ratz.jpgSaw Ratatouille today. Never once checked the time. Very good film. So far Yahoo Movie critics & users give it an A-, and it seems like it’ll win the box office. Much recommended (Pixar animation is the bomb obviously, but the story is really good and could only be told in a non-live action context for obvious reasons). This is a movie whose target audience are children and foodies, so definitely a strange and surprising beast. A flavor you won’t forget.

Genome transplantation in bacteria

The folks at the Craig Venter Institute, having patented the technology for creating a synthetic organism, now have at least part of the process working: they report that they can take an entire bacterial genome from one organism and pop it into another, essentially “re-booting” the cell as a new species. The next step, obviously, is to synthesize a custom genome that does something you find worthwhile (digests some nasty chemical, if you’re feeling eco-conscious…or produces a nasty chemical, if you’re feeling more war-like), and create your own bacteria.

One interesting thing (from a methodological standpoint) about this procudre is that it appears to involve inducing the fusion of the two cells (the researchers don’t actually know; they just see the outcome), making it somewhat similar to procedures for creating hybrid cell types in mammals. It’s something of an unexpected connection between bacterial transformation and cell fusion.

Structural variation in humans

Nature Genetics has a free supplement on structural variation, with an emphasis on its role in human disease. Nothing too exciting– structural variation is simply a type of polymorphism, albeit with some interesting issues regarding detection, but if you’re looking for some background and discussion of future directions, it might be of interest.

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Genome-wide association study for breast cancer susceptibility

Another genome-wide association study:

Breast cancer exhibits familial aggregation, consistent with variation in genetic susceptibility to the disease. Known susceptibility genes account for less than 25% of the familial risk of breast cancer, and the residual genetic variance is likely to be due to variants conferring more moderate risks. To identify further susceptibility alleles, we conducted a two-stage genome-wide association study in 4,398 breast cancer cases and 4,316 controls, followed by a third stage in which 30 single nucleotide polymorphisms (SNPs) were tested for confirmation in 21,860 cases and 22,578 controls [!!!] from 22 studies… SNPs in five novel independent loci exhibited strong and consistent evidence of association with breast cancer (P < 10-7). Four of these contain plausible causative genes (FGFR2, TNRC9, MAP3K1 and LSP1).

These alleles are of small effect and in areas of the genome about which little is known, again showing that genome-wide association studies are a powerful way of opening up research into novel biology.

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Reanalysing gene expression differences between populations

Early this year, I commented on a paper showing large differences in gene expression between Europeans and Asians. A letter to the editor in this week’s Nature Genetics points out a major flaw in part of their analyses.

Expression arrays are tricky tools– they don’t provide a measure of absolute mRNA levels, but rather an output that corresponds to the binding affinities of the mRNA, the ambient conditions, the way the mRNA was handled, and absolute mRNA levels (and a billion and one other things). Study design is extremely important in isolating the effect of the variable you’re really interested in (mRNA levels), and it’s very difficult, if not impossible, to really compare the raw data from one array experiment with that from another.

The error the authors made is an unfortunate (and pretty elementary) one– they did the array experiments on the Europeans population in 2003-2004, and the array experiments on the Asian population in 2005-2006 (they actually erroneously claimed the samples were randomized with regard to year in the paper, which would explain why it got past peer review). This means that any variation between the European and Asian populations is perfectly confounded with variation between those two batches. There’s no way to correct for this; any difference in mean expression between the two populations is due to a mixture of the “real” effects and the bias from the batch effect. That’s a bitch.

Luckily, the authors also did additional analyses (as they point out in their reply)– they looked at the correlation of expression levels with genotypes. In the figure, you see the population distributions of expression for a given gene on the left, and the within-genotype levels on the right. There doesn’t seem to be much of a differences between the two populations within each genotype class, but the population difference is explained almost entirely by the difference in allele frequency between the two populations.

So was their claim of finding nearly 25% of all genes differentially expressed between the two populations likely wrong? Yes. But their conclusion that allele frequency differences play a role in expression differences between populations stands– it will just take a better-designed study to quantify the effect.

Domestication of humans by the cat

kitten.jpgThere’s a paper to be published on domestic cat phylogenetics in Science tomorrow. National Geographic has a summary, but Forbes has a more thorough treatment. The short of it is that the maternal lineages (mtDNA) of domestic cats seem derived from the Near Eastern varieties . The acculturation of humanity toward domestic cats seems to have taken place gradually between 12,000 and 3,600 years ago, the presence of five distinct maternal lineages suggests that it wasn’t one event, but several simultaneous parallel ones. Sedentary populations rooted around agriculture were the likely necessary environment for the emergence of the cultural co-evolution between cats and humans. Though this study is interesting, please note that the survey of female lineages is a small slice of the total ancestry. Male mediated hybridization wouldn’t be picked up, and the interfertility of domestic and wild cats means there likely has been genetic exchange between the two groups over time.
Update: Nick Wade in The New York Time has more.

Coeliac disease – gluten intolerance

A comment below about gluten intolerance (which is associated with problems digesting products with wheat) made me curious. In much of Eurasia this would be a serious problem since wheat is the staff of life. Hard numbers are difficult to come by. This is as good as anything else I’ve seen:

Celiac disease affects as many as 1 in 300 people in Italy and southwestern Ireland, but is extremely rare in Africa, Japan, and China…According to a multicenter study in 2003, there is a 1 in 133 chance that people with no risk factors or family history in the U.S. have celiac disease. Additionally, a person’s risk increases to a 1 in 22 chance if they have a first-degree relative with celiac disease and a 1 in 39 chance if they have a second-degree relative…Around 60,000 Americans are diagnosed with celiac disease annually and a total of over 2 million have the disease, making it perhaps the most common genetic disorder in the United States…Celiac disease can occur at any age, and females are more commonly affected than males. Of females presenting during their fertile years, the male to female ratio is almost 3 to 1….

From Wiki:

The vast majority of coeliac patients have one of two types of HLA DQ, a gene that is part of the MHC class II antigen-presenting receptor (also called the human leukocyte antigen) system and distinguishes cells between self and non-self for the purposes of the immune system. There are 7 HLA DQ variants (DQ2 and D4 through 9). Two of these variants-DQ2 and DQ8-are associated with coeliac disease. Every person inherits two copies, one from each parent. The gene is located on the short arm of the sixth chromosome, and as a result of the linkage this locus has been labeled CELIAC1.

Coeliac disease shows incomplete penetrance, as the gene alleles associated with the disease appear in most patients, but are neither present in all cases nor sufficient by themselves cause the disease. Over 95% of coeliac patients have an isoform of DQ2 (DQA1*0501:DQB1*0201 haplotype or more simply DQ2.5) and DQ8 (DQA1*0301:DQB1*0302), which is inherited in families.

Incomplete penetrance might be due to the fact that there are other genetic actors which haven’t been elucidated that are necessary for the emergence of this syndrome. Or, there might be environmental or pathogenic triggers which only affect a minority with the necessary genetic predisposition. But in any case, my first thought was gluten intolerance might be the result of an incomplete selection sweep as populations shifted from hunter-gatherer lifestyles to agricultural ones. I’m skeptical of this since populations in Africa and Australia which don’t have a history of wheat agriculture don’t exhibit this syndrome. Additionally, though wheat agriculture is practiced in north China this was originally a region of millet production. Finally, all the reports suggest massive underestimates of the extent of this condition within the population. Like lactose intolerance this isn’t a disease with a clean set of symptoms which are easy to assay quantitatively (is there a way a metric for stool firmness?). The implication of MHC loci as necessary preconditions makes me wonder if gluten intolerance is simply a low frequency condition which is a byproduct of a disease adaptation on the genes in question which was operant in western Eurasia.