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5.5.1 Overview

From the birth of the field of genetics until a decade ago, it was generally assumed that the parental origin of a gene could have no effect on its function. In the vast majority of studies carried out during the last 90 years, this paradigm has appeared to hold true. However, with increasingly sophisticated genetic and embryological investigations in the mouse, important exceptions to this rule have been uncovered over the last decade. First, the results of nuclear transplantation experiments carried out with single-cell fertilized embryos have demonstrated an absolute requirement for both a maternally-derived and a paternally-derived pronculeus to allow full-term development (McGrath and Solter, 1983). Second, in animals that receive both homologs of certain chromosomes or subchromosomal regions from one parent and not the other (through the mating of translocation heterozygotes as described in Section 5.2.3), dramatic effects on development can be observed including enhanced or retarded growth and outright lethality (Cattanach and Kirk, 1985). Third, either of two deletions that cover a small region of mouse chromosome 17 can be transmitted normally from a father to his offspring, but these same deletions cause prenatal lethality when they are maternally transmitted (Johnson, 1974; Winking and Silver, 1984). Fourth, similar parent-of-origin effects have been observed on the phenotypes expressed by animals that carry a targeted knock-out allele at the Igf2 locus (DeChiara et al., 1991). Finally, molecular techniques have been used to directly demonstrate the expression of transcripts from one parental allele and not the other at the Igf2r locus (Barlow et al., 1991) and the H19 locus (Bartolomei et al., 1991).

The accumulated data indicate that a subset of mouse genes (on the order of 0.2%) will function differently in normal embryos depending on whether they have been inherited through the male or the female gamete, such that one allele will be expressed and the other will be silent. Genomic imprinting is the term that has been coined to describe this situation in which the phenotype expressed by a gene varies depending on its parental origin (Sapienza, 1989). Further experiments have demonstrated that, in general, the "imprint" is erased and regenerated during gametogenesis so that the function of an imprintable gene is fully determined by the sex of its progenitor alone, and not by earlier ancestors.

With the demonstration of genomic imprinting in the mouse, patterns of disease inheritance in humans have been investigated for the possibility of phenotypes determined by parent of origin in this mammal as well. To date, clear-cut parental effects have been uncovered in the transmission of the juvenile form of Huntington disease (Ridley et al., 1991), Prader-Willi and Angelman deletion syndromes (Nicholls et al., 1989) and certain forms of juvenile familial carcinomas such as multifocal retinoblastoma, Wilm's tumor, embryonal rhabdomyosarcoma and Beckwith-Wiedemann syndrome (Ferguson-Smith et al., 1990; Henry et al., 1991; Sapienza, 1991).

5.5.2 Why is there imprinting?

The first explanation for the existence of imprinting was as a mechanism to prevent the full-term development of parthenogenetic embryos. This explanation was never satisfactory because it did not account for the intricate control of imprinting at multiple well-bounded loci. An alternative hypothesis put forward by Haig and his colleagues is based on a tug of war between the sexes (Haig and Graham, 1991; Moore and Haig, 1991). According to this hypothesis, it is in the interest of a male to attempt to recover more maternal resources for his developing offspring in relation to offspring in the same mother that were sired by other males. This can be accomplished with a paternal imprint that down-regulates the expression of genes that normally act to slow down the growth of embryos. As a consequence, embryos that are sired by these males will grow more rapidly than half-siblings sired by other males. Although overgrowth may be beneficial to these offspring, it extracts a heavy reproductive cost from the mother. Consequently, it is in the interest of the mother to counteract this increased level of growth. She can do this with an imprint that down-regulates the relevant growth factor genes themselves. The evolutionary endpoint of this tug of war is the current day situation where genes that act to increase embryonic growth (such as Igf2) have inactivated maternal alleles, and genes that act to limit growth (such as Igf2r) have inactivated paternal alleles.

The only other currently viable hypothesis to explain imprinting is that it results from the accidental, ectopic use of machinery that has evolved for the really important imprinting associated with X chromosome inactivation. According to this hypothesis, autosomal imprinting is a red herring whose study is unlikely to provide information of significance to an understanding of developmental genetics. The major strike against this hypothesis is dealt by selectionists who would contend that genetic accidents of this magnitude just do not happen and there must be something peculiar about mammals that has promoted the evolution of imprinting. In support of the selectionist view is the recent demonstration of mono-allelic expression of the H19 gene in humans (Zhang and Tycko, 1992). Conservation of imprinting during the evolution of both humans and mice from a common ancestor strongly suggests the existence of selective forces. Nevertheless, it is still possible that the Haig hypothesis is not entirely correct and that other reasons for imprinting lie hidden beneath the surface waiting to be uncovered.

5.5.3 The molecular basis for imprinting

The question "how does it happen?" can be easily separated from the question "why does it happen?". However, here again, our understanding is still quite rudimentary. Figure 5.8 illustrates in a very general way the essential requirements of a paternal imprinting system. Both parents have one imprinted allele (derived from their fathers) and one active allele (derived from their mothers). During oogenesis, the imprint must be erased so that all eggs will contain equivalent alleles that can become activated in all offspring. In contrast, at the completion of spermatogenesis in the father, all sperm will contain alleles that are "marked" for imprinting. It is possible that the mark present on one of the father's alleles is erased and both copies are marked de novo in all spermatogenic cells, or the one imprinted copy may retain its mark, with de novo marking applied only at the second copy. In either case, the new embryo will receive one "marked" gene from the father and one non-marked gene from the mother.

The "mark" may itself be replicated faithfully along with its homolog, and the "mark" may itself be responsible for the actual repression of gene activity. On the other hand, the "mark" may simply identify the paternal allele so that a separate imprinting machinery that acts to prevent gene repression can be laid down within the developing embryo. If there is a separate imprinting machinery, either it or the "mark" could be replicated along with the paternal homolog to maintain the imprint through each cell division.

It is still the case in 1993 that the nature of both the mark and the imprinting machinery (if it exists as a separate entity) are entirely unknown. Both could presumably entail direct chemical modifications of DNA and/or specific protein components (that might lead to changes in the local chromatin configuration). In addition, the specific DNA sequences that must be recognized by the gametogenic marker are also unknown at this time.

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