Evolutionary constraints on yeast protein size
© Warringer and Blomberg; licensee BioMed Central Ltd. 2006
Received: 25 April 2006
Accepted: 15 August 2006
Published: 15 August 2006
Despite a strong evolutionary pressure to reduce genome size, proteins vary in length over a surprisingly wide range also in very compact genomes. Here we investigated the evolutionary forces that act on protein size in the yeast Saccharomyces cerevisiae utilizing a system-wide bioinformatics approach. Data on yeast protein size was compared to global experimental data on protein expression, phenotypic pleiotropy, protein-protein interactions, protein evolutionary rate and biochemical classification.
Comparing the experimentally determined abundance of individual proteins, highly expressed proteins were found to be consistently smaller than lowly expressed proteins, in accordance with the biosynthetic cost minimization hypothesis. Yeast proteins able to maintain a high expression level despite a large size tended to belong to a very distinct set of protein families, notably nuclear transport and translation initiation/elongation. Large proteins have significantly more protein-protein interactions than small proteins, suggesting that a requirement for multiple interaction domains may constitute a positive selective pressure for large protein size in yeast. The higher frequency of protein-protein interactions in large proteins was not accompanied by a higher phenotypic pleiotropy. Hence, the increase in interactions may not reflect an increase in function differentiation. Proteins of different sizes also evolved at similar rates. Finally, whereas the biological process involved was found to have little influence on protein size the biochemical activity exerted by the protein represented a dominant factor. More than one third of all biochemical activity classes were enriched in one or more size intervals.
In yeast, there is an inverse relationship between protein size and protein expression such that highly expressed proteins tend to be of smaller size. Also, protein size is moderately affected by protein connectivity and strongly affected by biochemical activity. Phenotypic pleiotropy does not seem to affect protein size.
One of the more surprising observations in the early genome studies was the enormous variation in genome size, not only among eukaryotes in general (>200,000 fold variation), but also within kingdoms (e.g. plants, >1,000 fold variation) . Even among closely related species, genome size has been found to exhibit remarkably large variation . Nevertheless, the evolutionary significance of this variation is still unknown. Given that the number of genes varies much less than overall genome size (e.g. only 5-fold between yeast and humans) scientific focus has been on the intergenic DNA that makes up the bulk of most eukaryotic genomes. Several hypothesizes has also been put forward to explain the variation in the size of intergenic DNA, ranging from the notion that the unnecessary "junk" DNA is not really unnecessary at all  to the suggestion that the evolutionary cost of carrying junk DNA is so minimal that the negative selective consequences may be disregarded. The latter hypothesis stems from the observation that much of the junk DNA is selfish in nature [4, 5] making it more likely that its accumulation has little to do with the fitness of the organism itself . Currently, it is becoming increasingly apparent that a large genome size constitutes a real and considerable burden. A large genome size tends to correlate with delayed mitotic and meiotic division [6–8] decreased plant invasiveness of disturbed sites  lower maximum photosynthetic rates in plants  and lower metabolic rates in mammals  and birds [11, 12]. Furthermore, genera with large genome sizes tend to contain fewer species and species with large genomes tend to be underrepresented in harsh environments . These observations suggest that genome size minimization constitute a dominant selective force.
In lower organisms such as yeast where intergenic DNA comprise less than 30% of the genome  – as opposed to 98% in human  – it may be argued that reducing the size of coding DNA significantly affects genome size. Thus, in lower organisms minimizing protein size would enable a higher cell division rate and result in lower DNA maintenance costs. In addition it has been suggested  that a reduction in protein size vastly reduces protein biosynthetic costs, directly by decreasing the energetic costs of translation  and indirectly by reducing the cost of chaperones required to fold large multi-domain proteins . Indeed, gene length in eukaryotes tends to correlate negatively with synonymous codon usage bias [17–20], a tentative measure of protein expression levels. In addition, proteins with a high synonymous codon usage bias tend to preferentially contain amino acids that are less energetically costly , a factor essentially determined by amino acid weight . Thus, a requirement for high protein expression may impose a biosynthetic cost constraint on protein size.
Despite the seeming fitness benefits of minimizing protein size, the size of individual proteins within a genome displays as remarkable a variation as the size of genomes within a kingdom; for example in S. cerevisiae, the protein size range spans over two orders of magnitude; from 25 to more than 4.100 amino acids. Thus, strong selective forces counterbalance the evolutionary pressure to minimize protein size. In this article we considered four hypotheses regarding the nature of the selective forces that favor a large protein size: i) Larger proteins are involved in multiple biological processes, therefore requiring multiple functional domains. This may be reflected in a higher extent of phenotypic pleiotropy among large proteins. ii) Larger proteins need to be more interconnected in the protein-protein network and thus may contain more protein-protein interaction domains. iii) The size requirements of individual functional domains may infer vastly different size constrains on different classes of proteins, i.e. large and small proteins would tend to exert very different biochemical activities in the cell and have differing function annotations. iv) Large proteins are more robust to changes in amino acid composition and may tolerate a higher mutation rate without loss of function.
These hypotheses were considered using the S. cerevisiae genome which has been re-annotated [13, 23] and is essentially definite with regards to protein size annotation and for which there is ample genome-wide, experimental data on available.
Results and discussion
Smaller proteins are more abundant than larger proteins
In the light of the selective pressure to minimize biosynthetic cots by reducing the size of highly expressed proteins we reason that proteins that are expressed to high levels despite a large size may be especially interesting from a biological function perspective. Comparing the 56 proteins that are both highly expressed (above the overall average of 12,273 molecules/cell) and large (length>771 amino acids) to all large proteins we find that these proteins are especially prone (hypergeometric distribution assumption, p < 0.001) to be involved in protein synthesis, energy metabolism, and cellular transport (Fig 1E). Notably, three translation initiation factors, Fun12p, Clu1p and Rpg1p as well as three translation elongation factors, Eft1p, Eft2p andYef3p are both large and highly expressed. It may also be noted that the enrichment of cellular transport functions include four of the eight components of the COPI coatomer vesicle complex, Sec21p, Sec26p, Sec27p and Cop1p as well as a high proportion of nuclear transport function genes, both mRNA export and protein import.
Protein connectivity affects protein size in yeast
We conclude that the selective pressure to maintain a large protein size at least partially may be a selective pressure to entertain more protein-protein interactions.
Multi-functionality does not favor a large protein size
To account for the possibility that the lack of correlation arises from the use of a limited and biased number of growth conditions we performed in depth phenotypic profiling data for 96 deletion strains, randomly selected with regards to protein size, during 36 very diverse growth conditions. This data was further compared to the size of each deleted protein. However, for none of the fitness measures investigated, adaptation time, growth rate and growth efficiency, did we find a significant difference in the number of significant phenotypes between large and small proteins (Fig 3D–F); neither did we find any significant correlation between protein size and the level of protein dispensability as the magnitude of phenotypes (LPI) were similar for large and small proteins (data not shown). The selective pressure to maintain protein size therefore does not appear to be a selective pressure for pleiotrophy/multi-functionality within individual proteins.
Proteins of different sizes evolve at similar rates
Using a limited set of 31 Drosophila melanogaster proteins Seligmann observed that amino acid weight minimization, i.e. the selective pressure to reduce the number of heavy amino acids in large proteins, affected the rate of amino acid replacements . Our final hypothesis raised the possibility that large proteins are more robust to changes in amino acid composition and may tolerate a higher mutation rate without loss of protein function simply because of their size. To investigate whether large proteins in yeast are more tolerant to mutations and hence evolve at a higher rate we correlated protein size data to data on the rate of individual changes of base pairs within proteins as represented by the ratio of amino acids changing mutations versus silent mutations (dN/dS) . We found no significant correlation between dN/dS ratios (linear correlation, r2 = E-6) and protein size in yeast. Protein evolutionary rate is known to be strongly influenced by protein expression level , however, even controlling for this variable (protein absolute abundance) no correlation was found between evolutionary rate and protein size (partial correlation, p = 0.15).
We conclude that the evolutionary rate does not constitute a selective force that substantially constrains protein size.
Protein size is constrained by the size requirements of the biochemical domain
To ascertain that the observed correlation between biochemical activity and protein size was not an artifact arising from an underlying correlation between biological process and protein size, we also analyzed the frequency distribution of biological process annotation data with regards to protein size. Of 299 analyzed biological processes none were highly overrepresented (p < 0.001) among either large or small proteins (data not shown). A clear example of that it is the biochemical activity rather than the biological process that forms the correlation between protein function and protein length is provided by proteins involved in ubiquitin mediated proteolysis. Components of this biological process were evenly distributed with regards to protein size. However, on the level of biochemical activity both ubiquitin protein ligase activity and ubiquitin specific protease activity were enriched among the largest proteins whereas ubiquitin conjugating activity was highly enriched among the smallest proteins (Fig 4B). We conclude that the nature of the biochemical activity exerted by a protein constitute a dominant selective pressure to maintain large protein size.
Using experimental data from a global S. cerevisiae study on protein abundance , we here demonstrated that smaller proteins tended to be more highly expressed than larger proteins. Our observations are in line with reports of a negative correlation between codon usage and protein size in eukaryotes [17–19] as well as with observations that large proteins tend to contain energetically less costly amino acids [21, 22]. Also, it has been reported that mRNA abundance restricts maximum protein length . Taken together, these observations strongly suggest that the biosynthetic cost minimization hypothesis is biologically relevant.
The correlation between protein size and expression was found to be strongest for the smallest and most expressed proteins, which include a disproportionably high frequency of ribosomal proteins. In a rapidly growing yeast cell as much as 50% of RNA polymerase II transcription is devoted to ribosomal proteins ; thus, the biosynthetic cost constraints that limit the size of highly expressed proteins are expected be extremely strong for these proteins.
It should be observed that the here presented correlation between protein length and low protein abundance does not allow for a clear determination of cause/effect relationships. In fact the two alternatives – i.e. protein size acting as evolutionary constraint on protein expression and protein expression restricting protein size – are not mutually exclusive and may reflect parallel selective forces.
Additionally, we investigated the nature of the evolutionary forces that maintain the size of large proteins despite the selective pressure to minimize DNA maintenance/replication times as well as biosynthetic costs. Genetic pleiotropy, i.e. the ability of a mutation in a single gene to give rise to multiple phenotypic outcomes , has been shown to be surprisingly wide-spread in yeast and to correlate to a variety of protein features, such as function and chromosomal position [25, 34]. Although a single function may have multiple phenotypic outcomes, pleiotropy may be argued to be at least a vague indicator of the degree of multi-functionality. We hypothesized that if there is a general requirement for multi-functionality in large proteins, thus imposing evolutionary constrains on size, we expected to see some sort of correlation between the degree of pleiotropy and protein size. However, no such correlation was found, providing tentative indications that large proteins in general do not possess more functions than smaller proteins.
We also investigated a possible selective pressure for more protein-protein interactions, requiring multiple interaction domains, in large proteins. Protein connectivity is widely known to affect the functional importance of proteins  which in turn is known to correlate positively with protein size , supporting the plausibility of such a hypothesis. Mining available 2-hybrid and protein affinity precipitation data, we found larger proteins to have significantly more interaction partners than smaller proteins. Thus, a requirement for multiple interaction domains may be considered to act as a balancing selective force, partially offsetting the general fitness benefit of minimizing protein size. This higher connectivity does not transform into higher pleiotrophy. One possible explanation of this seeming anomaly is that the more frequent protein-protein interactions in large proteins may reflect a specific increase in input connectivity. In other words, large proteins would be subject to more regulatory signals but would not have more functional targets.
It is tempting to interpret the correlation between protein size and a high number of protein interactions as a demand for a larger protein size in proteins whose functions require a high connectivity. However, the here presented correlation does not allow for such a strict assignment of evolutionary cause/effect relationship. It cannot be excluded that proteins of larger size are more prone to form protein-protein interactions and, hence, that increasing protein size drives connectivity.
In the idealized situation of a total absence of general constraints on protein size, the length of an individual protein would be completely dependent on the size requirements of its domains. However, in the non-idealized reality the extent to which function balances the different general constraints and determines protein size is unknown. It has been observed that proteins with conserved and essential functions tend to be longer than proteins with highly less conserved and non-essential functions . We here show that the individual protein function constitutes a dominant factor in the determination of protein size in yeast. Interestingly, it was found that it is the actual biochemical activity exerted by the protein, rather than the biological process involved, that is crucial. Not a single protein-size dependent enrichment was observed for different biological processes whereas one third of the investigated biochemical activities were highly overrepresented among either the smallest or the largest proteins. This strongly suggests that it is the size requirements of the individual biochemical domains that impose the strict limits on protein size. Some of the biochemical activity categories here revealed to contain disproportionably many large proteins, notably protein kinases and transcription factors had earlier been noted to produce above average-sized transcripts . It should be noted that, using much broader definitions of biological processes than the here applied, Brocchieri et al. showed that proteins involved in "metabolism" and "cellular processes" tended to be longer than expected . The here reported strong correlation between size and functional variability among yeast proteins probably reflects the underlying size requirements imposed by different structure motifs. Such an assumption is supported by the observation that it is biochemical activity rather than biological process which correlates to protein size. It is well established that proteins with similar biochemical activities share extensive structure similarities whereas few such correlations have been reported among proteins involved in the same cellular pathways.
Protein size data
A complete set of S. cerevisiae genes was obtained from the Saccharomyces Genome Database . To avoid infiltration from dubious open reading frames and to decrease statistical noise data was filtered according to Kellis et al ; dubious genes not conserved between closely related yeast species were thus discarded (5256 genes were retained). Protein size was here considered as protein length (number of amino acids), however, as the correlation between protein length and protein weight in yeast is essentially linear (r2 = 0.9987) protein length and weight may be regarded as equivalent measures.
Protein expression data
To investigate whether the reported negative correlation between codon bias and protein size reflects a true evolutionary constraint by protein size on protein expression, protein size data (as above) was compared to data on protein abundance (molecules/cell) obtained by Ghaemmaghami et al . The comparison encompassed 3663 epitope-tagged open reading frames expressed from their natural chromosomal locus during exponential growth in optimal conditions.
To investigate whether the demand for increased protein size represents a demand for multiple functional domains and pleiotrophy, protein size data (as above) was compared to quantitative data on the phenotypes of haploid deletion strains cultivated in isolation. To avoid possible biases arising from the use of either a limited number of growth conditions or a limited number of deletion strains two separate sets of phenotypic data was used [27, 39]: i) phenotypic data on 96 deletion strains, randomly chosen with regards to protein size and cultivated in 40 diverse conditions of environmental stress ii) phenotypic data on all 4,220 deletion strains cultivated in optimal conditions as well as during four conditions of environmental stress – sodium chloride (salt stress), paraquat (superoxid anion production), diamide (elevated oxidation levels) and DTT (decreased oxidation levels). Strain- and environment normalized phenotypes (Logarithmic Phenotypic Indexes – LPI) reflecting genuine strain-by-environment interactions were used in both comparisons. Analyses using Logarithmic Strain Coefficient, LSC, data not normalized to the growth behavior of the knockout strain in non-stressed conditions yielded similar results (data not shown). Furthermore, to avoid possible biases arising from the use of phenotypic data representing a single component of fitness three distinct fitness indicators were used: i) time to adapt to the environmental stress (lag phase) ii) rate of reproduction during exponential growth and efficiency of growth (population density reached). Phenotypic data for all genes in question can be accessed at the Prophecy database .
Evolutionary rate/duplication data
To investigate the possibility of a correlation between protein size and the rate of individual protein evolution protein size data (as above) was compared to data dN/dS and dN/dS' ratios taken from Wall et al . The comparison comprised all genes conserved between four closely related species of the Saccharomyces sensu stricto group , excluding frame shifted or intron containing open reading frames, for a total of 2,918 genes.
To investigate whether the demand for increased protein size represents a demand for multiple protein-protein interaction domains, protein size data (as above) was compared to protein-protein interaction data obtained from the GRID database  encompassing several large scale yeast 2-hybrid and affinity precipitation studies as well as numerous small scale investigations. Protein-protein interaction data, corresponding to 25,215 interactions, was obtained for the 5,256 genes.
Functional classification data
To investigate whether the demand for increased protein size represents a demand for certain large biochemical domains, i.e. if certain biochemical functions are overrepresented among proteins of larger size, protein size data (as above) was compared to the GO biochemical activity classification data obtained from SGD . For each biochemical activity (total of 65 activities) the frequency in each protein size category was compared to the frequency among all proteins included in the study. Significant overrepresentations were determined assuming a hypergeometric data distribution. To account for the possibility of extensive sequence similarity causing the observed overrepresentation, an additional functional enrichment analysis was carried out excluding all paralogous yeast proteins. Yeast sequence paralogs were defined as yeast proteins with a (Blastp) sequence similarity (e-value) to another yeast protein of less than 10-10 over at least 50% of the coding sequence. With the exception of ribosomal proteins, the exclusion of paralogous proteins did not substantially affect the enrichment of specific functional classes. Protein size data was also compared to biological process classification data obtained from MIPS  in a similar manner.
J.W. is financially-supported by the National Research School in Genomics and Bioinformatics (Southwest Sweden).
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