Essays on Science and SocietyGenome-Sequencing Anniversary

The Genomic Foundation Is Shifting

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Science  18 Feb 2011:
Vol. 331, Issue 6019, pp. 874
DOI: 10.1126/science.1203703

For me, the most important outcome of the human genome project has been to expose the fallacy that most genetic information is expressed as proteins. The biggest shock was that the number of conventional genes, despite some lineage-specific expansions and occasional innovations, does not scale with developmental and cognitive complexity: Humans and other vertebrates have only about 20,000 protein-coding genes, a similar number with functions largely similar to those in nematode worms that have just 1000 somatic cells. There have been several aftershocks: In contrast to protein-coding genes, the extent of noncoding intronic and intergenic sequences increases markedly with complexity; only 1.5% of the human genome encodes proteins. Subsequent tremors include the findings that the vast majority of the mammalian genome is dynamically transcribed in a developmental stage- and cell type–specific manner to produce huge numbers of noncoding RNAs and that the extent of the genome imputed to be functional by this measure and others, such as chromatin modifications, is far greater than that suggested by analyses of sequence conservation based on circular assumptions about the nonfunctionality of transposon-derived sequences. These observations suggest that we need to reassess the underlying genetic orthodoxy, which is deeply ingrained and has been given superficial reprieve by uncritically accepted assumptions about the nature and power of combinatorial control. As Nobel laureate Barbara McClintock wrote in 1950: “Are we letting a philosophy of the [protein-coding] gene control [our] reasoning? What, then, is the philosophy of the gene? Is it a valid philosophy?” … There is an alternative: Human complexity has been built on a massive expansion of genomic regulatory sequences, most of which are transacted by RNAs that use generic protein infrastructure and control the epigenetic mechanisms underpinning embryogenesis and brain function. I see the human genome not simply as providing detail, but more importantly, as the beginning of a conceptual enlightenment in biology.

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