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. 2005 Jan;95(1):147-75.
doi: 10.1093/aob/mci010.

Economy, Speed and Size Matter: Evolutionary Forces Driving Nuclear Genome Miniaturization and Expansion

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Economy, Speed and Size Matter: Evolutionary Forces Driving Nuclear Genome Miniaturization and Expansion

Thomas Cavalier-Smith. Ann Bot. .
Free PMC article


Background: Nuclear genome size varies 300 000-fold, whereas transcriptome size varies merely 17-fold. In the largest genomes nearly all DNA is non-genic secondary DNA, mostly intergenic but also within introns. There is now compelling evidence that secondary DNA is functional, i.e. positively selected by organismal selection, not the purely neutral or 'selfish' outcome of mutation pressure. The skeletal DNA theory argued that nuclear volumes are genetically determined primarily by nuclear DNA amounts, modulated somewhat by genes affecting the degree of DNA packing or unfolding; the huge spread of nuclear genome sizes is the necessary consequence of the origin of the nuclear envelope and the nucleation of its assembly by DNA, plus the adaptively significant 300 000-fold range of cell volumes and selection for balanced growth by optimizing karyoplasmic volume ratios (essentially invariant with cell volume in growing/multiplying cells). This simple explanation of the C-value paradox is refined here in the light of new insights into the nature of heterochromatin and the nuclear lamina, the genetic control of cell volume, and large-scale eukaryote phylogeny, placing special emphasis on protist test cases of the basic principles of nuclear genome size evolution.

Genome miniaturization: and Expansion Intracellular parasites (e.g. Plasmodium, microsporidia) dwarfed their genomes by gene loss and eliminating virtually all secondary DNA. The primary driving forces for genome reduction are metabolic and spatial economy and cell multiplication speed. Most extreme nuclear shrinkage yielded genomes as tiny as 0.38 Mb (making the nuclear genome size range effectively 1.8 million-fold!) in some minute enslaved nuclei (nucleomorphs) of cryptomonads and chlorarachneans, chimaeric cells that also retain a separate normal large nucleus. The latter shows typical correlation between genome size and cell volume, but nucleomorphs do not despite co-existing in the same cell for >500 My. Thus mutation pressure does not inexorably increase genome size; selection can eliminate essentially all non-coding DNA if need be. Nucleomorphs and microsporidia even reduced gene size. Expansion of secondary DNA in the main nucleus, and in large-celled eukaryotes generally, must be positively selected for function. Ciliate nuclear dimorphism provides a key test that refutes the selfish DNA and strongly supports the skeletal DNA/karyoplasmic ratio interpretation of genome size evolution.

Genetic control of cell volume is multigenic: The quantitatively proportional correlation between genome size and cell size cannot be explained by purely mutational theories, as eukaryote cell volumes are causally determined by cell cycle control genes, not by DNA amounts.


F<sc>ig</sc>. 1.
Fig. 1.
Three contrasting scaling laws for genome size evolution. Law 1. Bacteria have single replicons per chromosome, so are under constant selective pressure to limit the accumulation of non-genic DNA that would lengthen replication times and slow reproductive rates. Thus their genome size (open circles) is related simply to gene numbers, which increase in proportion to metabolic and structural complexity—on average somewhat greater in larger cells (slope of 0·28). Law 2. Nuclei have numerous replicons origins per chromosome, which can be replicated simultaneously—so replication time is mechanistically independent of genome size and can be far less than in bacteria. When the nucleus evolved, DNA acquired a new function—to nucleate assembly of the nuclear envelope; in eukaryotes genome size scales proportionally to cell volume (slope 1·03, not significantly different from 1) because of this function and because the karyoplasmic volume ratio is essentially invariant with cell volume—probably because of a functionally essential quantitative balance between rates of nuclear RNA and cytoplasmic protein synthesis. The relationship is complicated by the presence of heterochromatin. It is simplest in unicellular eukaryotes with negligible amounts of heterochromatin (filled circles and line U: mostly green algae, diatoms and dinoflagellates, plus a few yeasts with tiny cells and amoebae with giant ones: Shuter et al., 1983), where the DNA/cell volume is minimal. In salamander red blood cells (S) the whole nucleus is heterochromatic and shrunken, so the DNA/cell volume ratio is about 50-fold greater. Cells with a mixture of compact heterochromatin and swollen euchromatin have intermediate DNA/cell volume ratios irrespective of whether they are unicellular (like cryptomonads: crosses) or multicellular (angiosperm meristem cells: dashed line). Law 3. Nucleomorph genome size is essentially invariant with cell volume because, unlike bacteria, their gene content is virtually constant and, unlike ordinary nuclei, their transcriptional/RNA processing needs do not increase significantly with cell volume (squares if volume measured by Beaton and Cavalier-Smith [1999] and stars if estimated from the literature); selection prevents non-coding DNA accumulating—because of its metabolic cost and perhaps also a constraint on chromosome arm length arising from the loss of higher-order chromatin folding (Cavalier-Smith, 1985b). Figure based on Shuter et al. (1983) and Cavalier-Smith and Beaton (1999).
F<sc>ig</sc>. 2.
Fig. 2.
The tree of life based on molecular, ultrastructural and palaeontological evidence. Contrary to widespread assumptions, the root is among the eubacteria, probably within the double-enveloped Negibacteria, not between eubacteria and archaebacteria (Cavalier-Smith, 2002b); it may lie between Eobacteria and other Negibacteria (Cavalier-Smith, 2002b). The position of the eukaryotic root has been nearly as controversial, but is less hard to establish: it probably lies between unikonts and bikonts (Lang et al., 2002; Stechmann and Cavalier-Smith, 2002, 2003). For clarity the basal eukaryotic kingdom Protozoa is not labelled; it comprises four major groups (alveolates, cabozoa, Amoebozoa and Choanozoa) plus the small bikont phylum Apusozoa of unclear precise position; whether Heliozoa are protozoa as shown or chromists is uncertain (Cavalier-Smith, 2003b). Symbiogenetic cell enslavement occurred four or five times: in the origin of mitochondria and chloroplasts from different negibacteria, of chromalveolates by the enslaving of a red alga (Cavalier-Smith, 1999, 2003; Harper and Keeling, 2003) and in the origin of the green plastids of euglenoid (excavate) and chlorarachnean (cercozoan) algae—a green algal cell was enslaved either by the ancestral cabozoan (arrow) or (less likely) twice independently within excavates and Cercozoa (asterisks) (Cavalier-Smith, 2003a). The upper thumbnail sketch shows membrane topology in the chimaeric cryptophytes (class Cryptophyceae of the phylum Cryptista); in the ancestral chromist the former food vacuole membrane fused with the rough endoplasmic reticulum placing the enslaved cell within its lumen (red) to yield the complex membrane topology shown. The large host nucleus and the tiny nucleomorph are shown in blue, chloroplast green and mitochondrion purple. In chlorarachneans (class Chlorarachnea of phylum Cercozoa) the former food vacuole membrane remained topologically distinct from the ER to become an epiplastid membrane and so did not acquire ribosomes on its surface, but their membrane topology is otherwise similar to the cryptophytes. The other sketches portray the four major kinds of cell in the living world and their membrane topology. The upper ones show the contrasting ancestral microtubular cytoskeleton (ciliary roots, in red) of unikonts (a cone of single microtubules attaching the single centriole to the nucleus, blue) and bikonts (two bands of microtubules attached to the posterior centriole and an anterior fan of microtubules attached to the anterior centriole). The lower ones show the single plasma membrane of unibacteria (posibacteria plus archaebacteria), which were ancestral to eukaryotes and the double envelope of negibacteria, which were ancestral to mitochondria and chloroplasts (which retained the outer membrane, red).
F<sc>ig</sc>. 3.
Fig. 3.
Scaling of nuclear volume (means of root and shoot meristem cells) with DNA content in 30 species of herbaceous angiosperms. Data from Baetke et al. (1967). Slope 0·826. From Cavalier-Smith (1985a).
F<sc>ig</sc>. 4.
Fig. 4.
Proteins involved in the attachment of chromatin to the nuclear envelope in animals. The outer membrane domain of the envelope is ordinary rough endoplasmic reticulum (RER) with bound ribosomes; the inner membrane domain of the envelope is a specialized domain of the RER, separated from the ribosome-binding region by the integral membrane proteins that attach the nuclear pore complexes (NPC). A considerable variety of amphipathic integral membrane proteins are embedded in the inner membrane domain of the envelope and several mediate attachment to the underlying lamina and chromatin. The N-terminal regions of one phylogenetically widespread family of inner membrane proteins that includes lamina-associated protein2 (LAP2), emerin, and MAN1 share a 43-residue subterminal LEM domain (so called after their initials). All three bind to the nuclear lamina, while LAP2 and emerin also bind chromatin directly. The lamin B receptor (LBR) belongs to a different family of sterol biosynthesis enzymes found in the ER and can bind both the lamina and DNA in addition to its biosynthetic enzymatic activity. Lamin filaments also permeate the interior of the nucleus, as part of the inner nuclear matrix and can bind to specific matrix attachment regions (MARs) on the chromosomes. During mitosis the lamina is disassembled and the inner matrix is reorganized to form chromosomal cores.
F<sc>ig</sc>. 5.
Fig. 5.
The eukaryote cell cycle as a bistable oscillator. The central logic of a typical binary fission cell cycle is that the cell can switch suddenly between two metastable states, one (G1) with low and one (S + M) with high cyclin-dependent kinase activity. The master controlling switch activates the anaphase-promoting complex (APC) that uses ubiquitin/proteasome-mediated proteolysis to digest the cohesins that bind sister chromatids together and reset the cell cycle by digesting cyclins and many other proteins. This sudden proteolytic destruction of cyclin-dependent kinase causes a precipitous drop in its activity (downward pointing arrow). As the cell grows the ratio of cyclins to their inhibitors increases gradually so eventually there is enough active cyclin to stimulate its associated kinase to initiate a burst of phosphorylations of numerous proteins critical to the G1/S-phase transition (called START in budding yeast, although the beginning of the cycle is more logically the onset of synthesis of origin recognition complexes, cyclins and their inhibitors immediately following the massive proteolysis that initiates anaphase). The upward pointing arrow represents this sudden activation of cyclin-dependent kinase without significant change in cyclin concentration, which typically occurs at a particular cell size effectively set by the rate of cyclin accumulation. Note that it is the ratio of cyclin to APC (abscissa) that is the master controller, not the absolute level of cyclin. START involves the initiation of DNA replication and of centriole duplication: like chromatin centrioles exist in two states, duplicatable and non-duplicatable. The centrosome and centriole evolved at the same time as the nucleus and their duplication cycles have been coupled ever since (Wong and Stearns, 2003); many organisms that lost cilia have also lost centrioles (e.g. higher plants and fungi) and are thus degenerate compared with animals and most protozoa. A second set of cyclin-dependent processes (not shown) is triggered after replication is complete to initiate chromosome condensation and spindle assembly.

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