68 A. Wilson: More on the Molecular Biology of the Gene

In the last section, "One Eve or Many?," the author claims that "all present-day humans may have shared a common ancestral mother." This claim is based on the analysis of mitochondrial DNA by Cann and her co-wor- kers. I do not know how comfortable Cann would feel with such a conclusion, but I do know that this conclusion is contradicted by other data. The study of nuclear genes has shown that during the entire evolution from our com- mon ancestor with chimpanzees there was never a single female from which we are all derived.

Three sections in a textbook, three false claims, and

just for the sake of sensationalism, or so it seems. "Wor- my Mice in a Hybrid Zone," °'Mitochondrial DNA In- vades House Mice," "Eve Did Exist!" What newspaper headlines these would make-- and in fact, they did! It is bad enough when journalists exaggerate, twist the truth, and make up sensational stories; it is much worse when irresponsible scientists make unfounded claims and play into the hands of unscrupulous journalists; but it is totally unacceptable to make sensationalism part of a textbook and teach students things that simply are not true.

Jan Klein

More on the Molecular Biology o f the Gene

Jan Klein's contribution (Klein 1988) to this issue of Im- munogenetics could be a valuable stimulus to think more deeply about the implications of the last three pages in the fourth edition of the Molecular Biology of the Gene by Watson and colleagues (1987). Those concluding pages suggest explicitly that population biology will have a vital role in the future of molecular biology, because many of the more puzzling features of genomes will prove comprehensible only when it is understood that population genetics is the arbiter of the forces moulding genomes. Although it is unclear whether Klein agrees with this sug- gestion, he does object strongly to the three publications (Cann et al. 1987, Sage et al. 1986a, Ferris et al. 1983) that form a basis for the concluding remarks of Watson and co-workers (1987). Since my laboratory is the source of the publications that Klein criticizes, it is appropriate for me to respond to his comments while keeping in mind the possibility that he is also objecting to the message im- plied in the final part of the book.

I would have expected Klein to endorse the view that the growth of biology will soon be limited by a lack of knowledge of population biology on the part of molecular biologists. He is well known for his studies of polymor- phisms in the major complex of histocompatibility genes (Klein 1986). Despite many lines of evidence suggesting that strong selection must be operating to maintain the un- precedented levels of polymorphism found in this region of the genome, we know little about which types of selec- tion are actually responsible (Klein 1986, Potts et al. 1988). Immunogeneticists should therefore be supporters of the view that there is a pressing need to investigate the roles of heterozygote advantage, frequency-dependent selection, mating preferences, and other forms of social competition in maintaining these polymorphisms. In

short, I would expect immunogeneticists to be especially aware of the need for a synthesis of molecular and popula- tion biology.

However, Klein's criticisms of the three publications cited above make me wonder whether my expectation was realistic. His comments on Cann and co-workers (1987) seem to neglect a basic principle of population biology, namely, that all the maternal lineages in a population or species must ultimately trace back to one and only one mother. This principle, which is implicit in contributions by Kimura (1968) as well as by King and Jukes (1969) and summarized in Kimura's book (1983), is illustrated by the history of maternal lineages in a hypothetical popu- lation founded by 100 females 200 generations ago. Sup- pose that in every generation each female is replaced on average by one daughter, so that the population size stays steady through time. By chance, about 37 % of the females will produce no daughters. Hence, many maternal line- ages become extinct in each generation, while some sur- viving lineages proliferate at their expense. It is only a matter of time until all but one of the maternal lineages become extinct. The mean length of time required for this to happen in a population containing equal numbers of breeding males and females is 2N generations, where N is the number of breeding females per generation (Tajima 1983). In our example, it takes an average of 200 genera- tions for 99 of the 100 founding lineages to be lost from the population. This is not to say, of course, that the nuclear genes of the contemporary population trace back to only one founding female. Because nuclear genes are inherited biparentally, they are likely to stem from many of the founding mothers (via male descendants) and found- ing fathers as well. We therefore agree with Klein that Eve is a poor term to use for the common ancestor of all

A. Wilson: More on the Molecular Biology of the Gene 69

maternal lineages in a species. In publications from my laboratory, the term Eve has always been avoided. The above statements refer to elementary principles of theoret- ical population genetics, which were understood by Cann and co-workers (1987). It is regrettable that these princi- ples are unfamiliar to the many biologists who have been puzzled or even offended by the concept of one mother for the whole human species.

Another of Klein ' s criticisms appears to be directed against the concept that the narrow hybrid zone between domes t i cus and muscu lus mice in Bavaria (Sage et al. 1986a, Sage et al. 1986b) is the result of reduced fitness in some of the hybrids, most of which have recombinant genotypes. It is a well-established concept that hybrid zones act as genetic sinks, which serve as barriers to gene flow between two species (Barton and Hewitt 1985, Szymura and Barton 1986). It is also clear from the results of Sage and co-workers (1986a) that mice from the hybrid zone have a significantly higher burden of parasites than do mice from outside the zone. We used to think (Ferris et al. 1983, Sage et al. 1986b), as Klein (1988) does, that sterility of F1 males may also help retard gene flow be- tween the two species of mice, but new findings give us two reasons for minimizing the importance of this factor. First , hardly any of the mice in the hybrid zone are F~s, 98 % being backcross individuals (Sage et al. 1986a). Se- cond, the sterility of F1 males, although evident when m u s c u l u s mice are crossed with certain inbred strains of d o m e s t i c u s (Forejt 1981; R. D. Sage and A. Wilson, un- published data), is not evident in interspecific crosses in- volving wild domes t i cus mice captured near the hybrid zone (Vanlerberghe et al. 1986; R. D. Sage and A. Wil- son, unpublished observations).

Final ly, I refer to Klein 's remarks about our surprising observation (Ferris et al. 1983) that the mice of Northern Jutland and the Fennoscandian peninsula bear muscu lus

nuclear genes and mitochondrial genes that are exclusive- ly of d o m e s t i c u s origin. I want to emphasize that there has been no " re t rac t ion" of this finding; yet Klein ' s state- ment could imply the opposite. Indeed, the extent of the phenomenon is now known to be more pronounced than was apparent at first (Gyllensten and Wilson 1987). What has changed is our interpretation of the facts. We now propose that the takeover event happened in a small found- er population that later colonized the geographic areas mentioned above (Gyllensten and Wilson 1987).

The three publications (Cann et al. 1987, Sage et al. 1986a, Ferr is et al. 1983) therefore seem to withstand Klein 's criticisms and retain their suitability for use in a textbook as examples of attempts to integrate molecular and population biology. Although only the future will re- veal whether Watson and co-workers (1987) are right in

predicting that population biology will have much to tell molecular biology, my hunch is not only that they are right, but also that some of the most vivid examples will come from the field of immunogenetics.

Acknowledgments. I thank R. D. Sage and A. M. Weiner for discussion.

References

Barton, N. H. and Hewitt, G. M.: Analysis of hybrid zones. Annu. Rev. Ecol. Systematics 16: 113-148, 1985

Cann, R. L., Stoneking, M., and Wilson, A. C. : Mitochondrial DNA and human evolution. Nature 325: 31-36, 1987

Ferris, S. D., Sage, R. D., Huang, C.-M., Nielsen, J. T., Ritte, U., and Wilson, A. C.: Flow of mitochondrial DNA across a species bound- ary. Proc. Natl. Acad. Sci. U.S.A. 80: 2290-2294, 1983

Forejt, J.: Hybrid sterility gene located in the T/t H-2 supergene on chro- mosome 17. In R. A. Reisfeld and S. Ferrone (eds.): Current Trends in Histocompatibility, Volume 1, pp. 103-131, Plenum Press, New York, 1981

Gyllensten, U. and Wilson, A.C.: Interspecific mitochondrial DNA transfer and the colonization of Scandinavia by mice. Genet. Res. 49: 25-29, 1987

Kimura, M.: Evolutionary rate at the molecular level. Nature 217: 624-626, 1968

Kimura, M.: The Neutral Theory of Molecular Evolution, Cambridge University Press, Cambridge, 1983

King, J.L. and Jukes, T. H.: Non-Darwinian evolution. Science 164: 788-798, 1969

Klein, J. : Natural History of the Major Histocompatibility Complex, John Wiley, New York, 1986

Klein J.: Book review. Immunogenetics 27: 327-328, 1988 Potts, W.K., Manning, C.J., Peck, A.B., Price-Laface, M., and

Wakeland, E.K.: Can heterozygote advantage account for the maintenance of H-2 polymorphisms? In C. S. David (ed.): Major Histocompatibility Genes and Their Roles in Immune Function, in press, Plenum Press, New York, 1988

Sage, R. D., Heyneman, D., Lim, K.-C., and Wilson, A. C.: Wormy mice in a hybrid zone. Nature 324: 60-63, 1986a

Sage, R. D., Whitney, J.B., III, and Wilson, A. C.: Genetic analysis of a hybrid zone between domesticus and musculus mice (Mus mus- culus complex): hemoglobin polymorphisms. Curr. Top. Microbi- ol. Immunol. 127: 75-85, 1986b

Szymura, J.M. and Barton, N. H.: Genetic analysis of a hybrid zone between fire-bellied toads. Evolution 40:1141-1159, 1986

Tajima, F.: Evolutionary relationship of DNA sequences in finite popu- lations. Genetics 105: 437-460, 1983

Vanlerberghe, F., Dod, B., Boursot, P., Bellis, M., and Bonhomme, F.: Absence of Y chromosome introgression across the hybrid zone between Mus domesticus and Mus musculus. Genet. Res. 48: 191-197, 1986

Watson, J.D., Hopkins, N.H., Roberts, J.W., Steitz, J.A., and Weiner, A.M. : Molecular Biology of the Gene, 4th edn., Benjamin/Cummings, Menlo Park, California, 1987

Allan Wilson Biochemistry Department University of California, Berkeley