Lamarck’s revenge

December 7, 2011

Lamarck himself of course did not know about molecular genetics, but in biology it is becoming more and more clear that inheritance of acquired traits might also be possible. However, most of these traits are transmitted via epigenetics (methylation, acetylation, etc.) which is essentially chromatin and thus DNA based. A mechanism which enables the “inheritance” of acquired traits and in which DNA is not the central element, has now been published in the Cell journal (Transgenerational Inheritance of an Acquired Small RNA-Based Antiviral Response in C. elegans).   The group of  Oliver Hobert from the Department of Biochemistry at Columbia University in New York has reported that upon viral infection of their model organism Caenorhabditis elegans, the worm activates its defense mechanisms in such a way that it is also transferred to later generations which did not have contact with the virus at all (1). In this case the immunological response of C. elegansis is based on the so-called RNA interference (RNAi) mechanism. RNAi is generally known to silence genes in the cadre of genetic regulation and works by the binding of specially synthesized small RNA molecules to regular mRNA which is subsequently up- or downregulated thereby influencing protein production. For quite some years it has also been known that RNAi is used in viral defense by utilizing the double stranded RNA (dsRNA) of the virus as a template for the production small RNAs (viRNA) that subsequently lead to the breakdown of the viral genes and an effective protection. Also in the present study this behavior of the RNAi system is important.

By saying “gene-silencing effects evoked by exogenously added dsRNA can be observed not only in the treated animals, but […] also in the progeny of the treated worms” the authors summarize the findings of other scientists, who had found in previous studies that upon RNAi system stimulation by foreign dsRNA (for example from a virus) the viRNA parts of this defense mechanisms could also be traced back in generations that never encountered the dsRNA (i. e. virus). Therefore some kind of “inheritance” must have taken place. In this paper Hobert and coworkers tried to identify whether this “inheritance”  is rather traditional and therefore DNA or chromatin mediated (for example epigenetic) or whether it involves some kind of novel mechanism that transgenerationally “directly” transmits the RNA .

In order to test this the scientists introduced dsRNA containing the FR1gfp transgene into the C. elegans worms. This dsRNA was responsive to a heat-shock signal due to a promoter which was able to sense abrupt increase of temperature. By means of raising the temperature the virus could thus be induced. Under conditions where the worm RNAi machinery is functional the replication and distribution of the foreign viral RNA is of course inhibited. The worms keep their regular phenotype. When, however, the RNAi machinery is mutated the worm cannot defend itself against the replication of the foreign RNA. In this case also the FR1 gene which is fused to a green fluorescent protein (gfp) gene is expressed. The worms appear greenish after excitation with light of the fitting wavelength. Mutations where induced in two genes called rde-1 and rde-4. These two genes are normally responsible for the expression of dsRNA binding proteins that induce the RNAi response. Fig. 1 (left) depicts the general experimental setup in which immunodeficient mutant worms are crossed with immunocompetent worms (parental generation) what results in heterozygotic (for this allele) worms in the F1 generation (kids). When these worms are crossed with each other a Mendl-like inheritance pattern results in the F2 generation (grandchildren). The essential question is: Are the homozygotic mutants of the F2 generation resistant to the virus dsRNA even though they have never encountered the virus before and do not possess the machinery to combat the dsRNA? In case they are not resistant the researchers would observe a green fluorescence signal due to the replicating RNA (see also above).

Fig. 1: The genetic principle behind this study (left) and some results showing the generational transmittance of viRNA into mutant worms what consequently renders them resistant to the virus (no green fluorescent signal) (right). The transmission effect eventually “wears off” after 4-5 generations.

After performing the above described heat-shock induction of the F2 generation worms, the hypothesis derived results could indeed be observed (Fig. 1 (right)). Even viRNA transmission up to the 5th generation was present. The authors excluded the possibility that the resistance of the homozygous mutants is based exclusively on maternal deposition by the heterozygous parents since it has been demonstrated before that none of the gene activity is transmitted between generations (2). In addition the necessary viRNA is transmitted over several generations also if no viral stimulus is added. However the virus resistance “wears off” after 4-5 generations.

That viRNA is really transmitted among generations is proven by a physical RNA detection assay in which the 20–30 nt viRNAs are quantified in accordance to their alignment on the viral RNA and qualified based on their strandedness.

All together these results indicate that classical genetics based on DNA and even relatively new elements of it such as epigenetics are not the whole picture of biological adaption and evolution. However, important molecular components of this viRNA transmittance system remain unidentified. Why does the protective effect “wear off”? How are the viRNAs transmitted from generation to generation if not by maternal deposition? What is the code if no viral dsRNA template is present and nothing is deposited?

In their conclusion the authors stress the point that the above described mechanism can have a strong evolutionary significance for organisms since it renders it possible to rapidly transmit the mechanisms of an adaptive response to the following generations. Short-term environmental stress can thus be effectively counter acted.

Even though many important questions, especially concerning the molecular basis, remain unanswered, this study shows that biology is far from being elucidated completely. In the search for answers it can thus sometimes be helpful to look into a direction that seems the least probable. Lamarck might agree.

This blog-article is especially based on the two articles named below:

(1) O. Rechavi, G. Minevich, O. Hobert, Transgenerational Inheritance of an Acquired Small RNA-Based Antiviral Response in C. elegans. Cell147 (2011). (online publication)

(2) D. Blanchard, P. Parameswaran, J. Lopez-Molina, J. Gent, J.F. Saynuk and A. Fire, On the nature of in vivo requirements for rde-4 in RNAi and developmental pathways in C. elegans. RNA Biol.,  8  (2011).

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