Question

4. One of the great science fiction movies so far this century was Alfonso Cuarón’s Children of Men (2006), in which infertility threatens humanity with extinction.

(a) P-element hybrid dysgenesis in the fruit fly Drosophila is a frightening illustration of a mechanism by which this might happen in an animal species. Do some background research on this phenomenon in order to explain its molecular basis.

(b) Xenotransplantation has been suggested as a temporary solution of the problem of getting sufficient replacement organs to meet current needs. Pigs have been suggested as a potential source of organs, but most research was halted due to worries about potential risks to not just organ recipients, but to the human species as a whole from porcine endogenous retroviruses. What are endogenous retroviruses, and why do these pose a potential risk to humans.

(c) The CRISPR-Cas system for gene editing has been used to remove all known copies of porcine endogenous retroviruses from a pig cell genome. Does this suggest that xenotransplantation should now proceed (a moratorium on research was in effect until recently)? Explain your reasoning.

Answer 1

a) P-elements are transposable elements (TEs, or transposons, popularly called "jumping genes" are DNA sequences that move from one location to another within the genome. This mechanism is catalysed by a group of enzymes called transposase.) in Drosophila (popularly called fruit fly) that encode genes for transposase activity, as well as genes which encode for repressors of those transposase activity.

Hybrid dysgenesis is a genetic syndrome characterised by high rate of mutation, sterility and chromosomal alterations in the germ line cells of Drosophila. The presence of P element is called a P cytotype and the lack of P element is called an M cytotype.

In a cross between a P cytotype female x M cytotype male, repressors of transposase activity in the maternally derived cytoplasm repress expression of the maternally inherited P elements. The resulting offspring show the wild-type phenotype and is normal.

In a cross between M cytotype female x P cytotype male, repressors of transposase activity are absent in the maternally derived cytoplasm, resulting in activation of P elements, causing transposition and activation of dysgenic phenotypes in the offspring.

b) Retroviruses can trigger the activation of their own reverse transcription machinery, once inside the host cell. They can reverse transcribe DNA from their single stranded RNA, which then gets incorporated within the host genome, triggerring the activation of several viral components, with debilitating effect to the host. It is due to this reason that porcine endogenous retroviruses pose threats to the human genome.

c) Until and unless we are sure of the full spectrum of CRISPR-Cas mediated knock-out loci, any kind of xenotransplantation should be be held on check. CRISPR-Cas mediated gene knock-out strategy has reports of inducing off-target effects and might hamper the expression of critical genes needed for the stability of the system. Furthermore, xenotransplantation has dire consequences of immune rejection in case of an incompatible host and further research is required to properly address these issues before this method can be thought scalable.