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Genomic imprinting is an epigenetic phenomenon by which the two
parental alleles of a gene are differentially expressed. As of 1997
there are at least twenty genes known to be subject to genomic imprinting
in mammals: five genes are maternally expressed and the remainder
are paternally expressed. The laboratory has been studying the mechanism
of genomic imprinting at a cluster of imprinting genes on the distal
end of mouse Chromosome 7. At one end of the cluster are three genes
that are exclusively expressed from the maternal chromosome. In
the middle of the cluster are two paternally expressed genes encoding
the growth factors insulin and insulin-like growth factor II (IGFII).
At the far end of the cluster lies the H19 gene, an unusual
gene that codes for a non-translatable RNA whose expression is exclusively
maternal.
The clustering of five imprinted genes raised the possibility that
imprinting, like X chromosome inactivation, is controlled by a signal
or signals which can act over large distances and multiple genes.
To date there is little evidence to support this notion. However
the laboratory has established a mechanistic link between the expression
of H19,Igf-2 and Ins-2 that relies on a competition
between their promoters for a set of shared enhancers. The competition
is regulated by a region of extensive paternal-specific DNA methylation
on the H19. A possible role for the H19 gene product
itself in imprinting has been excluded by the analysis of a null
allele of H19 that shows no disruption in the imprinting
process.
With a growing list of imprinted genes in hand, the challenge is
now to determine the function of allelic inactivation by imprinting.
The function presumably must confer some selective advantage to
the organism, as it must counterbalance the obvious attendant risk
of hemizygosity. Several explanations have been proposed for the
acquisition of genomic imprinting in eutherian mammals. To date
the most compelling model has been provided by David Haig and his
colleagues who suggest that imprinting evolved in mammals because
of the conflicting interests of maternal and paternal genomes within
a litter. In mammals, which are primarily non-monogamous, the mother
provides significant maternal resources to the offspring both during
intra-uterine life as well as during suckling after birth. Successful
passage of paternal genes into the next generation is best ensured
by having the embryos consume maternal resources, even if by so
doing the fitness of her future litters is compromised. The mother's
interests are best served by distributing her resources more equitably
among litters. According to this model, the two parents have silenced
or imprinted different sets of growth-promoting and growth-restricting
genes in order to accomplish their differing reproductive goals.
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