What is a gene?

Now: The Rest of the Genome
by Carl Zimmer

In this jungle of invading viruses, undead pseudogenes, shuffled exons and epigenetic marks, can the classical concept of the gene survive? It is an open question, one that Dr. Prohaska hopes to address at a meeting she is organizing at the Santa Fe Institute in New Mexico next March.

In the current issue of American Scientist, Dr. Gerstein and his former graduate student Michael Seringhaus argue that in order to define a gene, scientists must start with the RNA transcript and trace it back to the DNA. Whatever exons are used to make that transcript would constitute a gene. Dr. Prohaska argues that a gene should be the smallest unit underlying inherited traits. It may include not just a collection of exons, but the epigenetic marks on them that are inherited as well.

These new concepts are moving the gene away from a physical snippet of DNA and back to a more abstract definition. “It’s almost a recapture of what the term was originally meant to convey,” Dr. Gingeras said.

A hundred years after it was born, the gene is coming home.

Genome 2.0: Mountains Of New Data Are Challenging Old Views
by Patrick Barry

This complex interweaving of genes, transcripts, and regulation makes the net effect of a single mutation on an organism much more difficult to predict, Gingeras says.

More fundamentally, it muddies scientists’ conception of just what constitutes a gene. In the established definition, a gene is a discrete region of DNA that produces a single, identifiable protein in a cell. But the functioning of a protein often depends on a host of RNAs that control its activity. If a stretch of DNA known to be a protein-coding gene also produces regulatory RNAs essential for several other genes, is it somehow a part of all those other genes as well?

To make things even messier, the genetic code for a protein can be scattered far and wide around the genome. The ENCODE project revealed that about 90 percent of protein-coding genes possessed previously unknown coding fragments that were located far from the main gene, sometimes on other chromosomes. Many scientists now argue that this overlapping and dispersal of genes, along with the swelling ranks of functional RNAs, renders the standard gene concept of the central dogma obsolete.

Long Live The Gene

Offering a radical new conception of the genome, Gingeras proposes shifting the focus away from protein-coding genes. Instead, he suggests that the fundamental units of the genome could be defined as functional RNA transcripts.

Since some of these transcripts ferry code for proteins as dutiful mRNAs, this new perspective would encompass traditional genes. But it would also accommodate new classes of functional RNAs as they’re discovered, while avoiding the confusion caused by several overlapping genes laying claim to a single stretch of DNA. The emerging picture of the genome “definitely shifts the emphasis from genes to transcripts,” agrees Mark B. Gerstein, a bioinformaticist at Yale University.

Scientists’ definition of a gene has evolved several times since Gregor Mendel first deduced the idea in the 1860s from his work with pea plants. Now, about 50 years after its last major revision, the gene concept is once again being called into question.

Theory Suggests That All Genes Affect Every Complex Trait
by Veronique Greenwood

Over the years, however, what scientists might consider “a lot” in this context has quietly inflated. Last June, Pritchard and his Stanford colleagues Evan Boyle and Yang Li (now at the University of Chicago) published a paper about this in Cell that immediately sparked controversy, although it also had many people nodding in cautious agreement. The authors described what they called the “omnigenic” model of complex traits. Drawing on GWAS analyses of three diseases, they concluded that in the cell types that are relevant to a disease, it appears that not 15, not 100, but essentially all genes contribute to the condition. The authors suggested that for some traits, “multiple” loci could mean more than 100,000. […]

For most complex conditions and diseases, however, she thinks that the idea of a tiny coterie of identifiable core genes is a red herring because the effects might truly stem from disturbances at innumerable loci — and from the environment — working in concert. In a new paper out in Cell this week, Wray and her colleagues argue that the core gene idea amounts to an unwarranted assumption, and that researchers should simply let the experimental data about particular traits or conditions lead their thinking. (In their paper proposing omnigenics, Pritchard and his co-authors also asked whether the distinction between core and peripheral genes was useful and acknowledged that some diseases might not have them.)

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