The Molecular Underpinnings of Genetic Phenomena

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The Molecular Underpinnings of Genetic Phenomena Heredity (2008) 100, 6–12 & 2008 Nature Publishing Group All rights reserved 0018-067X/08 $30.00 www.nature.com/hdy SHORT REVIEW The molecular underpinnings of genetic phenomena N Lehman Department of Chemistry, Portland State University, Portland, OR, USA Epiphenomena are those processes that ostensibly have no whole organisms and populations may have their ultimate precedent at lower levels of scientific organization. In this evolutionary roots in the chemical repertoire of catalytic review, it is argued that many genetic processes, including RNAs. Some of these phenomena will eventually prove to be ploidy, dominance, heritability, pleiotropy, epistasis, muta- not only analogous but homologous to ribozyme activities. tional load and recombination, all are at least analogous to Heredity (2008) 100, 6–12; doi:10.1038/sj.hdy.6801053; biochemical events that were requisite features of the RNA published online 29 August 2007 world. Most, if not all, of these features of contemporary Keywords: RNA; ploidy; pleiotropy; epistasis; heritability; recombination Introduction Below are discussed seven well-known genetic pro- cesses for which a clear molecular basis can be The history of life, if traced with perfect detail, would postulated. By ‘molecular basis’ it is meant that a reveal a long and gradual expansion of networks of chemical property of biopolymers, usually RNA, can be chemical reactions. If viewed in less detail, a series of identified as a direct forbearer of the higher-order plateaus would be seen, each representing a discrete property observed in whole organisms. Again, an advancement in complexity (Fontana and Schuster, 1998; important aspect of this is the idea that many of these Hazen et al., 2007). Some of these steps could be molecular events may have been the ultimate causal described as emergent properties, or epiphenomena: agents of the organismal events, as opposed to the biological processes that would not be predicted from alternative that the two processes are merely analogous. knowledge of lower-level phenomena. Investigations into epiphenomena, especially epigenetics, are currently very popular. This is true in large part because the identification of a previously unappreciated level of Ploidy complexity can lead to great excitement and a vast One can begin the search for the molecular roots of improvement in our understanding of biology. The role genetics in an obvious location: the existence of more of DNA methylation in gene expression and transmis- than one copy of genomic information in the cell, or sion is an excellent example (cf. Robertson and Wolffe, ploidy. This is traceable to the existence of double- 2000), as we now realize that there are mechanisms of stranded nucleic acids, which in turn has its basis in the heredity beyond the primary sequence of germline DNA. complementarity of nitrogenous bases. The discrete Nevertheless, it is important to keep in mind that patterns of hydrogen-bond donors and acceptors on the many genetic phenomena can in fact be traced back to Watson–Crick surface lead to a coding process by which familiar biochemical events. This is true even of many information can be copied. This point is not as trivial as it events often described as epiphenomena. The purpose of sounds. Under the RNA world hypothesis (Gilbert, this review is to survey the wealth of recent data on in 1986), an RNA-like polymer was responsible for both vitro studies of biopolymer function with the goal of genotypic and phenotypic functions in the most primi- detecting parallels between what molecules can do and tive of life forms. At issue for many years has been the what organisms can do. In some of these cases the two mode of replication of such entities. Naturally, much actions will eventually turn out not to be homologous, in attention has been focused on the concept of an RNA the sense that they will not share a common evolutionary replicase, which would have been a catalytic RNA ancestry. But in some cases they will, and it will be (ribozyme) capable of making a copy of an RNA strand enlightening to explore the generality of the molecular in much the same way that contemporary DNA poly- underpinnings of these genetic phenomena. merases function. However, all known protein poly- merases do not make exact copies, they make complementary copies. Thus, as noted by Eigen and Correspondence: Dr N Lehman, Department of Chemistry, Portland State Schuster (1977) and others, an RNA replicase would only University, PO Box 751, Portland, OR 97207, USA. E-mail: [email protected] be functional in a system where there exist þ and – Received 29 June 2007; revised 2 August 2007; accepted 3 August strands, requiring not one, but two copies of the genome. 2007;published online 29 August 2007 This would have been the ultimate origin of ploidy. Genetic underpinnings N Lehman 7 Search for an RNA replicase in the laboratory has made Turning again to the RNA world, substrate binding is a some progress with in vitro evolution (Bartel and Szostak, well-studied phenomenon, both for ribozyme and for 1993; Johnston et al., 2001; Zaher and Unrau, 2007), but we RNAs that simply bind their substrates in a highly still have a long way to go, in part because of the lack of specific fashion (aptamers). We have been able to processivity of replicase ribozymes discovered so far measure the binding constants between RNAs and their (p20 nt), but also in part because a self-replicating RNA substrates in hundreds of cases. The Km (Michaelis - - replicase would need to copy itself twice ( þ À þ constant) or the Kd (dissociation constant) for RNAs can dashed lines in Figure 1a) and/or be functional in both þ be quite impressive, in some cases plunging into the low and – stranded forms (Joyce and Orgel, 2006). Moreover, mM range (Puglisi and Williamson, 1999; Bunka and such an enzyme would depend on efficient separation of Stockley, 2006). RNAs achieve tight and specific binding the product strand from the template strand, a chemical by employing most of the intermolecular interaction event that has a poor compatibility with the conditions tools at their disposal, including hydrogen bonding, under which replication takes place. Inspired by the hydrophobic interactions and the use of cationic metal power of the PCR, some have proposed tidal or thermal ligands. A classic example is the ATP aptamer originally cycling as a means to overcome this problem (Lathe, 2003; discovered in the Szostak laboratory through selection Braun and Libchaber, 2004). Also, there is some pre- from a random pool of RNA sequences (Sassanfar and cedence for both strand alternation and dual-strand Szostak, 1993). RNAs that possess a particular 12 or so functionality in the replicative pathways of some viruses, nucleotides arranged in a highly asymmetrical internal such as the human delta virus (HDV), which undergoes loop can bind their substrate molecule with high affinity rolling-circle replication involving two complementary and can even discriminate against similar substrates single-stranded versions of its genome. Interestingly, this such as GTP. Single mutations can affect the shapes of pathway also involves a self-cleaving RNA motif, the these loops enough to destroy the binding affinity, such HDV ribozyme, which comes in two forms, a genomic and that allelic variations could possess a dominance– an antigenomic, although these are not direct comple- recessive relationship if the phenotype were an eventual ments of each other. In any event, the advent of an RNA manifestation of the binding event. replicase allowed (or required) two copies of the genome. The recent discovery (Winkler et al., 2004) and It is debatable whether this happened at the RNA stage or structural elucidation (Kline and Ferre´-D’Amare´, 2006) was concomitant with the first utilization of DNA of the glmS riboswitch ribozyme is a good demonstration (Breaker and Joyce, 1994). of how substrate binding by RNAs could directly affect Of course, the genomic duplication most commonly the phenotype of a cell and potentially give rise to a associated with ploidy is a subsequent copying of an dominance relationship upon polyploidy. The 50 un- entire group of nucleic acids into a noncomplementary translated region of the mRNA of a Bacillus subtilis gene set. This created a genomic redundancy that allowed that encodes the enzyme glutamine-fructose-6- evolutionary benefits such as gene divergence, dom- phosphate amidotransferase folds into a motif that binds inance, certain modes of speciation and meiotic replica- an effector molecule, glucosamine-6-phosphate (GlcN6P, tion. Ploidy of this type can arise from a variety of a component of cell walls) with extremely high specifi- mechanisms such as endosymbiosis, disruptions in the city. Upon doing so, the RNA turns into a self-cleaving chromosomal segregation process or unequal crossover, ribozyme, effectively shutting down protein synthesis discussed in more detail elsewhere (Lynch and Conery, and altering the phenotype of the cell. These events are 2000; Wolfe, 2001). Brosius (2003) has pointed out how useful when GlcN6P concentrations are high, because the retrotransposition could have led to many, if not all, of protein’s role is to convert a precursor molecule into the complex genomes found today. Some of the afore- GlcN6P. A hypothetical gene duplication and subsequent mentioned processes can be traced back to DNA splicing mutation of any one of a dozen or so key nucleotides that and rejoining catalytic activities such as those affiliated disrupted the ability of the RNA to bind (or react with) with recombination (discussed below), while others GlcN6P would lead to a second allele that would be cannot, making ploidy a phenomenon with multifaceted dominant over the wild type, as the enzyme would molecular underpinnings. be produced in heterozygotes. This new allele would be disadvantageous in environments with limited resources as a consequence of the spurious production of the Dominance protein in the absence of its substrate, but could be selected for in environments with abundant resources Dominance results when the phenotypic expression of where cell-wall production is in high demand.
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