Exclusive feature of paternally expressed genes. The differences between mouse and human can in parts be explained by evolutionary divergence. For example, human and mouse placentae show pronounced differences in morphology. In a previous publication we have shown that especially maternally expressed genes experienced an accelerated sequence divergence that were less prominent in the human [6]. These differences in molecular evolution might be associated with functional differences. In this context we will briefly consider possible biases in the results obtained. The annotations stored 25033180 in the Gene Ontology of course only represent a fraction of all knowledge in the original scientific literature and it is impossible to estimate how much we still don’t know. It is quite likely that the GO gives a more complete picture about the cellular functions of genes that have been studied intensely compared to the average gene. It is furthermore possible that some of the known MedChemExpress Chebulagic acid imprinted genes such as IGF2 belong to the group of intensely studied genes so that their cellular functions are known to a larger extent than those of less well studied genes and when compared to the average bi-allelically expressed gene. In agreement with this idea, we found that the three well-known genes IGF2, INS, and GRB10 (out of 30) tended to dominate the functional enrichments in the group of paternally expressed genes. In contrast, the enrichments in the group of all imprinted genes were stable even when we removed the wellknown genes IGF2, INS, and GRB10. When grouping the imprinted genes by enriched GO annotations found for at least two genes, we applied the lowest recommended threshold value of 0.3. In future, when more complete functional associations will be available, it remains to be tested whether a higher, more cautious threshold would be advantageous. We found that when applied to the currently available data, this threshold gave a good compromise between coverage and specificity of the obtained results. In the second part of the study, we were interested in the question if functionally related gene groups such as the prominent groups of transcription factors, and transport related proteins, areco-regulated by similar sets of transcription factor families. This is obviously not the case. Interestingly, also maternally 23727046 and paternally expressed genes are not regulated by distinct sets of transcription factor families. In general, a few genes, i.e. UBE3A, KLF14, BLCAP, NAP1L5, NNAT, and GNAS, show an overproportional enrichment of distinct transcription factor binding sites. Interestingly, these genes possess rather diverse functions. For example, UBE3A seems to act in neuronal development, whereas GNAS acts mostly in endocrinal pathways. Although imprinted genes appear to be regulated by similar sets of transcription factors in mouse and human, it is difficult to identify a typical transcription factor that regulates imprinted genes. The most prominent factor appears to be SP1. This rather ubiquitous factor might be responsible for the broad tissue spectrum of imprinted genes [24]. On the other hand SP1 deficiency is to some extent associated with placental defects and impaired ossification, that are typical features of defects in imprinting [25]. Varrault and co-workers have recently identified a network of coregulated imprinted genes involving the genes Plagl1, Gtl2, H19, Mest, Dlk1, Peg3, Grb10, Igf2, Igf2r, Dcn, Gnas, Gatm, Ndn, Cdkn1c and MedChemExpress 80-49-9 Slc33a4 [26].Exclusive feature of paternally expressed genes. The differences between mouse and human can in parts be explained by evolutionary divergence. For example, human and mouse placentae show pronounced differences in morphology. In a previous publication we have shown that especially maternally expressed genes experienced an accelerated sequence divergence that were less prominent in the human [6]. These differences in molecular evolution might be associated with functional differences. In this context we will briefly consider possible biases in the results obtained. The annotations stored 25033180 in the Gene Ontology of course only represent a fraction of all knowledge in the original scientific literature and it is impossible to estimate how much we still don’t know. It is quite likely that the GO gives a more complete picture about the cellular functions of genes that have been studied intensely compared to the average gene. It is furthermore possible that some of the known imprinted genes such as IGF2 belong to the group of intensely studied genes so that their cellular functions are known to a larger extent than those of less well studied genes and when compared to the average bi-allelically expressed gene. In agreement with this idea, we found that the three well-known genes IGF2, INS, and GRB10 (out of 30) tended to dominate the functional enrichments in the group of paternally expressed genes. In contrast, the enrichments in the group of all imprinted genes were stable even when we removed the wellknown genes IGF2, INS, and GRB10. When grouping the imprinted genes by enriched GO annotations found for at least two genes, we applied the lowest recommended threshold value of 0.3. In future, when more complete functional associations will be available, it remains to be tested whether a higher, more cautious threshold would be advantageous. We found that when applied to the currently available data, this threshold gave a good compromise between coverage and specificity of the obtained results. In the second part of the study, we were interested in the question if functionally related gene groups such as the prominent groups of transcription factors, and transport related proteins, areco-regulated by similar sets of transcription factor families. This is obviously not the case. Interestingly, also maternally 23727046 and paternally expressed genes are not regulated by distinct sets of transcription factor families. In general, a few genes, i.e. UBE3A, KLF14, BLCAP, NAP1L5, NNAT, and GNAS, show an overproportional enrichment of distinct transcription factor binding sites. Interestingly, these genes possess rather diverse functions. For example, UBE3A seems to act in neuronal development, whereas GNAS acts mostly in endocrinal pathways. Although imprinted genes appear to be regulated by similar sets of transcription factors in mouse and human, it is difficult to identify a typical transcription factor that regulates imprinted genes. The most prominent factor appears to be SP1. This rather ubiquitous factor might be responsible for the broad tissue spectrum of imprinted genes [24]. On the other hand SP1 deficiency is to some extent associated with placental defects and impaired ossification, that are typical features of defects in imprinting [25]. Varrault and co-workers have recently identified a network of coregulated imprinted genes involving the genes Plagl1, Gtl2, H19, Mest, Dlk1, Peg3, Grb10, Igf2, Igf2r, Dcn, Gnas, Gatm, Ndn, Cdkn1c and Slc33a4 [26].
