Heredity and epigenetics: an unexpected role of RNA

摘要

Although Mendel's first laws explain the transmission of most characteristics, there has recently been a renewed interest in the notion that DNA is not the sole determinant of our inherited phenotype. Human epidemiology studies and animal and plant genetic studies have provided evidence that epigenetic information ("epigenetic" describes an inherited effect on chromosome or gene function that is not accompanied by any alteration of the nucleotide sequence) can be inherited from parents to offspring. Most of the mechanisms involved in epigenetic "memory" are paramutation events, which are heritable epigenetic changes in the phenotype of a "paramutsble" allele. Initially demonstrated in plants, paramutation is defined as an interaction between two alleles of a single locus that results in heritable changes of one allele that is induced by the other. The authors describe an unexpected example of paramutation in the mouse revealed by a recent analysis of an epigenetic variation modulating expression of the Kit locus. The progeny of heterozygote intercrosses (carrying one mutant and one wild-type allele) showed persistence of the white patches (characteristic of heterozygotes) in the homozygous Kit(+/+) progeny. The DNA sequences of the two wild-type alleles were structurally normal, revealing an epigenetic modification. Further investigations showed that RNA and microRNA, released by sperm, mediate this epigenetic inheritance. The molecular mechanisms involved in this unexpected mode of inheritance and the role of RNA molecules in the spermatozoon head as possible vectors for the hereditary transfer of such modifications - implying that paternal inheritance is not limited to just one haploid copy of the genome - are still a matter of debate. Paramutations may be considered to be one possibility of epigenetic modification in the case of familial disease predispositions not fully explained by Mendelian analysis.