Paramutation

Paramutation, in epigenetics, is an interaction between two alleles of a single locus, resulting in a heritable change of one allele that is induced by the other allele. Paramutation violates Mendel’s first law, which states that in the process of the formation of the gametes (egg or sperm) the allelic pairs separate, one going to each gamete, and that each gene remains completely uninfluenced by the other. In paramutation an allele in one generation heritably affects the other allele in future generations, even if the allele causing the change is itself not transmitted. What may be transmitted in such a case are RNAs such as piRNAs, siRNAs, miRNAs or other regulatory RNAs. These are packaged in egg or sperm and cause paramutation upon transmission to the next generation. This means that RNA is a molecule of inheritance, just like DNA.

Paramutation was first discovered and studied in maize (Zea mays) by R.A. Brink at the University of Wisconsin-Madison in the 1950s. Brink noticed that specific weakly expressed alleles of the red1 (r1) locus in maize, which confers red pigment to corn kernels, can heritably change specific strongly expressed alleles to a weaker expression state. The weaker expression state adopted by the changed allele is heritable and can, in turn, change the expression state of other active alleles in a process termed secondary paramutation. Brink showed that the influence of the paramutagenic allele could persist for many generations. However, since paramutation is an epigenetic phenomenon, it can be attenuated over successive generations by dilution of the causative RNA. This contrasts sharply with ordinary mutations in DNA, which do not fade away.

Interestingly, paramutation can result in a single allele of a gene controlling a spectrum of phenotypes. At r1 in maize, for example, the weaker expression state adopted by an allele following paramutation can range from completely colorless to nearly fully-colored kernels. This is an exception to the rule that continuous variation is controlled by many genes (see multi-genic traits).

Allelic interactions similar to paramutation have since been reported in other organisms, including tomato, pea, and mice.

The molecular basis of paramutation is being unraveled. Paramutation may share common mechanisms with other epigenetic phenomena, such as gene silencing, imprinting, and transvection (genetics). Alleman (2006) proposed that "paramutation is RNA-directed. Stability of the chromatin states associated with paramutation and transposon silencing requires the mop1 gene, which encodes an RNA-dependent RNA polymerase." This polymerase is required to maintain a threshold level of the repeat RNA, which causes the paramutation. Exactly how the RNA does this is not understood, but like other epigenetic changes, it involves a covalent modification of the DNA and/or the DNA-bound histone proteins without changing the DNA sequence of the gene itself.