the frequency of chromosomal syndromes in newborns is >0.5%. Despite thes e disorders making a large contribution to human morbidity and mortality, w e have little understanding of their aetiology and little molecular data on the importance of gene dosage to mammalian cells. Trisomy 21, which result s in Down syndrome (DS), is the most frequent aneuploidy in humans (1 in 60 0 live births, up to 1 in 150 pregnancies world-wide) and is the most commo n known genetic cause of mental retardation. To investigate the molecular g enetics of DS, we report here the creation of mice that carry different hum an chromosome 21 (Hsa21) fragments as a freely segregating extra chromosome . To produce these 'transchromosomal' animals, we placed a selectable marke r into Hsa21 and transferred the chromosome from a human somatic cell line into mouse embryonic stem (ES) cells using irradiation microcell-mediated c hromosome transfer (XMMCT), 'Transchromosomal' ES cells containing differen t Hsa21 regions ranging in size from similar to 50 to similar to 0.2 Mb hav e been used to create chimeric mice. These mice maintain Hsa21 sequences an d express Hsa21 genes in multiple tissues, This novel use of the XMMCT prot ocol is applicable to investigations requiring the transfer of large chromo somal regions into ES or other cells and, in particular, the modelling of D S and other human aneuploidy syndromes.