Although separated by hundreds of millions of years of evolution, flies, worms, and humans share ancient patterns of gene expression, according to a massive Yale-led analysis of genomic data.
Two related studies led by scientists at Harvard and Stanford, also published Aug. 28 in the same issue of the journal Nature, tell a similar story: Even though humans, worms, and flies bear little obvious similarity to each other, evolution used remarkably similar molecular toolkits to shape them.
However, the same Yale lab reports in a separate paper published in the Proceedings of the National Academy of Sciences dramatic differences between species in genomic regions populated by pseudogenes, molecular fossils of working genes.
The human, worm, and fly genomes are all composed of the same building blocks (i.e. nucleotides) but differ greatly in size. The human genome, for instance, is more than 10 times larger than those of the worm and fly. However, the three have comparable numbers of functioning genes that code for proteins. Even more striking, note the researchers, the three share many expression programs turning genes on and off in a coordinated fashion. The gene expression patterns were so similar, in fact, that investigators were able to use them to match up the stages in worm and fly development.
“It is remarkable to find these similarities across a half billion years,’’ said Mark Gerstein, the Albert L. Williams Professor of Biomedical Informatics at Yale and senior author of one of the Nature papers. “It also illustrates how studying model organisms can help us to annotate the human genome.”
The study — spearheaded by members of the Gerstein Lab, including Joel Rozowsky, Koon-Kiu Yan, Daifeng Wang, Baikang Pei, and Arif Harmanci — looked at patterns of transcription, the process by which information encoded in DNA is transferred to RNA. The paper also reported that the control of this process by the packaging of DNA is very similar in all of the organisms. In fact, the authors were able to build a quantitative model of transcription for humans and then successfully apply it without alteration to the fly and worm.
More than 200 scientists from dozens of institutions contributed to this effort, which is collectively part of the ENCODE genomics consortium. The resulting papers published in Nature all tell similar stories of shared evolution between species — for instance, the commonalities of regulatory networks of genes and the transcription factors that control their activation.
“When we look at flies or worms, it is difficult to believe that humans have anything in common with them,” Gerstein said. “But now we can see deep similarities in them that better help us interpret the human genome.”
Stark differences emerged, however, when Gerstein’s lab looked at pseudogenes — stretches of DNA that have lost their original protein-coding gene function and are no longer under strong selective constraint, effectively representing molecular fossils. In the Aug. 25 issue of the Proceedings of the National Academy of Sciences, the Yale scientists reported vast differences between organisms in terms of these fossils, reflecting the divergent evolutionary histories of flies, worms, and humans.
“On one hand, we saw similarities that reflect biological necessity and, on the other hand, differences that mirrored the organism's history,” said Cristina Sisu, postdoctoral fellow in Gerstein's lab and the first author of the pseudogene study.
The work was funded by the National Human Genome Research Institute.