john hawks weblog

paleoanthropology, genetics and evolution

history of genetics

  • Unraveling Fisher's mysteries

    Wed, 2013-04-10 09:11 -- John Hawks

    Haldane's Sieve has a great post by James Lee giving context to a new preprint from him and Carson Chow: "Our paper: The causal meaning of Fisher’s average effect".

    This paradox continued to bother me over the next several years. Soon after my daughter was born, I indulged one of those wild impulses that strike the sleepless: I emailed my questions regarding this matter to Anthony W. F. Edwards, the last student of the great Fisher himself. Anthony very generously sent me some of his unpublished work and also his correspondence with Falconer about the very article that had spurred my thoughts. This correspondence spanned a period of more than 20 years, and it provided a very poignant portrait of Douglas Falconer as a scientist (Hill and Mackay, 2004). I did not immediately find the answers to my questions in the materials that Anthony sent to me, but they set me on the path toward finding the answers. These are presented in the paper, which will shortly appear in Genetics Research.

    Fisher invented a lot of statistical concepts, many of which are used universally by everybody, even far outside genetics. But he also invented some that nobody else has been able to understand. The "average effect" of an allele is one of them. The concept was central in the development of his "Fundamental Theorem" of natural selection, but why it works is not obvious. Lee's post does a great job explaining why this was an interesting and useful project to undertake.

  • Quote: Lederberg on the candidate gene approach

    Sun, 2012-09-30 00:46 -- John Hawks

    In my last post ("Quote: Lederberg on Haldane") I pointed to a 1999 article by Joshua Lederberg [1]. Later in the article, he considers an interesting question:

    Outside the domain of malaria and the erythrocyte, the pickings for established polymorphisms in relation to human disease are rather thin. Why have they predominated for malaria? Its geographic, climatic, and altitudinal restrictions–related to the habitats of vector mosquitoes–lend themselves to epidemiological revelation. In addition, few diseases, barring mainly tuberculosis, have a prevalence and fitness-impairing morbidity so high that subject genes will have significant penetrance. Most other morbid infections will attack a small sector of the population, thus introducing high “environmental” variance into the heritability calculations. This is also compounded by maternally inherited immunity and, needless to say, elements of culture (including saluto-genic technology). Most of our successes have entailed the ascertainment of candidate genes, e.g., the blood group and MHC polymorphisms, and searches for disease correlations to them. These are abundant and can be partially explained by specializations in epitope presentation to the immune system or antigenic mimicry between parasites' surface antigens and self-antigens of the host.

    Today we have GWAS, which has potentially much greater power to show associations between large samples of people and previously unknown risk loci. Yet the same limitations remain true that Lederberg pointed out in 1999: Environmental variance in parasite or pathogen incidence and load is very high, acquired immunity complicates the analysis of effects, and the present effects of pathogens are different than they would have been in past populations with greater frailty.


    References

  • Quote: Lederberg on Haldane

    Sun, 2012-09-30 00:16 -- John Hawks

    J. B. S. Haldane has typically been assigned credit for the first suggestion that human hemoglobinopathies are adaptations to malaria. In 1999, Joshua Lederberg examined the history of this question [1].

    Haldane's most often remembered attribution, to malaria, oddly enough does not appear at all in the formal article but in the discussion footnotes. Therein, Montalenti acknowledges a verbal communication from Haldane suggesting that thalassemia heterozygotes may be more resistant to malaria. In his rejoinder, Haldane goes on to suggest that “microcythemic heterozygotes may be at an advantage on diets deficient in iron or other substances, thus leading to anemia” (HALDANE 1949, p. 76). This has been widely viewed as an anticipation of much later research on heterozygote advantage of blood dyscrasias in relation to malaria.1

    In this regard, the work of A. C. ALLISON (1954) is well known. However, he remarks (private e-mail communication, April 26, 1999):

    At the time of publication of my finding that sickle-cell heterozygotes have some protection against malaria (1954), I was unaware that J. B. S. Haldane had made a similar suggestion for thalassemia. After my publication I was invited to make a presentation at University College, London, and we had a friendly discussion. Haldane said that he had recognized that heterozygotes for the thalassemia gene are likely to have some advantage to counter-balance selection against homozygotes and suggested several possible candidates, among them malaria and better absorption of iron. He added that to speculate about the problem was one thing and to provide experimental evidence for a solution was altogether another. This was the first evidence that natural selection operates in humans.

    Meanwhile, Allison himself [2] cited the earlier work of Beet, who showed in 1946 and 1947 that the blood of East African peoples with the sickle-cell trait carried a lower incidence of malaria parasites than the blood of normal individuals [3][4]. Beet's articles are of interest because they precede Haldane's oblique suggestion about the adaptive value of thalassemia. Still, the relatively weak observation that sickle-cell individuals have a slightly lower incidence of parasites was not a sufficient proof that the sickle-cell trait actually protected its carriers.

    Allison demonstrated the connection between sickle-cell and malaria resistance in two ways. He undertook an epidemiological survey among children, showing a very strong statistical association between non-sicklers and parasites in the blood. Then, he performed an experiment in which 15 sickle-cell trait and 15 normal individuals were injected with the malaria parasites in a controlled way. These two groups were starkly different in their parasite response, with only two of the sickle-cell trait individuals showing any parasites at all, and then at low blood counts; while 14 out of 15 of the normal individuals had parasite infections. His article is notable not only for this clear demonstration, but because of its direct discussion of the other major arguments in favor of the malaria resistance hypothesis, including the close examination of the geographic distribution of the sickle-cell trait in relation to endemic malaria, and the rejection of alternative hypothesis of high mutation rate. This paragraph is exceptionally clear:

    The main problem can be stated briefly: how can the sickle-cell gene be maintained at such a high frequency among so many peoples in spite of the constant elimination of these genes through deaths from the anaemia? Since most sickle-cell anaemia subjects are homozygotes, the failure of each one to reproduce usually means the loss of two sickle-cell genes in every generation. It can be estimated that for the lost genes to be replaced by recurrent mutation so as to leave a balanced state, assuming that the sickle-cell trait -- that is, the heterozygous condition -- is neutral from the point of view of natural selection, it would be necessary to have a mutation rate on the order of 10-1. This is about 3,000 times greater than naturally occurring mutation rates calculated for man and, with rare exceptions, in many other animals.

    Interesting: the mechanism by which the sickle-cell trait deters the parasites is even today not fully understood.


    References

  • Quote: Haldane on detecting variation in fitness

    Sat, 2012-09-29 22:27 -- John Hawks

    In a 1937 paper [1], J. B. S. Haldane covered some aspects of the evolutionary process in a particularly clear way. Not everything in the following paragraphs is correct or uncontroversial today, but Haldane gives a clear exposition of the power of small differences on an geological timescale:

    On the other hand, the evolutionary process is exceedingly slow. Forms usually change little in 100,000 years. Now Haldane (1924) showed that a dominant character causing an increase of 0.1 per cent. in the fitness of its carriers would increase from a frequency of .001 per cent. to one of 99 per cent. in a random mating population in 23,400 generations, and somewhat more rapidly in an inbred population; in fact, on a geological time scale, almost explosively. But a difference in fitness of this magnitude could not be detected. In order that an observed viability difference of 0.1 per cent. should exceed twice its standard error, we should have to observe at least sixteen million individuals. To detect so small a difference in fertility we should have to count their progeny.

    It may be possible to observe evolution by natural selection in a species which is adapting itself to a new environment. In other cases we can very rarely hope to notice evolutionary changes within a human lifetime. From the standpoint of an individual human observer species may be regarded as almost in equilibrium. Our only reason to hope for observable evolution is that owing to glaciation, agriculture, fishing and industry, the balance of nature has recently been upset in a manner probably without precedent in our planet's history; and hence on the Darwinian theory we should expect that evolution was proceeding with extreme and abnormal speed.

    Every so often as I'm reading classic pieces in population genetics, I look for statements that anticipate our recent observation that human evolution has accelerated during the last few thousand years. Haldane's comments on rapidly changing environments are among the first I've noticed along these lines, of course they pertain not to humans but to other possible examples of evolution in the natural environment.


    References

    1. Haldane JBS. The Effect of Variation of Fitness. The American Naturalist [Internet]. 1937;71:pp. 337-349. Available from: http://www.jstor.org/stable/2457289
  • Tomoko Ohta profile

    Thu, 2012-08-23 01:16 -- John Hawks

    Current Biology has published an interview of the esteemed Japanese population geneticist Tomoko Ohta [1].

    But, you chose not to stay in the US? I was a Fulbright student, and four years was the maximum time students were allowed to stay in the US. So, in 1966, after finishing my PhD, I went back to Japan. I asked Dr Motoo Kimura at the National Institute of Genetics, Mishima, if I could do research in his laboratory, simply because he was the only theoretical population geneticist in Japan at that time. At first, he was skeptical to let me do research in his field, but he finally accepted me as a postdoctoral fellow. Kimura was a typical Japanese man of his time, who regarded women's scientific activities as insignificant. After two years or so, I had convinced him that I should continue to do research.

    I think that if we plotted biologists on two axes, (1) Scientific Value, and (2) Public Awareness of Their Work, Kimura and Ohta would be outliers with high value and unusually low awareness.

    (via Sandwalk)


    References

    1. Ohta T. Tomoko Ohta. Current Biology. 2012;22(16):R618 - R619.
  • Guinea pigs in experiment and history

    Fri, 2012-06-22 08:09 -- John Hawks

    Daniel Engber in Slate: "Test-Tube Piggies: How did the guinea pig become a symbol of science?"

    The guinea pig's celebrity (and infamy) dates to the late 1800s and the sundry reputations of the early germ theorists. One by one, the major diseases of the time were reduced to their bacterial causes. Robert Koch, a country doctor working out of his cottage in Wollstein, Germany, identified the agents responsible for anthrax, cholera, and staphylococcus. He began by swapping sera from field mice, rabbits, monkeys, and guinea pigs, but the latter proved especially apt. Bred as a food source, guinea pigs were gentle, quiet, unperturbed by cages, and—by a fortunate coincidence, perhaps—prone to infectious disease. (You can give a Cavy full-blown tuberculosis with a single Mycobacterium tuberculosis, says TB researcher David McMurray.*) By the time he was named to a prestigious professorship in Berlin, Koch was using guinea pigs by the armful.

    Sewall Wright became well-known for doing his genetic experiments with guinea pigs, in contrast to others who used much faster-reproducing Drosophila. Jim Crow used to tell the story about how Wright once absent-mindedly used a guinea pig as a chalkboard eraser, but I'm sure he never witnessed this; it was a well-known story.

  • A story of methemoglobinemia

    Wed, 2012-02-22 19:57 -- John Hawks

    A story by Susan Donaldson James of a unique genetic disorder and the social stigma of inbreeding in Appalachia: "Fugates of Kentucky: Skin Bluer than Lake Louise".

    By the time reports appeared in the media on the disorder, the Stacy family was upset with insinuations about in-breeding that fed into stereotypes of backwoods Appalachia.

    "There was a pain not seen in lab tests," wrote Trost. "That was the pain of being blue in a world that is mostly shades of white to black."

    The disorder involves an excess of methemoglobin in the blood, related to the examples I've been relating in my Anthropology 105 course the last week or so.

  • James F. Crow, 1916-2012

    Wed, 2012-01-04 23:23 -- John Hawks

    I received today the sad news that my friend and colleague James F. Crow has died, at the age of 95. Jim was a legend in the field of population genetics, who remained active until his final year.

    James F. Crow

    Jim was always extraordinarily gracious and generous with his time, and was kind to me throughout the ten years I have known him. At our last meeting, before I went to Siberia last summer, Jim told me the story of his meeting Dmitry Belyaev, early in the days of his famous fox experiment. I was eager to see the foxes and I conveyed Jim's greetings and reminiscences to the researchers in Novosibirisk. Again and again during the years, I found Jim to be a rich source of information about topics in population genetics. Even as my work brought me to consider fundamentals often outside the current mainstream, Jim invariably had encountered similar problems and given them deep thought long before I arrived on the scene.

    During the last 25 years, Jim took on a role as unofficial historian for the field of genetics. He coedited the Perspectives feature in the journal Genetics, and for many of those years wrote the lion's share of them. He was proud to note that his birth coincided with the first issue of the journal (January,1916), but although he arrived on schedule, the first issue of the journal was mailed two months late! Reviewing the major figures in the history of genetics, Jim gave a narrative history of the science often from his own memories.

    During the next few months, the journal Genetics will be running a series of perspectives in Jim's honor, reviewing aspects of his extraordinary career. I recommend the introduction to the series, printed in the December 2011 issue [1], and the first entry written by Daniel Hartl about Jim as a teacher and advisor [2]. From the editorial introduction by Michael Turelli and Charles Langley:

    Jim Crow is a living link between our generations and the founders of population genetics. Jim was Sewall Wright's colleague at the University of Wisconsin, Madison, for decades (1955–1988); Jim initiated a friendship with Ronald Fisher over an impromptu champagne tête-à-tête in the 1940s; and he hosted J. B. S. Haldane for a memorable lecture visit to Madison in the early 1960s (after learning from the New York Times that North Carolina had just canceled a public lecture by this famous Communist). There are few population geneticists who do not owe Jim a significant intellectual debt; none are unaware of his mastery of our field and of human interactions. For many of us, Crow and Kimura (1970) was an inspiring and elegant introduction to the mathematical models that form the foundation of population genetics theory. Crow instantiates the ideal of a cherished era when manners and dress were a sign of gentility. And no one who meets Jim is surprised to learn that he is an accomplished violist.

    And from Hartl's contribution:

    Professor Crow ran his laboratory on the principles of bringing smart people together to pursue their passions and encouraging interaction, mutual respect and support, constructive criticism, and the free sharing of ideas and resources. There were no formal group meetings or reports, as there was so much daily interaction that group meetings would have been superfluous. He would advise, suggest, and encourage, but never direct or cajole. The standard of mutual respect was set by Professor Crow himself and extended not only to members of the lab but also to everyone in the field. I never heard him utter an unkind word about anyone. He also treated everyone in the lab as a colleague. One day he came to me and said, “Dan, there’s a matter on which I’d like your advice.” He must have seen how flattered I was at being asked because he quickly added, “That doesn’t mean I’ll take it. It only means I want to hear it.”

    Hartl gives some of the flavor of Crow's laboratory in the 1960's, when he was already one of the most prominent geneticists in the world, and was a frequent host to the field's legends and advisor to some of the brightest students. I can only wish that someday I will be so lucky.

    Several years ago, colleagues from several departments here at the University of Wisconsin-Madison succeeded in a long-time ambition of Jim's to found an Institute for the Study of Evolution. He had envisioned that the institute should be named for Sewall Wright, who had been important to Jim himself and forms a major part of the legacy of genetics and evolution. But the future institute's members insisted instead to name the new entity in honor of Jim. It is a fitting legacy for a great evolutionary geneticist.


    References

    Synopsis: 
    In memory of a friend and colleague, one of the most prominent figures in the history of genetics
  • Eighth day of creation

    Sun, 2011-07-17 16:13 -- John Hawks

    Larry Moran muses on the recent death of Horace Judson, author of The Eighth Day of Creation: Makers of the Revolution in Biology. This excellent history is rarely picked up by students anymore (and I will note, it's not available on Kindle), and Moran ties it to a broader theme: new molecular work in eukaryotes that ignores the long literature of work in bacteria:

    How does this happen? I think it's because modern researchers are completely unaware of the history of their field. That's partly because the work on bacteria and bacteriophage—where the basic concepts were often discovered—is no longer taught in biochemistry and molecular biology courses. This leads to the false idea, as expressed in the press release, that all new discoveries in eukaryotes are truly new concepts that nobody ever thought of before.

    I suppose we could rephrase Santayana: Those who ignore history feel privileged to reinvent it.

  • Galton remembered

    Thu, 2011-06-23 17:17 -- John Hawks

    Steve Jones writes in the BBC News on the occasion of the hundredth anniversary of Francis Galton's death: "Francis Galton: The man who drew up the 'ugly map' of Britain". He cites many interesting tidbits, this was my favorite:

    In a letter to Nature in 1879 entitled The Average Flush of Excitement, Galton recounts a visit to the Derby. He noted that while he was there he was able to assess what he called "the average tint of the complexion of the British upper classes" by observing the distant crowd through his opera glass.

    He observed that after the race started, the crowd became "suffused with a strong pink tint, just as though a sun-set glow had fallen upon it". Galton found that he could work out the mood of a mass of people even without being able to distinguish one person from the next.

Pages

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Neandertals

For years, I've worked on their bones. Now I'm working on their genes. Read more about the science studying these ancient people.

Denisova

From a finger bone of an ancient human came the record of a completely unexpected population. My lab is working on the science of the Denisova genome.

Acceleration

The advent of agriculture caused natural selection to speed up greatly in humans. We're uncovering some of the ways that populations have rapidly changed during the last 10,000 years.

Malapa

Just outside Johannesburg, the Malapa site is producing some of the most exciting finds in human evolution. This site is the headquarters of the Malapa Soft Tissue Project.