1) In 2002 in "Perspective: Here's to Fisher, additive genetic variance, and the fundamental theorem of natural selection," you conclude, "is there any other quantity that captures so much evolutionary meaning in such a simple way?" in reference to additive genetic variance. And yet, what about other factors like statistical epistasis? Do gene-gene interactions pack enough of an evolutionary punch to be anything more than a footnote in God's Book? Have you seen Loren Rieseberg's work at Indiana which points to the importance of loci of large effect?

The remarkable thing about additive genetic variance is that it predicts the effect of selection, even in the presence of dominance and epistasis. Nature seems to follow least-squares principles. The result is that the additive component of variance pulls out of dominance and epistatic variance those components associated with allele frequency change under selection. Of course the theory is not exact, but it is a very good first approximation. Fisher did not ignore epistasis, as some have said; rather he showed how selection can utilize epistatic (and dominance) components of variance.

On a more technical level, Kimura showed that under selection with loose linkage the population rather soon attains a state in which the linkage-disequilibrium variance approximately cancels the epistatic variance. Thus, under this circumstance the effects of selection are better predicted by ignoring additive by additive epistatic variance than by including it. See my book with Kimura (1970, p. 217 ff).

I am aware of Rieseberg's work on sunflowers. QTL mapping and various other molecular methods are indeed finding alleles with large effect in many species. It is inevitable that the first genes discovered will be those with largest effect, so I expect alleles with smaller effects to follow. How large a part genes with large effect have played in evolution is still up in the air, as far as I know. But they are getting more emphasis now than in the recent past.

2) R.A. Fisher is reputed to have aimed for an "ideal gas law" of evolutionary genetics (The Fundamental Theorem of Natural Selection?). In the paper above you state that you expect "mathematical theory" to become more "general and rigorous." How near are we to an "ideal gas law" for evolutionary genetics which takes the step beyond a qualitative heuristic, if such a thing is possible?

It is not surprising that Fisher, who was trained in classical physics, would use physical analogies. Various mathematical geneticists, such as Tom Nagylaki of the University of Chicago, have found more general and accurate expressions, and I expect this to continue. I don't expect evolution to imitate classical physics in such things as an ideal gas law. For example, Fisher's analogizing fitness with entropy is better regarded as a metaphor than as rigorous science.

3) Computational methods have come to the fore within the past generation as an alternative to analytic modes for attacking theoretical problems. Do you believe this has been wholly a good thing, and if not, can you elaborate?

Yes, I think it is a good thing. Many problems in population genetics cannot be solved by a mathematician, no matter how gifted. Although I expect improvements in the mathematical theory, it is already clear that computer methods are very powerful. This is good. It also permits people with limited mathematical knowledge to work on important problems; but I don't expect it to entirely replace mathematical theory.

4) The 1966 the Lewontin and Hubby allozyme papers reported a great deal more polymorphism than either the followers of Wright or Fisher expected (i.e., Balance School and Classical School). The work with Neutral Theory and its successors stepped into the theoretical breach. In hindsight, does it seem that Neutral Theory was plausible a priori, or did the evolutionary geneticists of the pre-DNA era simply miss the possibility (and ubiquity) of neutral substitutions because they did not have a good mental model of variation on the molecular level?

The amount of variability disclosed by Lewontin and Hubby was more than some expected, although it did not seem particularly surprising to me. It is important to say, as Lewontin was the first to articulate, that the difference between the classical and balance schools does not lie in the amount of variability (variability is an observable and not a theoretical quantity). Rather the difference in the two schools was the way in which variability was thought to be maintained: mainly by mutation-selection balance or mainly be heterosis.

I think neutral variability came as a surprise to almost everybody. Of course, it was an outgrowth of molecular methodology, which made possible the study of DNA itself rather than phenotypic traits. I don't think it was the absence of a mental model as much as not knowing in advance the enormous number of nucleotides in the genome, and how little of the DNA, especially in mammals, is protein-coding.

5) Do you believe that group selection (i.e., inter-demic selection) might have played a significant role in the evolution of H. sapiens sapiens?

I'm sure it did, for our ancestors for many years had a tribal existence with competition, even wars, between groups. I suspect that group structure may be responsible for much altruistic behavior. In a small group everyone is related, so behaving cooperatively or altruistically toward members of a group is the genetic equivalent of kin-selection. Muller and others emphasized this idea. There is a level of relatedness in a group at which the welfare of the group prevails over the welfare of individuals. Egbert Leigh quantified this as did Aoki and I.

6) When your commentary on Arthur Jensen's infamous Harvard Educational Review article on the inheritance of IQ and racial differences was published in 1969, did you have any inkling that the issues raised by Jensen would remain largely unresolved over thirty-five years later? What kind of evidence do you think would decide these issues one way or the other?

I did not expect the issues to be resolved soon, for there were no new methods that promised be more informative. Of course, the structure of DNA had been discovered, but the powerful methods now available had not yet been developed. I think further identification of individual genes, usually by molecular methods, and a combination of statistical and molecular methods are pointing the way toward a solution. I don't expect racial differences to be either entirely genetic or entirely environmental, but of course I don't know the relative amount; it is likely to be different for different traits and different human groups.

7) In you recent review of "Genes in Conflict" you state in reference to Robert Trivers' papers published in the 1970s that, "They were ignored by most social scientists, who were reluctant to consider natural selection as a cause of human behavioral traits, and they were bitterly attacked by marxists for reasons of doctrine." Recently the University of Chicago evolutionary genomicist Bruce Lahn has come under fire (as profiled in The Wall Street Journal, June 16^th edition) for his study of ASPM, a locus implicated in brain development, from both geneticists and non-geneticists because of the sensitivity of the possibility of intergroup variation due to differential evolutionary forces within the past 40,000 years. Last year the paper put forward by Gregory Cochran, Henry Harpending and Jason Hardy that argued high Ashkenazi IQ was due to recent natural selection also ignited a firestorm. It seems that we are entering a new era of human genetics as a great deal of data will soon be available for theorists to analyze (e.g. the HapMap and its successors). Are "controversial" questions still going to be off limits, or will the science compel the political and cultural taboos to step aside?

I hope that such questions can be approached with the same objectivity as that when we study inheritance of bristle number in Drosophila, but I don't expect it soon. There are too many strongly held opinions. I thought Lahn had a clever idea in thinking that the normal alleles of head-reducing mutants might be responsible for evolution of larger heads in human ancestry. Likewise, I think that Cochran et al. are fully entitled to consider the reasons for Jewish intelligence and I found their arguments interesting. In my view it is wrong to say that research in this area -- assuming it is well done -- is out of order. I feel srongly that we should not discourage a line of research because someone might not like a possible outcome.

8) If a budding evolutionary thinker had to read one book or paper that excluded Charles Darwin's body of work, what would you recommend?

I would recommend Fisher's "Genetical Theory of Natural Selection". But the reader should be prepared to find it tough going. Fisher's elegant obscurity has left many of us baffled, but entranced. Your "budding thinker" might want to stop before the last four chapters, which are more dated than the rest of the book. And by all means, read the 1999 variorum edition. It's appendices explain many of the book's obscurities.

9) You've defended "bean bag genetics" (Nature, 2001). Lynn Margulis has complimented you personally, but seems to dismiss the whole endeavor of theoretical evolutionary biology as trivial and irrelevant when set next to the concrete realities of molecular and cell biology. Over the past generation molecular biology has dethroned physics as the "Queen of Sciences" in regards to prestige, and many young biologists seemed to take the work of Fisher, Wright, Haldane, Kimura and yourself for granted and do not concern themselves with the abstract "big picture" when mechanistic details on the DNA scale needed to be elucidated. Do you believe that over the next generation more young people will begin to look once more at evolutionary biology in its grandest abstract reaches as the "low hanging fruit" in molecular biology is exhausted?

Lynn Margulis is a long-time personal friend and has done important work on the origin of cellular organelles, but I disagree with her on this issue. It is true that the elegant theory of Fisher, Wright, Haldane, Kimura, and Malécot was less useful than might have been expected, because of lack of good data to whieh the theory was applicable. But that is no longer true. Molecular evolution has provided an abundance of data and the theory now has plenty of important applications. In particular, the neutral theory of molecular evolution has had great heuristic and predictive value, and it owes a great deal to Kimura's earlier theoretical work, which built on the foundations of the pioneers. Lynn might change her mind if she looked at some of the striking results gotten by combining molecular measurements with population genetics theory. Maybe I should ask her!

10) If you had to have one last glass of beer, and your drinking partner was going to be either Fisher, Wright or Haldane, who would you choose, and why?

I would choose Haldane, for his uninhibited willingness to speculate, his enormous erudition, his interest in almost everything, his irreverence, his wit, and his enjoyment of conversation. I am told that much of the good biology in Huxley's "Brave New World" is the result of his drinking partnership with Haldane.