28 Sep 2000

The prion protein, so interesting to researchers of neurodegenerative disease for its novel capacity to cause disease through a change of conformation-and to transmit disease to other cells and organisms through its altered conformation-may have another astounding role in its repertoire. Writing in today's Nature, Susan Lindquist and Heather True of the University of Chicago suggest that the prion may help explain an enigma of evolutionary theory: the fact that new forms or functions usually require several independent genetic changes, changes that might be harmful to an organism if they appeared one at a time.

It is often said that only a portion of any genome is expressed during the life of an organism; the rest is sometimes dismissed as "noise" or "garbage." Apparently, though, it's not garbage for the purposes of evolutionary change. It has been theorized that multiple genetic changes might pile up in these inactive regions, being transmitted from generation to generation, without being detrimental in the organism's fitness. Then, the theory goes, some genetic or epigenetic change occurs that allows a group of inactive genes to be expressed all at once, producing a new phenotype. If this helps the organism survive, then the new genotype has produced a "new" organism. The key to proving the feasibility of such a mechanism is to find a "key" that unlocks the door for the inactive genes . . . Enter the prion.

Lindquist and True have spent a great deal of time studying a naturally occurring yeast protein called Sup35, whose normal function is to instruct ribosomes to stop translating mRNA at stop codons. But Sup35 has the capacity to shift conformation, i.e, to become a prion. In this new conformation (termed [PSI+]), it then induces other normal Sup35s (termed [psi-]) to also change conformation. More interestingly, the new Sup35 allows ribosomes to read right through stop codons, meaning in theory that proteins from the inactive part of the genome can be produced.

The authors tested the hypothesis that [PSI+] cells are capable of dramatic phenotypic change by challenging yeast colonies to live under an enormous variety of conditions, including media at different pHs or temperatures and media containing various carbon or nitrogen sources, salts and metals, or inhibitors such as antibiotics. What they found in each of the seven different strains of yeast tested, was that [PSI+] allowed yeast to adopt different phenotypes and enhanced its ability to survive, and propagate, in different environments. "We propose that the epigenetic and metastable nature of [PSI+] inheritance allows yeast cells to exploit preexisting genetic variation to thrive in fluctuating environments. Further, the capacity of [PSI+] to convert previously neutral genetic variation to a non-neutral state may facilitate the evolution of new traits," conclude the authors.—Hakon Heimer