New review paper on GWAS

Comput Struct Biotechnol J. 2015 Nov 23;14:28-34
Uncovering the Genetic Architectures of Quantitative Traits.
Lee JJ, Vattikuti S, Chow CC.

Abstract
The aim of a genome-wide association study (GWAS) is to identify loci in the human genome affecting a phenotype of interest. This review summarizes some recent work on conceptual and methodological aspects of GWAS. The average effect of gene substitution at a given causal site in the genome is the key estimand in GWAS, and we argue for its fundamental importance. Implicit in the definition of average effect is a linear model relating genotype to phenotype. The fraction of the phenotypic variance ascribable to polymorphic sites with nonzero average effects in this linear model is called the heritability, and we describe methods for estimating this quantity from GWAS data. Finally, we show that the theory of compressed sensing can be used to provide a sharp estimate of the sample size required to identify essentially all sites contributing to the heritability of a given phenotype.
KEYWORDS:
Average effect of gene substitution; Compressed sensing; GWAS; Heritability; Population genetics; Quantitative genetics; Review; Statistical genetics

Selection of the week

The first movement of Beethoven’s Violin and Piano Sonata No.5, Op. 24, dubbed the Spring Sonata, played by Gidon Kremer and Martha Argerich. I was fortunate enough to attend a concert by Kremer in the 1980’s. I don’t think I really understood what great musicianship was, as opposed to virtuosity, until that concert.  For Kremer, every note is part of a bigger whole. In this video, it is not clear that Kremer and Argerich are on the same page though.

Below is the whole thing with Anne Sophie Mutter and Lambert Orkis, which has better balance.

Selection of the week

The great Russian pianist Sviatoslav Richter playing Beethoven’s last piano sonata, No. 32 in C minor, Op 111, which really pushed the boundaries of music at that time. Beethoven was completely deaf when he composed it. Richter was considered to be a musical genius; he was admired by Glenn Gould. Richter also insisted that American pianist Van Cliburn should be the winner of the first International Tchaikovsky Piano Competition in Moscow in 1958. It was a controversial decision to say the least but Richter prevailed and that moment still resonates both musically and and geopolitically. It certainly launched Cliburn’s career and one could argue that it laid a path to the end of the cold war. Music can matter.

How to be a scientific dilettante

I have worked in a lot of disparate fields from plasma physics, to nonlinear dynamics, to posture control, to neuroscience, to inflammation, to obesity, to gene transcription, and population genetics. I have had a lot of fun doing this but I definitely do not recommend it as a career path for a young person. I may have gotten away with it but I was really lucky and it certainly carried a cost. First of all, by working in so many fields, I definitely lack the deep knowledge that specialists have. Thus, I don’t always see the big picture and am often a step behind others. Secondly, while I am pretty well cited, my citations are diluted over multiple fields. Thus, while my total H index (number of papers where number of citations exceeds rank) is pretty decent, my H index in each given field is relatively small. I thus do not have much impact in any given area. To be taken seriously as a scientist, one must be a world expert in something. The system is highly nonlinear; being pretty good in a lot of things is much worse than being really good in one thing. There is a threshold for relevance and if you don’t cross it then it is like you don’t exist.

However, if you do want to work in a lot of fields, the worse thing to do is to say, “Hey I really find field X to be interesting so I’m just going to read some books and papers on it and try to do something.” I have reviewed quite a few papers, where some mathematician or physicist has read some popular science book or newspaper article on the topic and then tried to publish a paper on a problem mentioned in the book. I then have to tell them to read up on four decades of previous work first, and then resubmit. The way I have managed to meander through multiple fields is that someone will either contact me directly about some specific question or mention something to me either in a casual setting or at a conference. I could not possibly have made any progress at all if I didn’t have great collaborators who really knew the field and the literature. Still, people constantly ask me if I still work in neuroscience, to which I can only respond “Just because you don’t cite me doesn’t mean I don’t publish!”

 

Chomsky on The Philosopher’s Zone

Listen to MIT Linguistics Professor Noam Chomsky on ABC’s radio show The Philosopher’s Zone (link here).  Even at 87, he is still as razor sharp as ever. I’ve always been an admirer of Chomsky although I think I now mostly disagree with his ideas about language. I do remember being completely mesmerized by the few talks I attended when I was a graduate student.

Chomsky is the father of modern linguistics. He turned it into a subfield of computer science and mathematics. People still use Chomsky Normal Form and the Chomsky Hierarchy in computer science. Chomsky believes that the language ability is universal among all humans and is genetically encoded. He comes to this conclusion because in his mathematical analysis of language he found what he called “deep structures”, which are embedded rules that we are consciously unaware of when we use language. He was adamantly opposed to the idea that language could be acquired via a probabilistic machine learning algorithm. His most famous example is that we know that the sentence “Colorless green ideas sleep furiously” makes grammatical sense but is nonsensical while the sentence “Furiously sleep ideas green colorless”, is nongrammatical. Since, neither of these sentences had ever been spoken nor written he surmised that no statistical algorithm could ever learn the difference between the two. I think it is pretty clear now that Chomsky was incorrect and machine learning can learn to parse language and classify these sentences. There has also been field work that seems to indicate that there do exist languages in the Amazon that are qualitatively different form the universal set. It seems that the brain, rather than having an innate ability for grammar and language, may have an innate ability to detect and learn deep structure with a very small amount of data.

The host Joe Gelonesi, who has filled in admirably for the sadly departed Alan Saunders, asks Chomsky about the hard problem of consciousness near the end of the program. Chomsky, in his typical fashion of invoking 17th and 18th century philosophy, dismisses it by claiming that science itself and physics in particular has long dispensed with the equivalent notion. He says that the moment that Newton wrote down the equation for gravitational force, which requires action at a distance, physics stopped being about making the universe intelligible and became about creating predictive theories. He thus believes that we will eventually be able to create a theory of consciousness although it may not be intelligible to humans. He also seems to subscribe to panpsychism, where consciousness is a property of matter like mass, an idea championed by Christof Koch and Giulio Tononi. However, as I pointed out before, panpsychism is dualism. If it does exist, then it exists apart from the way we currently describe the universe. Lately, I’ve come to believe and accept the fact that consciousness is an epiphenomenon and has no causal consequence in the universe. I must credit David Chalmers (e.g. see previous post) for making it clear that this is the only recourse to dualism. We are no more nor less than automata caroming through the universe, with the ability to spectate a few tens of milliseconds after the fact.

Addendum: As pointed out in the comments, there are monoistic theories, as espoused by Bishop Berkeley, where only ideas are real.  My point about the only recourse to dualism is epiphenomena for consciousness, is if one adheres to materialism.