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  • An important challenge for contemporary genetics is to understand the mechanisms underlying those traits and conditions that do not follow traditional patterns of inheritance. Many recent observations demonstrate that the expression of a number of traits in humans, mice, and other organisms depends on which parent transmitted the gene responsible for the trait.

  • In both the mouse and the human, inheritance of the entire chromosome complement from only one parent results in developmental failure. The gross morphologic complementarity of the phenotypes yielded by inheriting both sets of chromosomes from the father versus inheriting both sets from the mother suggests that the paternal genetic contribution is important to placental development, while the maternal contribution is essential for development of the embryo proper.

  • Inheritance of all or part of individual chromosomes from only one parent may also result in an abnormal phenotype, even if the genes responsible for that phenotype are demonstrably wild-type by both genetic and biochemical criteria. An important mechanism by which such uniparental disomy may be achieved in the human is by the in utero reduction of trisomies. Evidence derived from chorionic villus sampling indicates that as many as 1 percent of all pregnancies may carry uniparental disomy for particular chromosomes. Uniparental disomy has been demonstrated in several cases of a number of human diseases, including Beckwith-Wiedemann, Prader-Willi, and Angelman syndromes.

  • The mechanism by which differential expression of maternal and paternal genomes is achieved is unknown but there is a strong correlation between parental origin-specific gene expression and differential DNA methylation and chromatin structure. The tendency to find more than one gene to be imprinted in a region tends to argue for some imprinting controls to operate over domains that are larger than a single gene. Recent data also indicate that important biochemical differences between alleles at imprinted loci are manifested as asynchronous replication of the alleles during S phase of the cell cycle. In addition, “antisense” transcripts have been shown to be associated with silenced alleles at several imprinted loci.

  • Regardless of the biochemical mechanism by which alleles at imprinted loci are marked as “imprinted,” cases of most human disease phenotypes that exhibit a strong parental origin effect may be viewed as having failed to complete one or more steps in the imprinting process. These steps include: (a) erasure of the imprint from the previous generation; (b) establishment of a new imprint that is appropriate to the gender of the individual in which the gametes are being created; (c) transmission of a complete and appropriately imprinted genome to the zygote; (d) stable inheritance of the maternal and paternal imprint through somatic cell division; and (e) proper maintenance and translation of the imprint in those somatic cells in which a parental origin-dependent effect on phenotype is required or observed.*Genetics, Biochemistry, and Molecular Bases of Variant Human Phenotypes, Appendix 1 names all the genes referred to by their symbols (italicized uppercase) in the present chapter.

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