The structure of genomes, both spatially in the nucleus and syntenically on the chromosome (not that the two can necessarily be separated), is certainly one of the large problems in biology which is going to be addressed in the next decade. What's most exciting about this problem, at least, is it tractability on both a genetic and biochemical level (something, perhaps, evocative of the old problem of the cell cycle, tackled somewhat in tandem prominently by, among many others, Paul Nurse, Tim Hunt, and the local hero: Leland Hartwell).

My gut feeling is that transvection is the first loose thread to the Leviathan's unravelling. It's an effect that was first characterized by Lewis at Caltech over fifty years ago. That is, genetic complementation is easy enough: suppose I have a complementing transheterozygote organism for gene A--that is, the phenotype of the two mutant copies, A*A', is (roughly) the same as the wild type, AA. Usually, with complementation, the locus doesn't matter. That is, if I put A* under its endogenous promoter in one location in the genome, and A', also with its endogenous promoter, in a different locus, it would the same as if I were to put A in the first locus, and A in the second, heterologous locus.

But that's where's transvection turns weird: location matters for transvection (otherwise described as locus-specific complementation). Even weirder, the pairings of A' and A* are surprisingly specific (i.e., one mutation is usually in cis- regulatory regions, while another is in the open reading frame). The prevailing theory, of course, is that the cis regulatory elements of the allele impaired in the open reading frame are able to compensate for the deficiencies of the allele deficient in the cis regulation. I.e., the cis elements are actually working in trans.

But I feel like I've glossed over the punchline too quickly: locus specific complementation. As it turns out, there's remarkable specificity as to the locus of these things. Let me be a bit more specific: in order for cis elements to work in trans, there has to be some sort of pairing of the two copies of the genes. Of course we knew that this happened on some levels. In functional cells, usually, we see chromosomes line up with exquisite accuracy, locus for locus.

I argue transvection is even deeper than all that. It argues chromosomal/nuclear structure not only during condensation, but potentially also during decondensed function--that homologous pairs stay paired together even when they're not ready to divide.

The story, of course, gets richer: not all organisms seem to do this. The fruit fly Drosophila melanogaster and the fugus Neurospora crassa definitely seem to do this, D. melanogaster at a few characterized loci, with many different alleles for each loci, as far as I know. As of now, these seem to be the only two organisms (although, that's probably not correct).

Of course, we seem doomed: Saccharomyces cerevisiae, the blue-eyed hero of eukaryotic molecular biology in the twentieth century seems not to do this. In fact, other ascomycetes seem to have failed us. Candida albicans, the diploid whose asexuality has caused homologous copies of its genes to drift apart in homology seems also not to give us any insight on this field.

C. albicans, as a matter of fact, seems to almost vehemently argue against any sort of nuclear organization: tetraploid C. albicans (as a result of the rare event of mating) will, seemingly, lose chromosomes at random until it remains with its diploid number, regardless of any aneuploidy for its chromosomes. Which is interesting in itself: it knows how many chromosomes it's supposed to have, only not which ones its supposed to have.

And D. melanogaster seems to have failed us too: it's still early days for targeted ends-out transgenesis in the fruit fly, and until then (and potentially selection mechanisms, as opposed to screening through thousands of these flies, too) transvection genetics seems fairly doomed with this organism, with, of course, notable exception.

But perhaps I'm silencing the pianos too soon: transvection is a tantalizing genetic vision as to the potential genetic organization of the nucleus, and, one would argue, given recent insights into aneuploidy and regulation of gene numbers in normal cells versus tumorigenic cells, a glorious example of the underlying genetic principles behind cancer.

For those of you who missed it, conductor Daniel Barenboim, on June 17th, gave his final performance with the CSO.

There's a discussion here that needs to happen--one about who's next, and where the orchestra's going (comments, of course, are open)--but can't as hastily as this post is being written. Andrew Patner, long ago, had some insight when Barenboim first announced this.

Briefly, however, it's interesting to see the changes in Barenboim's reception: after Solti, it seemed that Barenboim would have big shoes to fill, and--if memory serves correctly (both New York Times and New Yorker say it does), his inception was less than enthusiastic.

The changes he's brought about certainly are welcome, and it's good to see his final concerts win such acclaim. But now the question which haunts us all: what next?