Saturday, July 16, 2016

Animals Use Their Genes Differently

Distal/distant enhancers really only took off in the animal lineage of eukaryotes.

Only 21,000 genes? What a paltry inheritance we have as humans. That is only twice the number of the honeybee, and three times that of yeast cells. How can a complicated, high-maintenance animal like us get by with so little genetic material? Much of the answer lies in how we use our genes, not in how many we have. There has been an explosion of regulatory complexity, even as there has been such a modest rise in the number of genes, from more humble species.

Evolutionary tree over eukaryotes, showing animals at the bottom, and Filozoa, which contain Capsaspora, nearby.

A recent paper discussed the genetic contents of a eukaryote called Capsaspora, which is thought to be sort of the last stop among the protists before we get to the multicellularity of animals. Not much is known about the filastereans, of which this species is a member, other than that in molecular terms, they are among the very closest eukaryotes to metazoans, while still being single-celled. But they are branching out, so to speak, with their filamentous processes and amoeboid form. They are parasites, (or symbionts), a bit like malaria, infecting the blood of a certain freshwater snail.

Its genome is only 28 megabases, compared to 3 gigabases for humans, so much more compact. And its count of genes is about 8,700, on par with yeast cells. The prior paper on its genome also points to a gradual increase through these lineages of new protein domains that become prominent in animals, like G-protein signalling components, cell-cell adhesion, meiosis, and developmental transcription factors. It has recently been reported to have a limited multicellular aggregation stage, when grown under agitating conditions, accounting for some of these evolutionary developments.

Capsaspora, in all its glory.

Nevertheless, these are not animals, and the authors asked what the genomic differences are that seem most relevant to the distinction. Given the large disparity of genome size, and relatively small difference in gene numbers, it seemed reasonable to look at the intergenic regions, where animals have a great deal of regulatory apparatus, not to mention junk DNA. This is where animals have enhancer cassettes that bind various transcription regulators, all of which loop around to cooperate with regulators bound at the promoter, the region directly around the transcription start site. Enhancer cassettes can come at many distances from their target gene, up to megabases away, and in many iterations, used alternately or combinatorially to drive gene expression in various developmental or inducible settings.

The authors, after having sequenced the genome of this organism previously, mapped regulatory regions all over using state-of-the-art techniques. And the upshot, as diagramed below, is that the upstream regions are indeed quite different in these organisms. Capsaspora has very little distal/distant intergenic regulatory matter (the green slice of the pie), while humans have vast amounts. Ditto for regulatory sites downstream (3' UTR) and in internal introns (intron, non-1st). Naturally, given the small genome size, coding sequences (tan or orange) take up one-third of the Capsaspora genome, but only a tiny 1% of the human genome. And the regulatory sites that Capsaspora does have are smaller, covering only 74 bases on average per gene, compared with 60 bases in humans.

Main findings, showing the dearth of distant enhancers (B; green) and the small size of regulatory elements (A) in Capsaspora, compared to its bigger relatives.

This is the evolutionary story in a nutshell. Growing new tissues and complex modes of cell-cell cooperation (and even brains!) doesn't take a lot of new material. Rather, it all uses cells- gussied up in many instances, but still basically eukaryotic cells- whose genes are put under tremendously more complex regulatory regimes so that these cells can be and do novel things in the thousands of new environments that multicellular organisms create internally.

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