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A stretch of DNA (Image credit: Wikipedia)Humans and chimpanzees famously share more than 98% of their genome and yet the two species look and behave quite differently.  This apparent paradox stretches well beyond our little corner of the tree of life; we share more than half our genes with chickens and those we share are 75% identical.  Two studies published together in the December issue of Science tackled this perplexing discrepancy by showing that there may be more to a genome than meets the eye.

The genes that make up our DNA carry the information to build and operate our bodies, but the actual work is done by proteins. Our genes simply encode proteins, carrying their blueprint so they can be assembled by the molecular factories in our cells. To make a protein, the blueprint is first copied from the DNA into a molecule called an mRNA; this copy is then processed in various ways before being sent to the factories. Some of this processing regulates how and when the final assembly happens. Another kind of processing, called splicing, involves building different proteins from a single blueprint. This is possible because the genetic blueprints contain subunits which can be combined to make different proteins.  Two teams of international researchers investigated how the splicing process has changed during vertebrate evolution to allow very different creatures to be made from relatively similar genomes.

To understand how a single gene can encode several proteins, let’s take the analogy of a sentence. You might think about a particular sentence (such as “Drew accidentally brought the wrong math book.”) before actually saying it; this potential utterance is the information encoded in the gene. The final meaning of the sentence will depend on which subunits are included when you say it aloud. Some words (like “brought”) are essential to the sentence — without a verb of some kind, it no longer works as a sentence. Other words are important but not critical; removing “the” results in the clumsy but still comprehensible “Drew accidentally brought wrong math book.” Finally, there are modifiers like “accidentally” and “wrong”; removing one or both of these words leaves the sentence intact but fundamentally alters its meaning. In the same manner, splicing together combinations of subunits from a gene creates different proteins, some of which might function differently while others might stop working altogether.

The researchers were able to investigate the frequency of these different variants using modern sequencing technology. Just as we can sequence the DNA from an organism to get its genome, we can sequence all the mRNA to get the transcriptome, the collection of all the variants of the different genes that are active.  By analyzing the transcriptomes of several organisms or even several organs from the same organism, it’s possible to figure out which genes are more or less active and which specific variants are present in each organ or organism. The team sequenced and compared the transcriptomes of the brain, liver, heart, kidney and testes of nine different vertebrate species and used a statistical method called clustering to group the genes based on similar patterns of activity or splicing.

When they clustered the genes in the transcriptome according to how active each was, the team found that the genes formed groups corresponding to the organs. In other words, the same genes are expressed at more or less the same levels in the heart of a chicken as in the heart of a human or frog despite the differences between the three species. Of course, some similarity was expected since each organ remains similar across the different species and continues to perform the same function, but these results didn’t provide an explanation for the differences between the species. To understand the basis of this, the researchers had to turn to the differences in splicing.

When the transcriptomes were clustered according to the splicing patterns — that is, what versions of each gene were active — they grouped according to species. When compared on the basis of how they get spliced, genes from a chicken heart or kidney look more similar to each other than either does to those from a human heart. Splicing a single gene into several different proteins seems to have become more common in the evolution of primates, particularly in genes that are active in the brain. Many of the splicing changes were predicted to affect how the resulting protein would interact with other proteins. A second study focused on the transcriptomes of mammals also found genes grouping by species when compared according to their splicing; however, this study also detected a group of genes from the brain with similar splicing patterns, which might be an indication that changes in splicing were important in the evolution of the mammalian brain.

Thanks to the use of modern sequencing technology and statistical techniques, these researchers were able to address the important question of how species develop differently despite their genetic similarity. While it has generally been assumed that this was due to differences in gene activity levels, these two studies showed that, in fact, gene expression doesn’t distinguish organs from different species. Based on their findings, the researchers suggest that many differences between species may have resulted from changes in how genes are spliced into different proteins, which may have been an important factor in vertebrate evolution over the last 350 million years, particularly in the evolution of mammals and the mammalian brain.

Refs
Barbosa-Morais, N., Irimia, M., Pan, Q., Xiong, H., Gueroussov, S., Lee, L., Slobodeniuc, V., Kutter, C., Watt, S., Colak, R., Kim, T., Misquitta-Ali, C., Wilson, M., Kim, P., Odom, D., Frey, B., & Blencowe, B. (2012). The Evolutionary Landscape of Alternative Splicing in Vertebrate Species Science, 338 (6114), 1587-1593 DOI: 10.1126/science.1230612

Merkin, J., Russell, C., Chen, P., & Burge, C. (2012). Evolutionary Dynamics of Gene and Isoform Regulation in Mammalian Tissues Science, 338 (6114), 1593-1599 DOI: 10.1126/science.1228186

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