biolog

A piece in the recent issue of Science runs with a captivating title: It’s the Sequence Stupid!. Also a bad joke considering the research model discussed is Down Syndrome. Anyway, according to work done on transgenic mice with Down Syndrome, the authors say,

[Wilson et al.,] findings also call into question one of the basic tenets of comparative genomics: that evolutionary conservation can serve as the primary tool for finding functional sequences [and] although many conserved noncoding sequences are functional, and interspecies comparisons can help us to identify these motifs, narrowing our attention only to these sequences must result in an incomplete understanding of the regulatory code. Indeed, this approach guarantees missing the species-specific regulatory instructions that make us different from mice.

So, what did they find? The researchers gifted a cohort of mice a few genes, the entire human 21 chromosome, relying on the mouses regulatory regions to govern them. They sat back and observed. Their tests showed that the regulatory mouse regions not only understood the foreign chromosome, but, in a way, honored its human integrity by incorporating it into mouse cells. Maybe all this tells us is that mouse and man are not that dissimilar. What about fish and human?

The Fugu hematopoietic transcription factor gene, Lck (Lymphoctye tyrosine kinase), is 4.2 kb, (twenty times shorter than its human ortholog), but apparently all the important stuff for this gene is functionally the same between teleosts and mammals. Fugu, like e. coli, keep a tidier sequence than most mammals, which is why theirs is often the preferred promoter element for regulating T cell activity in mouse models, despite some amino acid differences. The two promoters for Fugu Lck are only 2.3kb away from the coding region, whereas in humans, the proximal promoter is 40kb from the start of transcription. That’s not very proximal if you ask me, and makes me wonder how the hell they alighted on the sequence in the first place. Good work whomever!

Still, only a quarter of the entire Fugu gene (830 bp) is required to regulate human T cell maturation (in Jurkat cell lines). The obvious answer, then, is that the proximal and distal Lck promoters in Fugu are similar enough to human to regulate production of human LCK proteins, implying that this teeny stretch of non-coding DNA has been conserved in teleosts and mammals for 400 million years. Well, it must be useful.

The authors of the Science piece argue that they stumbled upon a highly conserved yet-to-be-deciphered genetic grammar somewhere in the transcriptional region that enables a mouse cell to read direct human genetic sequences. What about other closeley related species, or distant relatives, such as gator and girzzly? Their recommendation is ENCODE and more bioinformaticists.

Armed with this paper, Larry Moran shakes it like a stick at the evo-devo crowd and the cis-elements they rode in on.