10 Questions for Bruce Lahn
Bruce Lahn is a Professor of Human Genetics at the University of Chicago as well an Investigator at the Howard Hughes Medical Institute. In 2004, he was on the “Top 40 Under 40” list by Crain’s Chicago Business. Specifics of his research can be found on his faculty page. Our 10 questions are in bold below the fold.
1. One of the major trends in hominid evolution has been increasing brain size, with the somewhat confusing caveat that modern humans break that trend, with smaller brains than both Neanderthals and some earlier hominids. Many hypotheses have been proposed to explain this, from sexual selection for intelligence to selection pressures from culture. Do you have a favorite hypothesis? What evidence do you think could settle this issue?
Brain size is just a proxy for cognitive abilities. This proxy is very robust over long evolutionary periods (millions of years). But on a short time scale, fluctuation in brain size may not correlate well with cognitive abilities. Within humans, for example, brain size is only weakly correlated with cognitive test scores such as IQ (only about 15% of the variation in IQ can be explained by difference in brain size). Given this, perhaps we should not make too much out of the cognitive significance of brain size changes on a short time scale.
2. Your work on genes involved in human brain evolution (i.e. ASPM and microcephalin) has focused on amino acid changes. It has been hypothesized that most of the differences between humans and chimps are due to regulatory changes. Do you feel this is still a viable hypothesis? Do you consider your work a challenge to this hypothesis?
The hypothesis that most human-chimp differences are due to regulatory changes is proposed in the absence of any data. So, I don’t place too much weight on this hypothesis to begin with. Nevertheless, I acknowledge that this hypothesis has influenced the thinking of many people. Our work showed that coding region evolution is likely to be important for human brain evolution. In this regard, it can be considered to be a challenge to the hypothesis. However, our work by no means argues that regulatory changes are necessarily less important than coding changes. So, the jury is still out.
3. The aforementioned work on microcephalin and ASPM touched some nerves, due mostly to two issues: the difference in frequency of the derived haplotype in different populations, and co-incidence of major moments in human cultural evolution with the appearance of these derived haplotypes. Do you regret anything you wrote in either of those papers?
On the one hand, I don’t regret the things we wrote in the papers because they were scientifically justified and the speculative nature of some of our statements was clearly indicated as such. On the other hand, I can appreciate why some people might be concerned over the possibility that our results could be over-interpreted or even mis-interpreted to advance certain ideas about race and ethnicity, especially by people with certain political agenda. Our society, given its sordid history on race-related issues, is very confused about how to deal with racially and ethnically sensitive topics. As a result, science and politics get mixed up when they relate to these topics. I personally feel, like many other scientists, that science should be separate from politics. In particular, science should meet the same burden of proof regardless of what political implications it might have. But this may be too idealistic if not naive. I feel I am still learning how to handle such issues in a way that is honest to the science while at the same time sensitive and respectful to political and cultural needs.
4. You’ve speculated that humans will, at some time in the future, speciate. The evidence for clinal speciation in other taxa certainly supports this possibility. One possible counterargument is that germ-line genetic engineering or even pre-implantation genetic screening could lead to the human population becoming more homogenized, preventing the evolution of barriers to gene flow. What role do you see for technology in the future of human evolution?
I think we as a species now stand at a watershed moment in the history of life. For billions of years, evolution of life forms has been governed by the Darwinian process of random mutations followed by selection. Now, we are about to revise that principle dramatically by genetic engineering. Instead of starting with random mutations, of which only very few are advantageous, we can now prospectively change our genome (and the genomes of other species) in ways we intend. In a sense, genetic engineering will make Lamarckian evolution a reality. Given the revolutionary nature of this new technology, it is impossible to predict where the technology will take us into the future. But suffice it to say that genetic engineering, coupled with other technologies such as pre-implantation genetic screening, would likely speed up evolution enormously, and create life forms, including those derived from our own species, in ways that the Darwinian process can never hope to accomplish.
5. You’ve published a paper noting a correlation between mutation rate and the ratio of nonsynonymous to synonymous mutations in a gene. This ratio forms the basis for many tests for selection. What’s the best way to interpret such a test? You do much molecular work– how can one decide, using both statistical and molecular evidence, that the story for selection on a locus has been decided one way or another?
It is still debated among experts as to how to interpret the ratio of nonsynonymous to synonymous substitutions. The major difficult arises from the fact that both positive selection and relaxed constraint produce a high ratio. When a gene has a low ratio, one can argue that it has evolved predominantly under purifying selection. But when a gene has a high ratio, it is not clear whether it is due to strong positive selection, or relaxed constraint, or a bit of both. So, unless the ratio is very much greater than 1, it is not possible to conclude what a high ratio means. This is where other statistical and molecular evidence is needed. There are no clear-cut rules on what evidence can be considered “enough” for establishing (or refuting) positive selection. But the best cases usually involve multiple lines of evidence coming from several independent perspectives that are consistent with each other.
6. A lot of researchers studying human population genetics and evolution are strictly data miners (i.e., they generate/publish no original data). There are limitations to such an approach, as it depends on the available data and prevents certain analyses from being performed. Do you expect to see more research groups turning into pure data mining labs in the future? Or will there still be a place for independent labs generating their own data (for example, resequencing a gene in multiple individuals to study the polymorphism)?
Given the explosion of genomic data in the last decade or so, which shows no sign of slowing down any time soon, there is likely to be a proliferation of pure data miners just because there is a niche for them. But I suspect that many interesting findings will still require the combination of data mining and wet experiments to provide key pieces of data not already available in public databases. In this regard, labs that can do both data mining and wet experiments can have an advantage over labs that can only do data mining.
7. The politics behind the funding of stem-cell research in the US have sometimes obscures the actual science. As someone who works in the field, where is it headed? What is truly feasible in terms of medical progress using an approach based in stem cell research?
I personally feel that the promises of stem cells as a direct reagent in the treatment of disease are grossly exaggerated. I think it will be a very long time before Parkinson’s disease or Alzheimer’s disease could be treated by introducing stem cells (or their derivative cells) into a patient. However, stem cells offer a model for studying developmental processes. As such, stem cell biology will ultimately make valuable contributions to our ability to better understand disease and develop treatments. So, I believe that the future of stem cell research lies in its potential as a research tool, and to a lesser extent, its ability to provide direct cure for disease.
8. Much of your work on stem cells is done in collaboration with a center in China. What is the attitude towards such research there, and how does it compare with the attitude here in the US?
The attitude is much more progressive relative to the US. Religion is not a dominant force in molding Chinese cultural traditions, and people are generally not married to a particular doctrine. This attitude provides greater flexibility for stem cell research.
9. Ian Buruma has noted that many Chinese dissidents have converted to Christianity, while David Aikman, in “Jesus in Beijing”, argues that the Christianization of much of China will alter geopolitics. How accurate do you think is the perception by many Westerners that Christianity is filling the ideological void left by the fall of Marxism-Leninism?
I tend to agree that Christianity is filling an ideological void left by the dying out of the old communist ideology. But whether China will be Christianized is a separate matter. There is plenty of Chinese who are strongly opposed to the idea of allowing religion to play a major role in the culture. I suspect it will be a major uphill battle for one religion, be it Christianity or otherwise, to spread beyond a few limited sectors of society. But this is just my guess.
10. Looking back, would you make any changes in your educational path? If so, what?
Looking back, I might have chosen economics instead of biology, as it might have allowed my work to have a broader impact. But it’s a tossup, and my feeling may well have stemmed from my constant impatience with lack of progress in my own work and therefore the perception that grass is greener on the other guy’s pasture
Labels: 10 questions
The major difficult arises from the fact that both positive selection and relaxed constraint produce a high ratio.
This may be true, but in the extreme case, where we are talking about a single allele (i.e. where nonsynonymous substitutions = zero), the diversity of synonymous substitutions in the population should be a direct measure of the allele’s age (in the same population). Here we are NOT talking about ratios, but absolute numbers – this should help to distinguish between high positive selection (which would result in high ratios but low absolute numbers) and relaxed constraint (which would result in high ratios and high absolute numbers).
This is just an off-the-cuff observation, am I wrong?
Here we are NOT talking about ratios, but absolute numbers – this should help to distinguish between high positive selection (which would result in high ratios but low absolute numbers) and relaxed constraint (which would result in high ratios and high absolute numbers).
I’m not sure. why would selection give low absolute numbers, while relaxed constraint give high absolute numbers? also, note that absolute numbers are also influenced by the local mutation rate.
I’m not sure. why would selection give low absolute numbers, while relaxed constraint give high absolute numbers? also, note that absolute numbers are also influenced by the local mutation rate.
Since synonymous mutations are selection-neutral, given a large enough population, their number should be a very accurate measure of time – i.e. the probability of a synonymous mutation is constant, and will be preserved when it happens. It’s like carbon-14 dating for DNA. If an allele is even moderately selected for, it will increase rapidly within the population. The result will be a small absolute number of synonymous substitutions (i.e. short time-depth, but wide distribution). In other words, high ratios are achieved by both the numerators and denominators being low numbers.
In the case of relaxed constraint, both synonymous and non-synonomous mutations are selection-neutral, so high ratios are achieved by both numerators and denominators being high numbers.
(The normal case, purifying selection results in low numerators and high denominators.)
He was definitely wrong about the field of economics being greener than biology. There have been only two or three advances in our understanding of how the economy works over the past century that have made a significant contribution to human welfare (taming the business cycle being the most important). You can’t begin to count the number on the biology side of the equation, and the promise of future advances seems virtually unlimited.
Maybe he was imagining that a guy with his smarts could have risen to the very top of the economics profession by now, maybe even have won a “Nobel” prize, and not have to have slogged through the purgatory of being a post-doc. But in the long-run I suspect he would have felt far less fulfilled, maybe even sullied, by the experience, even if his academic salary would have been higher and he had penned a pop-science blockbuster like Freakanomics.
Having had some experience with Chinese people since I was a little tacker, I can say with some authority that they are just as capable of superstition as the rest of us …
Personally, of course, I would bow down to Chinese women any day :-)
Another nice one, tks.
I wince a bit when Bruce says, “Our society, given its sordid history on race-related issues, is very confused about …” You mean, as opposed to the brilliant and perfect way all other societies have dealt with race challenges? Seems to me that many tens of millions of people of many different races have come to this country and done awfully well for themselves. Whatever our gigantic and obvious imperfections, it seems to me that our batting average has to be above average.
But what the hell, still a good q&a.
Blowhard:
An excellent comment. I have always pointed this sort of thing out, not to deflect attention from the problems that still exist but to give PERSPECTIVE on the reality of the American situation. Because we make such a big deal out of any sort of problem, many of us grow up without realization that formerly and in other “societies” there existed no such freedom as has been created in America. This lends to his use of such words as “sordid” with regard to “race-related issues”. By the same token (and ironically for those who dwell on imperfections and consistently bitch), this same criticism is a proof that this society is tops, if not in the top few, of all time. How do we react now that science more clearly and clearly demonstrates differences. It will middle the so-called right and left and show how similar the “beliefs” are, in a certain way, of both groups. I agree, a nice Q & A.
C
Off topic but I thought this may be of some interest to you:
Dr. J. P. Rushton is supposed to be on CNN’s Paula Zahn Now at 8PM (EST) Tuesday according to a posting on the yahoo group evol-psych.
Since synonymous mutations are selection-neutral, given a large enough population, their number should be a very accurate measure of time
I think you’re talking about sites that are polymorphic within a population. If we compare the chimp genome to the human genome, however, time is fixed (at about 5 million years) and the challenge to to sort through the sites that have become fixed.
synonymous mutations are selection-neutral
see this paper:
http://www.pnas.org/cgi/content/full/102/40/14338
I think you’re talking about sites that are polymorphic within a population. If we compare the chimp genome to the human genome, however, time is fixed (at about 5 million years) and the challenge to to sort through the sites that have become fixed.
I’m talking about identifying whether an allele is under directional selection or relaxed constraint. If the allele is both widespread and has short time-depth, then obviously it is under directional selection. So, contrary to what I understand Lahn to be saying, it should be easily to distinguish between these two cases. Have I misunderstood him?
Rik,
From the link:
Surprisingly, from bacteria to mammals, the best indicator of a protein’s relative evolutionary rate is the expression level of the encoding gene, measured in mRNA transcripts per cell (5, 6, 11-14). Highly expressed proteins evolve slowly, accounting for as much as 34% of rate variation in yeast (5).
The way they measure “evolutionary rate” is by looking at the synonymous variation. Isn’t it the case that directional selection (i.e. non-synonymous variation) would decrease this? So maybe highly expressed proteins are evolving faster (in terms of functional evolution)? If expression is a proxy for importance, this might make sense.
Rik,
That was a very interesting link. The entire discussion was informative. I particularly liked the author?s analysis of ?translational robustness? and fitness.
I wonder how much the paper?s results depend on the high selection pressure in yeast. With less selection pressure, have humans been losing ?translational robustness? over hundreds of millions of years?
David: ?The way they measure “evolutionary rate” is by looking at the synonymous variation.?
From what I read, they measured ?evolutionary rate? by comparing amino acid substitutions in many proteins in a yeast clade. So the main focus was on ?dN?, non-synchronous changes.
They did discuss ?dS?, synchronous changes, to show evidence against the ?Translational Efficiency? hypothesis.
If the allele is both widespread and has short time-depth, then obviously it is under directional selection.
this is essentially the test used by lahn to show selection in MCH1 and ASPM, except that he used haplotype length as a proxy for time.
the nonsynonymous/synonymous substitution ratio is not comparing alleles, it’s comparing genes between species. that is, you’re comparing two genome sequences– the time of divergence between the two is fixed, and the sequences are representative of their respective species.
the nonsynonymous/synonymous substitution ratio is not comparing alleles
Why not?
Why not?
if you’re comparing two genome sequences–say rat and mouse–you don’t have polymorphism data, just a single sequence from each species. if there are different alleles of the gene segregating in mice, you can’t tell.
if you’re comparing two genome sequences–say rat and mouse–you don’t have polymorphism data, just a single sequence from each species. if there are different alleles of the gene segregating in mice, you can’t tell.
I mean, why not use this kind of analysis with allele data?
why not use this kind of analysis with allele data?
I think we’re talking on different time scales here. if we want to know what makes humans different from mice, one would imagine that the differences are fixed in both populations, i.e. there is no polymorphism in either species at the relevant loci.
the signature of selection in polymorphism data only lasts for something like Ne (effective population size) generations, so it doesn’t go back far enough to answer questions like the one above. for more recent selection, you use polymorphism data, but LD-based methods are more practical (and I think more powerful) than those based on the frequency spectrum).
for more recent selection, you use polymorphism data, but LD-based methods are more practical (and I think more powerful) than those based on the frequency spectrum).
Got it, thanks.