‘Hard cash paid down, over and over again’

The whole subject of inheritance is wonderful. When a new character arises, whatever its nature may be, it generally tends to be inherited, at least in a temporary and sometimes in a most persistent manner. What can be more wonderful than that some trifling peculiarity, not primordially attached to the species, should be transmitted through the male or female sexual cells, which are so minute as not to be visible to the naked eye, and afterwards through the incessant changes of a long course of development, undergone either in the womb or in the egg, and ultimately appear in the offspring when mature, or even when quite old, as in the case of certain diseases? Or again, what can be more wonderful than the well-ascertained fact that the minute ovule of a good milking cow will produce a male, from whom a cell, in union with an ovule, will produce a female, and she, when mature, will have large mammary glands, yielding an abundant supply of milk, and even milk of a particular quality?

Today is Charles Darwin’s birthday. I’m not such a serious Darwin reader, but it’s fun how it seems like you can open a Darwin book at almost any chapter and find something interesting or amusing. This is from The Variation of Animals And Plants Under Domestication, chapter twelve, ‘Inheritance’. Here we find Darwin overflowing with enthusiasm when trying to convince a sceptic about the importance of inheritance. In true Darwin style he launches into a long list of examples:

Some writers, who have not attended to natural history, have attempted to show that the force of inheritance has been much exaggerated. The breeders of animals would smile at such simplicity; and if they condescended to make any answer, might ask what would be the chance of winning a prize if two inferior animals were paired together? They might ask whether the half-wild Arabs were led by theoretical notions to keep pedigrees of their horses? Why have pedigrees been scrupulously kept and published of the Shorthorn cattle, and more recently of the Hereford breed? Is it an illusion that these recently improved animals safely transmit their excellent qualities even when crossed with other breeds? have the Shorthorns, without good reason, been purchased at immense prices and exported to almost every quarter of the globe, a thousand guineas having been given for a bull? With greyhounds pedigrees have likewise been kept, and the names of such dogs, as Snowball, Major, &c., are as well known to coursers as those of Eclipse and Herod on the turf. Even with the Gamecock, pedigrees of famous strains were formerly kept, and extended back for a century. With pigs, the Yorkshire and Cumberland breeders ”preserve and print pedigrees;” and to show how such highly-bred animals are valued, I may mention that Mr. Brown, who won all the first prizes for small breeds at Birmingham in 1850, sold a young sow and boar of his breed to Lord Ducie for 43 guineas; the sow alone was afterwards sold to the Rev. F. Thursby for 65 guineas; who writes, ”She paid me very well, having sold her produce for 300l., and having now four breeding sows from her.” Hard cash paid down, over and over again, is an excellent test of inherited superiority. In fact, the whole art of breeding, from which such great results have been attained during the present century, depends on the inheritance of each small detail of structure. But inheritance is not certain; for if it were, the breeder’s art would be reduced to a certainty, and there would be little scope left for that wonderful skill and perseverance shown by the men who have left an enduring monument of their success in the present state of our domesticated animals.

For the rest of the chapter, he will go on to talk about humans, again with long lists of examples, and then mixing in domestic animals and plants again. A lot of these examples of heredity surely hold up, and others seem like anecdotes. Here and even more in the following chapters–with subtitles including ‘reversion to atavism’, ‘prepotency’ and ‘on the good effects of crossing, and the evil effects of close interbreeding’–Darwin is trying hard to make sense of heredity. Why are certain features heritable? Why do they sometimes go away in the offspring but reappear in later generations? Why are offspring sometimes more like one parent than the other? In chapter 27, he will present his ‘provisional hypthesis of pangenesis’.

Literature

Darwin. 1875. The variation of animals and plants under domestication.

”These are all fairly obvious” (says Sewall Wright)

I was checking a quote from Sewall Wright, and it turned out that the whole passage was delightful. Here it is, from volume 1 of Genetics and the Evolution of Populations (pages 59-60):

There are a number of broad generalizations that follow from this netlike relationship between genome and complex characters. These are all fairly obvious but it may be well to state them explicitly.

1) The variations of most characters are affected by a great many loci (the multiple factor hypothesis).

2) In general, each gene replacement has effects on many characters (the principle of universal pleiotropy).

3) Each of the innumerable possible alleles at any locus has a unique array of differential effects on taking account of pleiotropy (uniqueness of alleles).

4) The dominance relation of two alleles is not an attribute of them but of the whole genome and of the environment. Dominance may differ for each pleiotropic effect and is in general easily modifiable (relativity of dominance).

5) The effects of multiple loci on a character in general involve much nonadditive interaction (universality of interaction effects).

6) Both ontogenetic and phylogenetic homology depend on calling into play similar chains of gene-controlled reactions under similar developmental conditions (homology).

7) The contributions of measurable characters to overall selective value usually involve interaction effects of the most extreme sort because of the usually intermediate position of the optimum grade, a situation that implies the existence of innumerable different selective peaks (multiple selective peaks).

What can we say about this?

It seems point one is true. People may argue about whether the variants behind complex traits are many, relatively common, with tiny individual effects or many, relatively rare, and with larger effects that average out to tiny effects when measured in the whole population. In any case, there are many causative variants, alright.

Point two — now also known as the omnigenetic model — hinges on how you read ”in general”, I guess. In some sense, universal pleiotropy follows from genome crowding. If there are enough causative variants and a limited number of genes, eventually every gene will be associated with every trait.

I don’t think that point three is true. I would assume that many loss of function mutations to protein coding genes, for example, would be interchangeable.

I don’t really understand points six and seven, about homology and fitness landscapes, that well. The later section about homology reads to me as if it could be part of a debate going on at the time. Number seven describes Wright’s view of natural selection as a kind of fitness whack-a-mole, where if a genotype is fit in one dimension, it probably loses in some other. The hypothesis and the metaphor have been extremely influential — I think largely because many people thought that it was wrong in many different ways.

Points four and five are related and, I imagine, the most controversial of the list. Why does Wright say that there is universal epistasis? Because of physiological genetics. Or, in modern parlance, maybe because of gene networks and systems biology. On page 71, he puts it like this:

Interaction effects necessarily occur with respect to the ultimate products of chains of metabolic processes in which each step is controlled by a different locus. This carries with it the implication that interaction effects are universal in the more complex characters that trace such processes.

The argument seems to persists to this day, and I think it is true. On the other hand, there is the question how much this matters to the variants that actually segregate in a given population and affect a given trait.

This is often framed as a question of variance. It turns out that even with epistatic gene action, in many cases, most of the genetic variance is still additive (Mäki-Tanila & Hill 2014, Huang & Mackay 2016). But something similar must apply to the effects that you will see from a locus. They also depend on the allele frequencies at other loci. An interaction does nothing when one of the interaction partners are fixed. If they are nearly to fixed, it will do nearly nothing. If they’re all at intermediate frequency, things become more interesting.

Wright’s principle of universal interaction is also grounded in his empirical work. A lot of space in this book is devoted to results from pigmentation genetics in guinea pigs, which includes lots of dominance and interaction. It could be that Wright was too quick to generalise from guinea pig coat colours to other traits. It could be that working in a system consisting of inbred lines draws your attention to nonlinearities that are rare and marginal in the source populations. On the other hand, it’s in these systems we can get a good handle on the dominance and interaction that may be missed elsewhere.

Study of effects in combination indicates a complicated network of interacting processes with numerous pleiotropic effects. There is no reason to suppose that a similar analysis of any character as complicated as melanin pigmentation would reveal a simpler genetic system. The inadequacy of any evolutionary theory that treats genes as if they had constant effects, favourable or unfavourable, irrespective of the rest of the genome, seems clear. (p. 88)

I’m not that well versed in pigmentation genetics, but I hope that someone is working on this. In an era where we can identify the molecular basis of classical genetic variants, I hope that someone keeps track of all these A, C, P, Q etc, and to what extent they’ve been mapped.

Literature

Wright, Sewall. ”Genetics and the Evolution of Populations” Volume 1 (1968).

Mäki-Tanila, Asko, and William G. Hill. ”Influence of gene interaction on complex trait variation with multilocus models.” Genetics 198.1 (2014): 355-367.

Huang, Wen, and Trudy FC Mackay. ”The genetic architecture of quantitative traits cannot be inferred from variance component analysis.” PLoS genetics 12.11 (2016): e1006421.

20170705_183042.jpg

Yours truly outside the library on Thomas Bayes’ road, incredibly happy with having found the book.

”Forskaren är fri”

Politiska ideologier
eländets filosofi
etablissemangets kotterier
men forskaren är fri
dogmatiska religiösa sekter
vetenskapens trolleri
materialismens effekter
men forskaren är fri

Kjell Höglund, Forskaren är fri

En behöver egentligen inte ens veta att Kjell Höglund skrivit böcker med någon sorts esoteriskt innehåll. Det räcker med att lyssna på texten för att förstå att forskaren i det här fallet inte är en akademisk forskare. Men ändå.

 

”Made obvious by our use of contraceptives”

I recently reread part of The Selfish Gene. The introduction to the 30th anniversary edition is great fun. For one thing, Dawkins expresses doubts about the word ”selfish” in the title, and ponders whether he should have called it the Immortal or Cooperative gene instead. That feels very ironic, and I for one think that he made the right choice. It also contains this nugget:

Our brains have evolved to a point where we are capable of rebelling against our selfish genes. The fact that we can do so is made obvious by our use of contraceptives. The same principle can and should work on a larger scale.

E. O. Wilson and B. F. Skinner

E.O. Wilson: This is going to be a conversation that I will have with B.F. Skinner. This is Ed Wilson. He invited me to talk about sociobiology. Our relations have always been very friendly and I look forward to it. This should be an interesting talk this Thursday morning.
B.F. Skinner: We will start with a basic statement. I assume that you are what I call a behaviorist. You would accept that an organism is a biophysical and biochemical system, a product of evolution.
E.O. Wilson: I am.

B.F. Skinner: That would include not only genetic behavior, but also the kinds of behavior that can be learned because of genetic processes. Of course it (behavior) always goes back to genetics.

Naour, P (2009) E. O. Wilson and B. F. Skinner. A dialogue between sociobiology and radical behaviorism. New York: Springer.

Dagens rekommendation: F Jalalvand m. fl. om värdet av mysko forskning

Vi vet för lite om allt för att kunna lösa problem snabbt. Vi vet för lite om allt. Vi vet för lite om mänsklig genetik. Vi vet för lite om cellens metabolism. Vi vet för lite om samspelet mellan sjukdomsframkallande organism och värd. Vi har för få metoder. Vi vet för lite om allt. Och om den tillämpade forskningen ska ta reda på allt som den behöver för att kunna lösa problemen den är ämnad för att lösa hade den behövt tillbringa ett par 100-200 år åt det innan den kunde sätta igång med det verkliga arbetet (uppdiktade siffror, men play with me here).

Den här bloggposten av F Jalalvand, doktorand i mikrobiologi i Lund, är en gammal favorit om varför det är viktigt att forska om saker som inte verkar ha någon omedelbar nytta. Han radar upp en serie exempel, som inte alls är långsökta eller udda, på hur nyfikenhetsdriven forskning senare kommit att bli väldigt fruktbar även för tillämpad forskning. Bloggen är även övrigt mycket läsvärd.

Låt oss nu säga att en forskargrupp jobbar med att förstå och utveckla ett botemedel mot bröstcancer. Om forskarna hade själva behövt upptäcka Taq-polymeraset, GFP, RNA silencing och all annan kunskap och metodologi som härstämmar från grundforskning förstår ni att botemedlet hade dröjt.

Och om läsaren råkar ha tillgång till ett forskningsbibliotek finns det en kolumn i en vetenskaplig tidskrift av Patricia Brennan m.fl. som säger ungefär samma sak:

Brennan, Patricia LR, et al. (2014) Oddball Science: Why Studies of Unusual Evolutionary Phenomena Are Crucial. BioScience 64.3 178-179.

Weird juxtapositions happen when you import Wikipedia

The network is available on IntegromeDB public database (http://integromedb.org) under the present manuscript title.

So I went there:

integromedb

Apparently, typing in journal article titles was not what the search field was for. Couldn’t find the network either, but the article is still in provisional pdf form so that may be the reason.

Dragana Stanley, Nathan S Watson-Haigh, Christopher JE Cowled, Robert J Moore. (2013) Genetic architecture of gene expression in the chicken. BMC Genomics 14