Epigenetic Factors

Genomic Imprinting, Uniparental Disomy, and Anticipation. Genomic imprinting, also known as parental imprinting, is an epigenetic, non-Mendelian phenomenon that occurs during gametogenesis in which the expression of a gene or chromosome region depends on whether it is inherited from the mother or the father, who is then called the parent-of-origin. Two modes have been proposed to explain the phenomenon: (1) inheritance of two copies of a gene from one parent as in cases of uniparental disomy (see below); and (2) methylation of the allele contributed by one parent, making an offspring effectively hemizygous for the other parent's allele. Four confirmed examples of genomic imprinting in humans include: (1) myotonic dystrophy, (2) retinoblastoma; (3) Huntington disease, where affected individuals have more severe clinical signs if the trait is inherited from the father; and (4) the Prader-Willi/Angelman syndromes, where a single genetic cause (a small deletion) if inherited from the father results in one syndrome (Prader-Willi), while if inherited from the mother results in another, completely different phenotypic syndrome (Angelman).

Double copies of certain alleles inherited from a male seem to control normal placental development. Double copies of certain alleles inherited from a female seem to control normal embryogenesis. Imprinting has been suggested as a mechanism that may be partly involved in the evolution of conflicting reproductive strategies between males and females (Haig, 2000; Terleph, 2000).

Genomic imprinting caused by uniparental disomy (as in mode (1), above) may be accompanied by loss of heterozygosity (LOH) of all loci along an entire chro-matid. In other words, several loci on a chromatid seem to convert spontaneously from heterozygosity (Rr) to homozygosity (rr). LOH is a feature of many malignant cell lines in genetic disease, and is an important non-Mendelian epigenetic phenomenon. LOH may be achieved by several modes, but it is suspected that non-disjunction is the most common modality. In this case, an individual who is heterozygous (Rr) in germline DNA for a cancer gene such as retinoblastoma could later acquire the cancer "spontaneously" during a cell division event and become an rr homozygote. During cell division the individual would be temporarily hemizygous at the RB locus due to isochromy in one cell line (R), and polyzy-gous (Rrr) due to trisomy in a second. The isochromic cell line containing the single R allele would most likely be inviable and resorb. In the remaining cell line, however, if the third trisomic chromosome is then lost such that the temporarily polysomic (Rrr) cell line reverts to a disomic (rr) cell line, this second mutation could give rise to a converted cell line in which the subsequent clone would be homozygous (rr) for all the loci on the affected chromatid pair. This altered cell line would be malignant.

Uniparental disomy, as this mechanism is termed, is one of several important new epigenetic non-Mendelian mechanisms that can now explain many formerly elusive developmental phenomena at the cellular level. One of the other important new epigenetic mechanisms is anticipation.

Anticipation is a phenomenon whereby a genetic disorder becomes increasingly severe from one generation to the next (the age of onset usually gets lower, as well), and is a feature of about 40 nucleotide triplet repeat expansion disorders in humans. In anticipation, a gene gets progressively longer, as generations pass, usually due to unequal crossing-over. This succession of lengthening events usually makes the gene progressively more dysfunctional with time, and apparently explains many cases where symptoms are similar, yet differ by degrees. Examples of genetic diseases characterized by anticipation are androgen insensitivity syndrome, fragile X syndrome, Huntington disease, and myotonic dystrophy (see Table 1 of the entry Genetic Disease II).

Genomic imprinting and anticipation have been recently implicated in the etiology of certain conditions long suspected to have a genetic component but that did not yield to simple Mendelian models of disease. Among the multifactorial, high heritability conditions that are being re-evaluated in the light of these new mechanisms are the major affective disorders (both bipolar and manic-depressive phases), Tourettesyndrome, and schizophrenia (Anonymous, 1997a, 1997b).

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