Author Archive

How much of the genome is transcribed? Or, the utility of a good genome browser

Recent genome-wide association studies have identified a large number of non-genic regions associated with disease risk; the standard interpretation of this observation is that these are regions involved in gene regulation. A few years back, though, another possibility was raised: what if there are simply a large number of genes in the human genome that […]

Genome-wide association studies work

A few months ago, I mentioned an article in Cell arguing that many results of genome-wide association studies are false positives. This is obviously wrong, and this week, a pair of letters to the editor (including one by Kai Wang summarizing arguments he made in various comment threads here and elsewhere) take the authors to […]

Is the “missing heritability” right under our noses?

One of the major criticisms leveled against genome-wide association studies for complex diseases is that they have identified loci which account for a relatively small proportion of the variance in most traits. The difference between this small proportion of variance explained by known loci and the (generally large) total amount of variance known to be […]

The Times on the human genome at 10

Two articles in the New York Times this week revisit the promises made 10 years ago about how the sequencing of the human genome would revolutionize medicine (and how, obviously, it has not). There are things to quibble about–I could go on again about how some of the arguments against genome-wide association studies are silly, […]

The importance of rare variants in common diseases

In a couple recent posts (and, I remember thanks to google, at least one very old–in internet years–post), I’ve pushed back against criticisms of genome-wide association studies using SNP genotyping arrays. This is despite the fact that I agree it’s clear that rare variants contribute to common diseases, and that sequencing technologies are eventually going […]

How do non-genic polymorphisms influence disease risk?

I think it is probably (or should be) an uncontroversial statement to say that recent genome-wide association studies have revolutionized our understanding of the molecular basis of variation in disease risk in humans. From a handful of polymorphisms reliably associated with a few diseases, there are now hundreds of such associations for a wide spectrum […]

Common versus rare variants, again

A commentary published this week in the prestigious journal Cell is the latest salvo in the rare variants versus common variants “debate” (see my overall thoughts on this topic here). The commentary contains a number of false claims (ie. many SNP-disease associations found to date are false positives due to population structure) and non sequiturs […]

Natural selection and recombination

Razib has a nice discussion of an interesting observation just published in PLoS Genetics– that there is a negative correlation between recombination rate in the human genome and population differentiation. This observation, along with the complementary observations of correlations between nucleotide diversity and recombination and between nucleotide diversity and density of functional elements, form part […]

Rare variants versus common variants in complex disease is a political, not a scientific, debate

There’s been a recent uptick in interest in the genetic architecture of complex traits (by which I mean the allele frequencies and effect sizes of the relevant loci), some of which has been driven by a much-hyped recent paper from David Goldstein’s group pointing out using simulations that, as one commenter put it, “LD exists”. […]

How long before the Y is incorporated into association studies?

I’ve been reading Sperm Biology: An Evolutionary Perspective; an engaging comparative look at, well, sperm biology. One fairly remarkable thing to me is that, while sperm evolve incredibly rapidly in morphology (at one point in the book, the claim is made that just about any animal can be distinguished visually by sperm cells alone[1]), the […]

Defining “synthetic associations” down

David Goldstein and collegues report today the results of a genome-wide association study for a particular side effect (treatment-induced anemia) of treatment for hepatitis C. It turns out that variants in a single gene–ITPA–are overwhelmingly associated with the development of this side effect. This is a nice, probably clinically-important result, and there’s likely some interesting […]

Small genetic effects do not preclude drug development

Daniel MacArthur points me to a Newsweek article on the bankruptcy of Decode Genetics. The author describes (one of) Decode’s problems like this: The genetics of illness turned out to be more complex than researchers expected. At deCODE and elsewhere, the new genes linked to common diseases turned out to be rare or to have […]

Homo erectus and EDAR?

In Why Evolution is True, Jerry Coyne has the following parenthetical aside about population variation in morphology in H. erectus: (H. erectus from China…had shovel-shaped incisor teeth not found in other populations) This stopped me dead in my tracks: modern East Asian populations have similar tooth morphology, caused in part by a positively-selected nonsynonymous change […]

“Synthetic associations” and sickle cell anemia

Last week, I made a silly error in describing a problem in the sickle cell anemia example given by Dickson et al. (2010) as an empirical example of the phenomenon they call “synthetic association”. So allow me to take a mulligan, and re-try this:The authors performed an association study in African-Americans, using ~200 individuals with […]

A bold prediction: “synthetic associations” are not a panacea

There’s a bit of press surrounding the interesting result from David Goldstein’s group that, in certain situations, a number of “rare” (defined as an allele frequency less than 5% [1]) variants influencing a trait can lead to an association signal at “common” SNPs. This phenomenon they authors call a “synthetic association”. The authors claim this […]

Localizing recent positive selection in humans using multiple statistics

Online this week in Science, a group presents a method for identifying genes under positive selection in humans, and gives some examples. I have somewhat mixed feelings about this paper, for reasons I’ll get to, but here’s their basic idea:Readers of this site will likely be familiar with genome-wide scans for loci under positive selection […]

PRDM9 and the evolution of recombination hotspots

This week in Science, three papers report that the product of the gene PRDM9 is an important determinant of where recombination occurs in the genome during meiosis. Though this may sound like something of an esoteric discovery, it’s actually pretty remarkable, and brings together a number of lines of research in evolutionary genetics. How so? […]

Mutation and selection in stickleback evolution

Understanding the precise molecular mechanisms underlying changes in animal morphology is a tricky problem–usually two species which have diverged morphologically (say, mice and humans) are now so unrelated as to make genetic study exceedingly difficult, if not impossible. For years, a group led by David Kingsley has been addressing this problem in a cleverly-chosen model–three-spined […]

Interpreting genetic association studies

There has previously been some discussion on this site about the failure of past candidate gene association studies for identification of genetic variants that truly influence a phenotype. Much of this involved discussion of the interpretation of p-values in this context (for example, see this thread). Nature Reviews Genetics has just published a must-read review […]

The randomness of model organisms

I thought I’d point quickly to a really nice paper showing that the RNAi pathway, thought to be absent in budding yeasts, is actually only missing from baker’s yeast, Saccharomyces cerevisiae. Remarkably, the authors are able to reconstitute the pathway (which was presumably present in the ancestor of all budding yeasts) in S. cerevisiae with […]

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