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Evolution of Genomic Expression C H A P T E R 5 Evolution of Genomic Expression Bernardo Lemos, Christian R. Landry, Pierre Fontanillas, Susan P. Renn, Rob Kulathinal, Kyle M. Brown, and Daniel L. Hartl Introduction Genomic regulation is key to cellular differentiation, tissue morphogenesis, and development. Increasing evidence indicates that evolutionary diversity of phenotypes—from cellular to organismic—may also be, in large part, the result of variation in the regulation of genomic expression. In this chapter we explore the complexity of gene regulation from the perspective of single genes and whole genomes. The first part describes the major factors affecting gene expression levels, from rates of gene transcrip- tion—as mediated by promoter–enhancer interactions and chromatin mod- ifications—to rates of mRNA degradation. This description underscores the multiple levels at which genomic expression can be regulated as well as the complexity and variety of mechanisms used. We then briefly describe the major experimental and computational biology techniques for analyzing gene expression variation and its underlying causes. The final section reviews our understanding of the role of regulatory variation in evolution, including the molecular evolution and population genetics of noncoding DNA, as well as the inheritance and phenotypic evolution of levels of mRNA abundance. The Complex Regulation of Genomic Expression The regulation of gene expression is a complex and dynamic process. It is not a simple matter to turn a gene on and off, let alone precisely regulate its level of expression. Regulation can be accomplished through various mech- anisms at nearly every step of the process of gene expression. Furthermore, each mechanism may require a variety of elements, including DNA sequences, RNA molecules, and proteins, acting in combination to deter- 2 Chapter Five Evolution of Genomic Expression 3 mine the final amount, timing, and location of functional gene product. The transcription factors). However, it should be stressed that this classification complexity of regulation is even more evident when it is considered in the of gene loci and their mutations breaks down for most genes. This is because context of evolution and from the standpoint of integrated gene expres- many proteins (structural) act in trans to alter the expression level of other sion across the genome. The dynamic process of genomic expression is not genes (regulatory), such that a single mutation can have both structural and strictly fixed but can be context dependent, responding to cellular (genomic) regulatory consequences. Work by Yvert and colleagues (2003) clearly exem- or environmental influences. Through successive generations, the interplay plifies this point. These authors mapped a large number of trans-acting loci of these mechanisms evolves, thus generating a selectively advantageous affecting gene expression differences between two strains of yeast, and amount and/or location of functional gene product. found that genes with a large variety of molecular functions, such as Most of the cellular elements regulating gene expression can be divided enzymes, signal transducers, and cytoskeleton-binding proteins, could influ- into two basic categories: cis- and trans-acting factors, from the Latin mean- ence gene expression levels. Accordingly, amongst trans-acting loci there is ing “on the same side” and “on the opposite side,” respectively. Both cis- no specific enrichment for transcription factors. and trans-acting regulatory elements may contribute to the various mech- In the following section, we outline the overall process of gene expres- anisms of gene expression regulation. Strictly, cis and trans effects do not sion by indicating the mechanisms known to regulate gene product level, refer to the physical location of the regulatory element, but are rather oper- location, or timing at various stages of transcription, translation, and post- ationally defined in terms of the way these regulatory elements segregate translation. Transcriptional regulation of gene expression can occur at the genetically with respect to the gene that is the target of the regulatory activ- level of genomic DNA prior to transcription, or at the step of transcription, ity. Promoters, enhancers, regulatory introns, and 3’ regulatory sequences when the RNA is being produced. Post-transcription regulation occurs are examples of cis-regulatory elements. This is because these elements are through several mechanisms affecting the processing, stability, and/or local- located within the gene locus itself or in close proximity to it, such that they ization of the mRNA. The amount of functional gene product can also be are generally inherited together as a unit (i.e., the probability of recombina- regulated post-translationally. For each stage in the process of gene expres- tion between the regulatory elements and the gene’s structural sequences sion, we provide examples of a few well-studied mechanisms of regulation, is virtually zero). and attempt to identify examples of both cis-acting and trans-acting elements Trans-acting factors include proteins and RNAs derived from distant sites involved in each of the regulatory mechanisms. Figure 5.1 gives examples in the genome that act as regulatory elements. These can be either on differ- of the different stages along the path to functional protein during which ent chromosomes or on the same chromosome far away from the gene locus, genomic expression may be regulated. In most instances, the evolutionary such that they can be independently inherited (i.e., the recombination fre- acquisition and consequences of these mechanisms have yet to be addressed. quency is virtually 50%). Specific factors necessary for initiating or block- Most research regarding the molecular evolution of gene or genomic expres- ing transcription, or proteins that allow for appropriate gene-specific mRNA sion has focused on transcription factors (TF), promoter sequences, and TF- trafficking and stability, are just a few of the myriad trans-acting factors that binding sites within promoters. Similarly, most research regarding the phe- contribute to gene expression. notypic evolution of genomic expression has focused on the evolution of the The definition of cis and trans with respect to segregation is important mRNA abundance phenotype, most often without an explicit connection to because these two types of elements work in concert and often there is no evolutionary variation in specific underlying mechanisms associated with clear functional (or even positional) distinction between cis and trans. Trans- variation in this phenotype. acting factors bind to or interact with cis-regulatory sequences of the DNA and RNA. It is therefore the interplay of cis- and trans-acting loci that deter- mines the amount of functional gene product. Indeed, this level of complex- Classical Transcriptional Regulation in Cis and Trans ity and interaction provide the very substrate for the evolution of regula- Promoters,enhancers,repressors,transcription factors, tion as various cis and trans factors are brought together through segregation and recombination. When combined, elements that have evolved under dif- and regulatory proteins fering selective pressures may produce novel phenotypes, thus offering Promoters are among the most thoroughly studied and best understood reg- novel substrates for natural selection. ulators of gene expression (Ptashne and Gann 2002; Thomas and Chiang Early work attempted to categorize genetic mutations affecting a partic- 2006). In eukaryotes, the promoter is defined as the DNA region within a ular phenotype as either structural or regulatory (e.g., Wilson et al. 1977). few hundred base pairs upstream of the transcription start site, the section This separation was motivated by the intuition that some proteins have of DNA where the basic machinery of gene expression is assembled. The clearly defined structural roles (e.g., collagen), while the function of other promoter region encodes various sequence motifs where transcription fac- proteins lies primarily in the regulation of other genes (e.g., muscle-specific tors bind along with RNA polymerase II to initiate transcription (Smale and 4 Chapter Five Evolution of Genomic Expression 5 Cis-regulatory elements Trans-regulatory elements Kadonaga 2003). The initiation and rate of transcription depend on the inter- segregate with the gene segregate independently play of many DNA and protein elements. Ultimately, a gene’s transcription level reflects the interactions between various activating and inhibitory com- plexes assembled not only at the promoter region, but also at various enhancer and silencer sites along the chromatin (Wray et al. 2003). The core promoter includes DNA elements that can extend about 35 Upstream S/MAR Binding proteins nucleotides upstream and/or downstream of the transcription initiation site sequences Nucleus (Smale and Kadonaga 2003). The core is obviously the archetype of cis-reg- AC ulatory factors. At least six core promoter elements have been discerned so AC AC Histone code far (Gershenzon et al. 2006): TATA box, Initiator (Inr), Downstream Promoter Element (DPE), TFIIB Recognition Element (BRE), Downstream Core Ele- Upstream Histone modifying ment (DCE), and Motif Ten Element (MTE). Although earlier studies sug- sequences enzymes gested that the structure of the core promoter might be highly conserved DNA methylation throughout the eukaryotes, tremendous diversity is now evident. First, the anscription CGCGCG
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