the 129 strain consists of many substrains and is thought to have been genetically contaminated to some extent 
 in the course of research and exchanges between laboratories   ( fig . the image shows a commonly used 129/sv mouse , which has the full designation , 
 129s1/sv - p<+ > tyr<+ > , indicating its substrain group (  129s  indicates a steel substrain 
 group ) and coat color ( wild type ) . this strain is available from the riken bioresource center 
 ( rbrc00002 ) . ) . these substrains can be divided into three major groups129s , 129p and 129t  according to their origin 
 . as far as has been examined to date , all these substrains show 
 unique and extensive genomic plasticity under specific circumstances . in early studies , 129 mice were 
 characterized by a low but consistent incidence ( 18% ) of spontaneous testicular germ cell tumors ( tgcts ) , which 
 contributed to the derivation of embryonic carcinoma ( ec ) cells . the 
 methodologies established for ec cells during the 1960s and 1970s , including l.c . stevens pioneering work 
 , provided the important foundation for establishing embryonic stem 
 ( es ) cell lines . es cells are pluripotent stem cells derived from the inner cell mass cells of blastocysts and 
 are considered to be the non - tumor counterparts of ec cells . at that time , the 129 mouse was the only inbred 
 strain that could give rise to stable es cell lines [ 7 , 8 ] . interestingly , not only the homozygous but also the heterozygous set of 
 the 129 genome can contribute to easier generation of es cell lines , as evidenced by the generation of hybrid 
 cell lines between 129 and  nonpermissive  strains such as the nod , ddk , and chinese kunming mouse strains 
 . currently , inbred strains other than 129such as c57bl , nod and msm  can also be sources 
 of es cells thanks to the recent development of serum - free media containing inhibitors of mek and gsk3 ( 2i ) and 
 lif , which potentially can maintain the pluripotency of es cells in the so - called  nave  state . nevertheless , it is apparent that the contribution of the 129 strain to 
 the advancements of biomedical science has been enormous , considering the thousands of gene - targeted mice 
 generated with a 129 genetic background . the image shows a commonly used 129/sv mouse , which has the full designation , 
 129s1/sv - p<+ > tyr<+ > , indicating its substrain group (  129s  indicates a steel substrain 
 group ) and coat color ( wild type ) . the uniqueness of the 129 strain was further recognized in somatic cell nuclear transfer ( scnt ) experiments in 
 mice . since the first report on the birth of mice cloned from cumulus cells in 1998 , f1 hybrid mice such as b6d2f1 ( cross of a c57bl/6 female mouse and a dba/2 male mouse ) 
 have been most frequently used for donors . the so - called  hybrid 
 vigor ,  which is known to increase the survivability of mouse embryos in vitro , is particularly 
 advantageous in the development of cloned embryos . the only exception of this is the 129 
 strain , as evidenced by the births of cloned offspring from cumulus cells [ 16 , 17 ] , immature sertoli cells , and tail - tip cells   with the 129 genetic 
 background . a global gene expression analysis we performed using blastocysts revealed the superior 
 reprogrammability of the 129 genome as a donor for scnt ( fig . 2 . principal component analysis for global gene expression profiles of blastocysts generated by icsi 
 ( intracytoplasmic sperm injection ) or scnt ( cumulus clone ) with the b6d2f1 or 129 genotypes . components 1 
 and 2 mean principal components with the first and second highest levels of variance , respectively . scnt - derived blastocysts from the 
 b6d2f1 strain showed scnt - specific expression profiles ( enclosed with blue dotted lines ) , but those from 
 129 did not ( enclosed with red dotted lines ) , indicating that the 129 genome was reprogrammed more 
 correctly than the b6d2f1 genome by nuclear transfer . ) . it is interesting to note that , as in the case of es cells , the presence of the haploid component of 
 the 129 genome in the donor genome has a beneficial effect . specifically , we have been able to produce cloned 
 mice successfully using new somatic cell types ( neural stem cells , natural killer t cells , hematopoietic stem 
 cells and primordial germ cells ) with the f1 hybrid 129 genotype . hematopoietic cells , for example , are difficult to clone by nuclear 
 transfer , but those from the 129 strain can be reprogrammed easily ( table 
 1table 1 . development in vitro of embryos cloned from hematopoietic stem cells from b6d2f1 or 
 129 strains of micedonor strainno . ( % ) blastocystsb6d2f14439 ( 89)8 ( 18)4 ( 9)129/sv - ter5848 ( 83)40 ( 69)30 ( 52)different superscript letters within columns indicate significance at p < 0.0001 ( fisher s exact 
 test ) . ) . similarly , hybrids between wild - derived mice ( jf1 ) and 129 mice were cloned successfully for 
 genomic imprinting studies , which analyzed the polymorphisms between these parental strains [ 17 , 23,24,25 ] . furthermore , one of the most outstanding experiments in 
 mammalian cloning the serial recloning of mice over 25 generations  was achieved with a donor genome partially 
 comprised of the 129 genome . in addition to its effect on promoting 
 development , the 129 genome exerts corrective effects on abnormal phenotypes associated with scnt . it is well 
 known that cloned placentas show hyperplastic enlargement with abnormal histology [ 27 , 28 ] ( fig . the image shows two- to three - fold 
 enlargement ( hyperplasia ) with characteristic histology ( upper ) . however , the presence of the 129 genome 
 in the donor nucleus ameliorated the scnt - associated placental abnormalities ( lower ) . this abnormality was not corrected even after significant improvements in cloning efficiency by 
 correction of xist gene expression   or the treatment 
 of cloned embryos with trichostatin a . however , the cloned placentas 
 of the 129 strain are nearly normal in appearance and histology 
 ( fig . 3 ) .   principal component analysis for global gene expression profiles of blastocysts generated by icsi 
 ( intracytoplasmic sperm injection ) or scnt ( cumulus clone ) with the b6d2f1 or 129 genotypes . components 1 
 and 2 mean principal components with the first and second highest levels of variance , respectively . scnt - derived blastocysts from the 
 b6d2f1 strain showed scnt - specific expression profiles ( enclosed with blue dotted lines ) , but those from 
 129 did not ( enclosed with red dotted lines ) , indicating that the 129 genome was reprogrammed more 
 correctly than the b6d2f1 genome by nuclear transfer . different superscript letters within columns indicate significance at p < 0.0001 ( fisher s exact 
 test ) . the image shows two- to three - fold 
 enlargement ( hyperplasia ) with characteristic histology ( upper ) . however , the presence of the 129 genome 
 in the donor nucleus ameliorated the scnt - associated placental abnormalities ( lower ) . these 129-specific features identified with es cells and cloned embryos cumulatively suggest the presence of 
 some factor ( or factors ) that promotes genomic flexibility or plasticity of the 129 genome . although the nature 
 of this factor remains elusive , we suppose that it might cause lability of epigenetic regulation in a 
 genome - wide manner . there are some findings that support this assumption . transgenic mice with a 129 genetic 
 background showed a moderate loss in dna methylation of transgenes , although the methylation levels varied with 
 the site of integration into the recipient genome . the nave status 
 of both es cells and embryonic germ ( eg ) cells was maintained by global dna hypomethylation . it is known that , like es cells , eg cells can also be easily established 
 from 129 mice . taken together , the plasticity factor in the 129 
 strain might endow the genome with a propensity towards dna hypomethylation in a genome - wide manner . in contrast to the situations of es cells and eg cells , 129 is known to be nonpermissive for the derivation of 
 germline stem ( gs ) cells , which were originally developed by shinohara s group . gs cells are derived from neonatal spermatogonial stem cells and have an unlimited ability to 
 proliferate in vitro while also maintaining full differentiation capacity in 
 vivo . it is possible that the inability of 129 spermatogonia to contribute to 
 the generation of gs cells might also be explained by dna methylation . genome - wide analysis of dna methylation 
 levels revealed that gs cells and neonatal spermatogonia are the most hypermethylated cells among different 
 types of germ and stem cells . therefore , the derivation of gs cells 
 from spermatogonia requires maintenance of the hypermethylated status in vitro , which might be 
 interfered with by the propensity of the 129 genome . notably , transformation of gs cells into es cell - like cells 
 ( multipotent gs cells ; mgs cells ) was made possible by the induction 
 of dna demethylation [ 39 , 40 ] , 
 indicating that gs cells are more methylated than pluripotent mgs cells . thus , although still speculative , the 
 epigenetic characters of gs cells and mgs cells might also be consistent with our assumption that the putative 
 plasticity factor within the 129 genome might help the entire genome in acquiring a hypomethylated status . so far , the search for genetic traits using the 129 strain has focused mainly on tgcts . among the major 
 substrain groups , the 129 t group ( the  t comes from teratoma ) is known to be susceptible to tgcts . genetic 
 analysis of segregating populations generated from 129 mice and from mice that do not form tgcts suggested that 
 at least 35 , or at maximum 15 , genes control the susceptibility to tgct . it is possible that one or more genes among them may be associated with the genomic plasticity of 
 129 mice . quantitative trait locus ( qtl ) analysis identified several genetic regions or specific genes , such as 
 ter , steel and trp53 . however , these recessive genes are not strong candidates for the 129 plasticity factor because it 
 exerts its effect as a dominant , not recessive , trait . experiments using chromosome substitution ( consomic ) 
 strains between 129 ( susceptible ) and molf ( non - susceptible ) strains identified that genes conferring strong 
 tgct susceptibility exist on chromosome ( chr ) 18 and chr 19 [ 41 , 42 ] . interestingly , a chr 18 consomic strain , 129-chr 18 , 
 showed not only a lower tgct frequency but also a worse capacity for es cell derivation than the 129 strain 
 [ 42 , 43 ] . this suggests that 
 tgct susceptibility and the capacity for es cell derivation in 129 strains can be attributed to a common gene(s ) 
 on chr 18 . it has been reported that es cells from permissive strains including 129 activated the jak - stat3 pathway rather 
 than the map kinase pathway downstream of lif , while those from nonpermissive strains showed the opposite 
 pattern . however , in this study , c57bl/6 was also classified as a 
 permissive strain , so any 129-specific characters associated with es cells remained unclear . further experiments 
 that discriminate 129 from the c57bl/6 strains might give clues to understanding the plasticity factor in the 
 129 genome . we sought to identify the plasticity factor present in the 129 genome by a forward genetics strategy using nine 
 recombinant inbred ( ri ) strains between 129 and c57bl/6 . these carry randomly distributed homozygous loci 
 derived from either parental strain , so a set of ri strains can be used for identifying genomic regions or genes 
 responsible for phenotypes of interest . first , we performed scnt experiments using cumulus cells from eleven strains ( nine ri strains and two parental 
 strains ) , and the resultant cloned blastocysts were subjected to global gene expression analysis by microarray . 
 as mentioned above , we expected that the ri strains that carry the putative 129-derived plasticity factor would 
 show a high level of genomic reprogrammability and more normal gene expression profiles . however , the gene 
 expression profiles obtained were too diverse among the strains , so we failed to identify the ri strains that 
 are close to the 129 strain in their gene expression profile . next , we examined the birth rates of clones and 
 the morphology of placentas at term in all ri strains . in total , we reconstructed 7454 embryos , and 6671 of them 
 were transferred into recipient pseudopregnant females . six of the nine ri strains gave rise to cloned 
 offspring , and the remaining three strains did not . based on the birth rates , the placental weights and the 
 genomic data of the ri strains , we ultimately identified four candidate genomic regions that might be 
 responsible for the plasticity of the 129 genome . we are now searching for polymorphisms between the 129 and c57bl/6 strains in these 
 candidate genes , while preparing another series of experiments on the ri strains based on derivation of es cell 
 lines . genomic reprogramming comprises the central part of induced pluripotent stem cell ( ipsc ) technology and scnt 
 cloning . therefore , if we could identify the genomic plasticity 
 factor ( or factors ) in 129 mice , it would contribute greatly to the safe and efficient development of new 
 technologies in regenerative medicine , farm animal production , and the pharmaceutical industries . at present however , it should be encoded in the 129 genome and could be 
 transferred into other mammalian species , provided the mechanisms involved are not specific to the mouse . it is 
 possible that novel agents that enhance genomic reprogramming could be synthesized if we could identify new 
 mechanisms for epigenetic regulation from the 129 factor . they would indeed comprise a genomic treasure to be 
 mined in the 129 genome , and humans would benefit from this in many aspects of science and medicine .
it should be emphasized that  129  is not simply a number but is also the designation of a mouse strain that 
 has made a great contribution to modern biological science and technology . 
 embryonic stem cells derived from 
 129 mice were essential components of gene - targeting strategies in early research . more recently , 
 129 mice 
 have provided superior donor genomes for cloning by nuclear transfer . some factor or factors conferring 
 genomic 
 plasticity must exist in the 129 genome , but these remain unidentified .