UNIVERSITY OF CAMBRIDGE : DEPARTMENT OF GENETICS HEAD OF DEPARTMENT K. J. R. EDWARDS. MA.. PH.D. Balfour Professor of Genetics J. M. THODAY. Sc.D.. F.R.S. Our Ref:GAD/JH DOWNING STREET CAMBRIDGE CR2 3EH 0223 69551 5th November, 1982. Ms. Christine Gilbert, (Letters) Science AAAS, 1515 Massachusettes Ave. N.W. Washington D.C. 200025, U.S.A. OPEN LETTER FOR PUBLICATION. While in general we have few quibbles over the substance of R, Lewin's clear description of the genetic system of molecular drive (Science 1982 218 '552-3), we feel that several comments in the report merit further discussion. Lewin's report basically asks two questions: how real and how important; and some commentators have offered answers. - In our two papers in which we have detailed the factual basis and theoretical implications of molecular drive, we have defined it as a process of fixing a mutation within multigene and non-genic families in a population, as a consequence of DNA turnover. that individuals of a sexual population would change in unison with respect to the changing'composition of a family. widespread phenomenon of concerted evolution. phenomenon is incontestable, we cannot accept the definitive statement of Lewin's,drawing in particular on remarks made by A. Jeffreys on the human globin cluster and - Alu family, "that it is not a universal phenomenon". Concerted evolution is occurring in the globin cluster; indeed this phenomenon was first defined as such in this cluster due to the homogenisation of pairs of ct and y genes, and their flanking sequences, by unequal exchange or gene conversion. clearly, concerted evolution is not a rare phenomenon, and seems to occur between even distantly related genes and between active genes and pse~dogenes"~. In the case of very large families, such as - Alu, detailed consideration needs to be given to the rates of homogenisation relative to the mutation rate. A 10% level of sequence variation between 10 cloned Alu repeats from the human genome4 reflects the constraints on homogenisation imposed by the presence of 500,000 copies finely dispersed over 46 chromosomes. the very low levels of homology revealed by hybridisation between human and mouse Alu families reflects a much greater between-species than within-species divergence. by an imperfect dimer whilst the mouse Turnover is occurring in the - Alu family, albeit slowly. families, whether tandem or interspersed, genic or non-genic that are imune from such processes. molecular drive and the subsequent interaction with natural selection is expected to be very different Consi-derations of rates of turnover indicate At the heart of molecular drive is the Although the reality of this In reviewing such events in the globin cluster Jeffreys has written, I1 - Despite these constraints I_ Furthermore the human _I Alu family has been homogenised throughout family consists only o€ monomers4. We are not aware of The evolutionary progress of each family under The importance of molecular drive as a genetic system can only be assessed An instructive example is provided by the phenomenon by consideration of the way in which the genetic and phenotypic cohesion of a population is maintained. of hybrid dysgenesis in - Drosophila. In this example the molecular process is one continued -2- of transposition; one of the three mechanisms underlying molecular drive. slow rate of transposition of P elements would lead to a genetic situation in which there would be little variation in the number of P's in each individual at any one time during the initial accumulation of the element. The small variance in P number would not lead to dysgenesis within the population, as is observed. and a non-P population does lead to dysgenesis. variance pattern of fixation would result from the slow rateso€ unequal exchange or gene conversion involving the homogenisation of existing families for one variant or another. A A large difference, however, in P number between a P population Precisely the same low Given this cohesive system of genetics, which contrasts remarkably with the classical population genetics of single-copy genes, we allowed ourselves some freedom in speculating on its involvement in the origin of the ontogenetic and reproductive differences between species, there are few experimental tests of the genetic mechanisms which are thought to underlie species differences. We do not disagree with the conventional viewpoint that such differences might be consequential upon natural selection and genetic drift working within mendelian populations. Nevertheless such external processes of fixation are inadequate in explaining species differences in multiple-copy families, i.e. the phenomenon of concerted evolution. The evolution of such families and their manifold phenotypic effects can be partly explained by the genetics of molecular drive, which is precisely based on internal molecular mechanisms of turnover. that Drs. Doolittle and Selander consider our speculation on the evolutionary biology of molecular drive ta be unhelpful. biology may be,in essence, a manifestation of molecular events, and the artificial separation of molecular and evolutionary biology is itself unhelpful. So far as we are aware, Consequently, we are perplexed We consider that all evolutionary Part of the problem seems to stem from a mistaken supposition that turnover is only observed in non-genic families whose biological effects have yet to be ascertained. Concerted evolution is an extensively documented observation in many multigene families. these families cannot be seriously challenged. It could well be that even the species differences in behaviour emphasised by John Maynard-Smith, are under multigene control, transformation in behaxiour under the aegis of the genetic system of molecular drive It would be a pity if this misunderstanding was widespread. The biological effects and evolutionary significance of changes in A population could undergo a long-term collective We do not consider molecular drive to be a catch-all for all genomic rearrangements and exchanges. If some rearrangements, for example inversions, deletions, or duplications turn out to be one-off events, then they are analogous to most point mutations which rely for their evolutionary progress on selection and drift. They do not contribute to the process of molecular drive. Prom what we now understand of the activities of unequal exchange, ger,e conversion and transposition in so many different families, the evolutionary differences between species must be considered a complex outcome of three processes of fixation - adaptive, accidental and cohesively driven. Despite Che seeming pitfalls in trying to promote a new perspective, we see no reason to be unenthusiastic about the implications of molecular drive. G. A. DOVER, ?'. STRACKAN, E. S. COEN, S. D. M. BROWN* *Dept. Biochemistry, address as above --..rl St. Mary's Hospital, London. 1. Dover, G.A., Brown, S.D.M., Coen, E.S., Dallas, J., Strachan, T. and Trick, M. (1982) in 'Genome Evolution' (eds. G. A. Dover and R. €5. Flavell) Acad. Press. p.343. 2. Dover, G.A. (1982). Nature 299 111. - 3. Jeffreys, A. (1982) in"Genome Evolution" (eds. G. A. Dover and R. 13. Flavell) Acad. Press. p.157. 4. Jelinek, W.R. & Schmid, C.W. (1982). Ann. Rev. Biochem. 51 813. -