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A project by Stephen L. Talbott

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Natural Genome Remodeling

Summary

In 1983, Nobelist Barbara McClintock suggested that organisms respond to stress by altering their own genomes “in a ‘thoughtful’ manner” and based on their “knowledge” of themselves. We know today that genomic change of all sorts is rooted in the remarkable expertise of the organism as a whole.

The organism sees to the replication of chromosomes in dividing cells, maintains surveillance for all sorts of damage, and repairs or alters damage when it occurs — all with an intricacy and subtlety of well-gauged action. In certain human immune system cells, portions of DNA are repeatedly cut and then stitched together in new patterns, yielding the huge variety of proteins required for recognizing an equally huge variety of foreign substances that need to be rendered harmless. Clearly, our bodies have gained the skills for elaborate reworking of their DNA

This reworking includes direct chemical modification (such as methylation) of millions of nucleotide bases in the human genome — modification that varies according to context. But the cell’s contextualization of its genome extends far beyond such changes, leading to the stable incorporation of the genome in some 250 major cell types, each of which has the “same” genome, yet a genome that functions in a radically different way, subserving the needs of radically different contexts, from bone to blood to liver to brain.

The organism also directly duplicates and modifies some of its genes, and indirectly duplicates genes or larger DNA segments through reverse transcription of RNA back into DNA. These processes have long been known, but our knowledge of the organism’s genome-modifying skills is now being hugely expanded. For example, two duplicated genes can, via a number of different pathways, fuse into a single chimeric gene. And not only protein-coding RNAs, but also small, regulatory RNAs, can be reverse transcribed into DNA and their functions diversified. Protein-coding genes have even been created from scratch — from non-protein-coding DNA — an unexpected feat once thought to be mathematically inconceivable. And again, various repetitive and mobile elements called “transposons” can move around in the genome, often being duplicated in the process and then co-opted either as new protein-coding genes or new regulatory genes.

Indeed, current findings “strongly support the existence of transposon-mediated gene regulatory innovation at the network level, a mechanism of gene regulation first suggested more than forty years ago by McClintock...Transposable elements are potent agents of gene regulatory network evolution” (Lynch et al. 2011).

None of this is yet to mention the way the organism massively structures, restructures, and regulates its genome through the intricate remodeling of chromatin (the DNA/protein/RNA complex comprising our chromosomes), or the way it shapes the dynamic, three-dimensional organization of the cell nucleus, which in turn has a great deal to do with how genes get expressed. (On this, see Getting Over the Code Delusion.)

All these processes can occur in germline cells, and meiotic cell division involves the elaborate choreography of recombination, whereby huge sections are exchanged between chromosomes.

All this (and much more) has prompted University of Chicago geneticist James Shapiro to speak of “natural genetic engineering”. “We have progressed from the Constant Genome, subject only to random, localized changes at a more or less constant mutation rate, to the Fluid Genome, subject to episodic, massive and non-random reorganizations capable of producing new functional architectures” (Shapiro 1997). Crucially, “genetic change is almost always the result of cellular action on the genome” (Shapiro 2009).

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Selected excerpts from the chapter
bullet Remodeling expertise
bullet Metamorphosis of the genome?
bullet The generation of new genetic material
bullet Jumping genes and the brain
bullet Mutations are not accidents
bullet Concerted change in the germline
bullet Unexpected plasticity of the genome
bullet “Astounding” diversity of methods for gene creation
bullet Which is our real genome?