A major role for noncoding regulatory mutations in the evolution of enzyme activity
| Autor: | Sean B. Carroll, Ames, Kathy Vaccaro, David W. Loehlin |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0106 biological sciences
Untranslated region Evolution Biology medicine.disease_cause 010603 evolutionary biology 01 natural sciences Models Biological 03 medical and health sciences Initiator element Species Specificity Gene expression medicine Animals Enhancer skin and connective tissue diseases Gene 030304 developmental biology Genetics 0303 health sciences Mutation Multidisciplinary Alcohol Dehydrogenase Promoter Biological Sciences Biological Evolution enzyme PNAS Plus Amino Acid Substitution Drosophila sense organs regulatory Functional divergence |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | Significance This study investigates how evolutionary changes in enzyme activity occur. Multiple species of Drosophila flies have adapted to food with different levels of alcohol. This study uncovers genetic changes responsible for these repeated adaptive events, focusing on the main enzyme responsible for alcohol metabolism, Alcohol dehydrogenase. Better alcohol metabolism could be achieved either through changes to the enzyme itself or through changes in DNA regulatory sequences that affect how many enzyme molecules are produced. In four different cases, it was found that regulatory changes were the most frequent contributors to evolution. These findings have important implications because most studies of enzyme evolution focus exclusively on changes to protein sequence, and thus a significant source of adaptive changes may be overlooked. The quantitative evolution of protein activity is a common phenomenon, yet we know little about any general mechanistic tendencies that underlie it. For example, an increase (or decrease) in enzyme activity may evolve from changes in protein sequence that alter specific activity, or from changes in gene expression that alter the amount of protein produced. The latter in turn could arise via mutations that affect gene transcription, posttranscriptional processes, or copy number. Here, to determine the types of genetic changes underlying the quantitative evolution of protein activity, we dissected the basis of ecologically relevant differences in Alcohol dehydrogenase (Adh) enzyme activity between and within several Drosophila species. By using recombinant Adh transgenes to map the functional divergence of ADH enzyme activity in vivo, we find that amino acid substitutions explain only a minority (0 to 25%) of between- and within-species differences in enzyme activity. Instead, noncoding substitutions that occur across many parts of the gene (enhancer, promoter, and 5′ and 3′ untranslated regions) account for the majority of activity differences. Surprisingly, one substitution in a transcriptional Initiator element has occurred in parallel in two species, indicating that core promoters can be an important natural source of the tuning of gene activity. Furthermore, we show that both regulatory and coding substitutions contribute to fitness (resistance to ethanol toxicity). Although qualitative changes in protein specificity necessarily derive from coding mutations, these results suggest that regulatory mutations may be the primary source of quantitative changes in protein activity, a possibility overlooked in most analyses of protein evolution. |
| Databáze: | OpenAIRE |
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