April 9, 2018

How to get from variants to genes?

Genome-wide association studies are great at identifying genetic variants associated with diseases and other traits of interest. However, for most of these variants there neither is a clear candidate gene nor an alternative mechanistic explanation for how they exert their effect.

Some thoughts on this:
  1. The vast majority of significant haplotypes (blocks of variants) reported by a given GWAS are causative for the trait of interest, assuming that the GWAS followed best practices
  2. Only a small proportion of those variants are coding or otherwise likely to affect protein function
  3. The proportion of coding variants decreases even further after finemapping to exclude variants that are not likely to be causative
  4. Some of the remaining noncoding variants act by changing gene expression, i.e. they're eQTLs
  5. Since many eQTLs are cell type and condition specific, and since data is not available for all cell types and conditions, it's unclear for what proportion of GWAS variants this applies
  6. There is a lack of understanding of how noncoding non-eQTL GWAS variants act mechanistically
  7. Some variants may not directly act through protein coding genes at all. Instead, they may act through noncoding RNAs (e.g. lncRNAs) or some other unknown mechanism
  8. Software tools for identifying causative genes from noncoding non-eQTL GWAS hits have been proposed. Here's one
  9. Experimental follow-up for those variants is hardly ever (never?) done, making it uncertain how well these tools work
  10. A lot of people are putting a lot of thought into how to approach this problem, and I expect some best practices to crystallize in the next few years

April 6, 2018

What have I been reading?

One author I keep returning to is Richard Russo: Nobody’s Fool, Everybody’s Fool, Empire Falls, The Risk Pool and The Bridge of Sighs are among my favorite novels. Nobody’s Fool and Empire Falls have been turned into first-rate movies. Yet there is also something about Russo's books that makes me uneasy. It's not that Russo could be called the Norman Rockwell of fiction, because that'd be unfair. If my livelihood depended on it – for example, if it were my job to review books – I’d have to come up with a post-hoc rationalization for that feeling. Fortunately, it doesn’t and therefore I won’t. 

Ready Player One by Ernest Cline is an entertaining science fiction novel, but not a particularly good one. The whole concept feels like the author looked for a way to cash in on his extensive knowledge of 1980s pop culture. The only reason why I'm still going to watch the movie is because it's directed by Stephen Spielberg.

Finally, here's a list of my favorite science fiction novels (inspired by this): 

 1. Vernor Vinge: Rainbows End
 2. Greg Egan: Permutation City
 3. Jack McDevitt: Engines of God
 4. Andy Weir: The Martian
 5. Ken MacLeod: Intrusion
 6-8. Kim Stanley Robinson: Red Mars, Blue Mars, Green Mars
 9. Mikael Niemi: Astrotruckers 

December 13, 2017

Why are good people divided by politics and religion?

I know I'm late to the party, but Jonathan Haidt's The Righteous Mind, published in 2012, is the most important books I've read in 2017.

Haidt's assertion that "anyone who values truth should stop worshipping reason" (page 104) neatly summarizes the book's first part. What he means by this is that we don't make judgements based on reason. Instead, we have a feeling about things, and we use reason to justify that feeling. Our reason is like a press secretary: Their job it is to come up with justifications for whichever statements and decisions the president has made, no matter how nonsensical they are. In this metaphor, the president is our subconscious gut feeling.

We're therefore unlikely to arrive at the truth by relying on reason alone, because reason will just confirm what we've felt all along. However, if we put individuals together the right way, they can use their reasoning power to disconfirm each other's claims. Finding the truth therefore must be a social enterprise, and one manifestation of such an enterprise is Science. Democracy would ideally be another one.

The second part of the book is about moral dimensions, or what Haidt calls Moral Foundations Theory. Many people, and especially those on the liberal end of the political spectrum, think there are only two moral rules: Don't harm others and don't cheat.

However, there are others too: Be loyal! Respect authority! Honor! Sanctity! Those additional dimensions have in common that their emphasis on self-control over self-expression and on duty over rights is likely to benefit families and groups rather than individuals. Ignoring those additional dimensions will results in an incomplete picture of morality and of how society works. Conservatives as well as many non-Western cultures value those moral dimensions more highly than do liberals, hence the conservative focus on "family values". Liberals put themselves at an electoral disadvantage by dismissing those dimensions.

I'm not convinced by Haidt's arguments regarding group selection, which is the theory that natural selection acts not only on individuals but also on groups. He tiptoes around the subject, but ultimately suggests that group selection is the most likely explanation for most aspects of human morality. This is problematic.

First of all, evolutionary theory indicates that group selection is only possible under implausibly narrow conditions that are unlikely to ever be met in reality. Haidt doesn't address this issue.

Secondly, his assertion that group selection is necessary to explain many aspects of morality is unconvincing. For example, that we feel moral outrage toward bullies can adequately be explained by individual selection. Allowing others to bully you isn't going to improve your fitness in the evolutionary sense. It's simply not necessary to resort to groups selection to explain this. 

However, Haidt's views on group selection are a relatively minor issue as the rest of the book holds up no matter how morality arose in the first place. I recommend The Righteous Mind to anyone who wants to understand why people on the other end of the political spectrum, but also in other cultures, have such wildly divergent opinions on moral issues. I'm also looking forward to the forthcoming The Coddling of the American Mind, which will likely expand on his somewhat controversial essay from 2015. This time, I won't wait five years to read it.

November 27, 2017

What have I been reading?

In The Berlin Project, Gregory Benford, who is deservedly known for writing some of the best hard science fiction around, asks what would've happened if the United States had developed a nuclear bomb early enough to use it against the Nazis during World War II. The book is very well researched, well written, plausible and makes you think. What more do you want from alternate history? Recommended.

Max Steele doesn't even have his own Wikipedia page. I feel that this is an injustice and that he should be more well known, but not strongly enough to actually do something about it and start that Wikipedia entry. Also, I don't know anything about him beyond what I can guess from reading two of his books, both of which I suspect are vaguely autobiographical. Debby plausibly describes what the inner life of a person with intellectual disability might look like. However I liked the short stories in the collection The Hat of My Mother even more, and it's one of the best books I've read all year. Hat tip to my mother for recommending this one to me.

Because of where and when they're set (1930s South), Steele's books reminded me of one of my all-time favorite novels: Look Homeward, Angel by Thomas Wolfe.

Mary Beard in SPQR provides an overview of the history of ancient Rome from its founding to the first century AD. She clearly knows her stuff and I learned a lot (for example I wasn't aware how much the Romans where sticklers for the rule of law), but I can't say I enjoyed the book because her prose is a little dry. If you're interested specifically in what ancient Rome can and can't teach us about what's going on with America, I highly recommend Vaclav Smil's Why America is Not a New Rome.

I picked up a copy of Vince Flynn's thriller Act of Treason that another passenger had left behind when deboarding a plane. It's a rather entertaining action novel starring the all-American CIA operative Mitch Rapp, giving some terrorists what he thinks they're deserving (death in most cases). The blurbs make it obvious who the intended audience is: Glenn Beck thinks it's "Captivating", Rush Limbaugh thinks it's "Just fabulous" and Bill O'Reilly thinks that "Every American should read this book". One good thing that came out of doing just that was that it made me avoid the Mitch Rapp movie that recently came out. Thanks Bill.

The central thesis of Iron John by Robert Bly is that men don't do themselves or society any favors by repressing their wilder side. Iron John contains some interesting ideas, but its central contradiction is that it massively, comically overthinks what it means to "be a man".

More reviews to come soon.

January 12, 2017

Which scientific concepts ought to be more well know?

The answers to John Brockman's annual question on Edge are always worth reading. This year, the question was which scientific concepts ought to be more well know. If you haven't done so already, I recommend that you take a look at what the more than 200 contributors thought here.

With all those excellent essays, what resonated with me most were a handful that emphasized the importance of humility, not only in science, but in societal discourse more generally.

For example, Barnaby Marsh writes:
You might not think of humility as a scientific concept, but the special brand of humility that is enshrined in scientific culture is deserving of special recognition for its unique heuristic transformative power ... Scientific humility is the key that opens a whole new possibility space -  a space where being unsure is the norm; where facts and logic are intertwined with imagination, intuition, and play
Oliver Scott Curry:
Fallibilism is the idea that we can never be 100% certain that we are right, and must therefore always be open to the possibility that we are wrong ... Fallibilism is also the guiding principle of free, open, liberal, secular societies
Nicholas G. Carr:
if our intellect is bounded, we can never know how much of existence lies beyond our grasp
And finally Sam Harris:
Our scientific, cultural, and moral progress is almost entirely the product of successful acts of persuasion. Therefore, an inability (or refusal) to reason honestly is a social problem. Indeed, to defy the logical expectations of others -to disregard the very standards of reasonableness that you demand of them - is a form of hostility.
Do read the whole thing though.

November 16, 2016

What should non-geneticists know about genetics?

There are things that geneticists hardly ever mention when talking to their non-geneticist collaborators, probably because they take them for granted. Stating them explicitly may be helpful for those of you who frequently work with geneticists. I'm assuming that you already know a little bit about genetic variants and association studies.
  1. When it comes to genetic association studies such as GWAS, correlation really is causation. If a genetic variant is associated with a trait, it or a variant close to it causes the trait, assuming it's not a spurious correlation. Because DNA is read-only, it's not possible that the trait causes the variant. This makes genetics different from e.g. gene expression analysis, where the arrow of causation can point both ways. A differentially expressed gene can cause a disease, but the disease can also cause genes to be up- or downregulated. Typically, you have to do follow-up experiments to determine what's going on. Not so in genetics.
  2. Genotyping isn't sequencing. Frequently, people will say something like, "we have sequenced those samples" when they were really genotyped on a chip. The difference is that genotyping chips are cheap ($200 or less per sample) and typically produce data on several hundreds of thousands of known genetic variants. Sequencing is more expensive (more than $1,000) and produces data on almost all the variants in the genome, including those that haven't been observed before. Unlike genotyping chips, sequencing also delivers data on structural variants such as insertions, deletions and copy number variation.
  3. Knowing the causal variant isn't the same than knowing the causal gene. Most of the human genome isn't coding for genes, and it's not clear what it actually does, or if it does anything important at all. The majority of variants that have been associated with traits and diseases are not located in the coding parts of genes either. For those variants it's difficult to tell how they exert their effect. Some that are known to change gene expression are called expression quantitative trait loci or eQTLs. For those variants that aren't eQTLs, people often assume that one of the genes that are encoded in their vicinity is the causal one.
  4. Knowing the gene isn't knowing the effect direction. Even if you know through which gene a variant exerts its effect, you still don't know in which direction the effect goes. Take the example of a genetic variant that has two alleles, G and T. Assume the G allele is the risk allele for a disease, and it's located in the intron of a gene. This does not immediately tell you if decreased gene function is associated with higher or lower disease risk. Again, eQTLs come to the rescue, as they will tell you if the risk allele is associated with higher or lower gene expression, which are reasonable proxies for increased and decreased gene function, respectively.
  5. Genotypes are discrete, phenotypes often aren't. A genetic variant typically has several genotypes. The example variant from the previous paragraph with the two alleles G and T will, in a diploid organism like humans, have three genotypes: G/G, G/T and T/T. It may therefore be tempting to assume that genetic variants are great biomarkers, as they will unambiguously show if the trait associated with the variant is present or not, maybe with heterozygotes being something in between. Unfortunately, this is often not the case, especially for complex diseases that have many variants associated with them. Each of these variants contributes to disease risk only a little bit, and as a result, individual variants aren't very informative.

There's more, but this post is already too long, so I'll save it for another time.

November 10, 2016

Is a third party candidate the solution?

This election was ugly, and the next four years are going to be traumatic. But America will get through them.

Even if Clinton had won, the election would have left scars. Just as Trump is strongly opposed by a portion of the country, she would have been hated by a different portion. True, that portion would not have had a rational reason to be as terrified as many Democrats are now, but that doesn't mean that their views don't count.

Repeating a campaign like this in four years wouldn't do anyone any favors and contribute nothing to healing the divides. But for any campaign that involves a Democrat running against Trump in 2020, this is what would happen.

Trump has said that he's going to erase the achievements of the Obama administration, and half the country already loathes him. I can't see how a Democrat replacing Trump in four years wouldn't be loathed by his supporters in turn. A large part of the country hating their president, no matter their motivation, and each president trying to erase what the one before them has done, cannot be a healthy state of affairs.

But what if someone who is not particularly objectionable to either camp were to run as an independent candidate? They would get the support of Republicans who stood up to Trump, of moderate Democrats, and of course of independent voters. And most importantly, they would break out of the self-reinforcing cycle of partisan hatred that casts its shadow over America.