Elsevier

Gene

Volume 390, Issues 1–2, 1 April 2007, Pages 232-242
Gene

Review
Combinatorial epigenetics, “junk DNA”, and the evolution of complex organisms

https://doi.org/10.1016/j.gene.2006.12.001Get rights and content

Abstract

At certain evolutionary junctures, two or more mutations participating in the build-up of a new complex function may be required to become available simultaneously in the same individuals. How could this happen in higher organisms whose populations are small compared to those of microbes, and in which chances of combined nearly simultaneous highly specific favorable mutations are correspondingly low? The question can in principle be answered for regulatory evolution, one of the basic processes of evolutionary change. A combined resetting of transcription rates in several genes could occur in the same individual. It is proposed that, in eukaryotes, changes in epigenetic trends and epigenetically transforming encounters between alternative chromatin structures could arise frequently enough so as to render probable particular conjunctions of changed transcription rates. Such conjunctions could involve mutational changes with low specificity requirements in gene-associated regions of non-protein-coding sequences. The effects of such mutations, notably when they determine the use of histone variants and covalent modifications of histones, can be among those that migrate along chromatin. Changes in chromatin structure are often cellularly inheritable over at least a limited number of generations of cells, and of individuals when the germ line is involved. SINEs and LINEs, which have been considered “junk DNA”, are among the repeat sequences that would appear liable to have teleregulatory effects on the function of a nearby promoter, through changes in their numbers and distribution. There may also be present preexisting unstably inheritable epigenetic trends leading to cellular variegation, trends endemic in a cell population based on DNA sequences previously established in the neighborhood. Either way, epigenetically conditioned teleregulatory trends may display only limited penetrance. The imposition at a distance of new chromatin structures with regulatory impact can occur in cis as well as in trans, and is examined as intrachromosomally spreading teleregulation and interchromosomal “gene kissing”. The chances for two or more particular epigenetically determined regulatory trends to occur together in a cell are increased thanks to the proposed low specificity requirements for most of the pertinent sequence changes in intergenic and intronic DNA or in the distribution of middle repetitive sequences that have teleregulatory impact. Inheritable epigenetic changes (“epimutations”) with effects at a distance would then perdure over the number of generations required for “assimilation” of the several regulatory novelties through the occurrence and selection, gene by gene, of specific classical mutations. These mutations would have effects similar to the epigenetic effects, yet would provide stability and penetrance. The described epigenetic/genetic partnership may well at times have opened the way toward certain complex new functions. Thus, the presence of “junk DNA”, through co-determining the (higher or lower) order and the variants of chromatin structure with regulatory effects at a distance, might make an important contribution to the evolution of complex organisms.

Section snippets

Some conditions under which “junk DNA” may help generate higher organisms

Genomes need to possess at least the following six basic properties (Table 1) if any sequences considered as “junk DNA” are to intervene in organismic evolution, as directly linked to the evolution of genes (leaving aside chromosomal evolution).

First, the distinction between genetic and epigenetic effects must apply. The existence of epigenetic effects is not episodic; it is at the core of living systems. The roles in chromatin of the polynucleotides and their interacting factors are

Degrees of specificity of regulatory effects originating in “junk DNA”

A general way for “junk DNA” to intervene in gene regulation no doubt depends on the capacity of this DNA to affect the balance of bound and free regulatory factors. Transcription factors extensively bind to non-protein-coding sequences (Cawley et al., 2004), either in functionally neutral associations, though often leading to perhaps functionally nonneutral local transcription of noncoding RNAs, or with effects on genome structure endowed with functional implications. In particular, factor

Junk DNA-dependent teleregulation of chromatin structure via spreading of chromatin modifications in cis

Regarding the question of the role that “junk DNA” located in the region of particular genes may play as originators of changes in transcriptional regulation, let us first consider effects in cis. We presume that, not infrequently, in some points of the genome, and within non-protein-coding DNA, a new chromatin structure is formed and is communicated to other points of the genome. The local nidus formation from which a new structure can spread or an old one can be selected for greater

Teleregulation of chromatin structure via spreading of chromatin modifications in trans

Indeed, another class of phenomena that might lead to teleregulatory effects relies on “gene clustering” or “gene kissing” processes, whereby genomic elements sharing sequence homology or analogous molecular regulatory complementary structural features meet in the three-dimensional space of the cell nucleus. Upon mutation of one interacting partner (that we may designate as “donor” locus), a change in chromatin structure may thus be communicated to the “acceptor” locus in contact with the

Wider implications of combinatorial epimutations

Selectable inheritable combinations of epigenetic changes in the transcription rate of individual genes can presumably be maintained in cells or organisms over a certain window of numbers of generations. That window can be of sufficient width to permit much rarer specific mutations with equivalent effects to occur and to be selected. These specific mutations would be of high penetrance and stability. They would produce the “assimilation” of certain constellations of epigenetic transmutations.

Acknowledgements

E.Z. was supported through the Institute of Molecular Medical Sciences by the Sylvia Robb Charitable Trust. G.C. was supported by grants from the Centre National de la Recherche Scientifique, the Human Frontier Science Program Organization, the European Union FP 6 (Network of Excellence “The Epigenome” and STREP “3D Genome”), the Ministère de la Recherche (ACI BCMS 2004), the Agence Nationale de la Recherche, and by the Association pour la Recherche sur le Cancer.

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