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Expression patterns of protein kinases correlate with gene architecture and evolutionary rates.

Ogurtsov AY, Mariño-Ramírez L, Johnson GR, Landsman D, Shabalina SA, Spiridonov NA - PLoS ONE (2008)

Bottom Line: The primary transcript length of PK genes, similar to other protein coding genes, inversely correlates with gene expression level and expression breadth, which is likely due to the necessity to reduce metabolic costs of transcription for abundant messages.Structure and evolutionary divergence of tissue-specific PK genes is related to the proliferative activity of the tissue where these genes are predominantly expressed.Our data provide evidence that physiological requirements for transcription intensity, ubiquitous expression, and tissue-specific regulation shape gene structure and affect rates of evolution.

View Article: PubMed Central - PubMed

Affiliation: National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, Maryland, USA.

ABSTRACT

Background: Protein kinase (PK) genes comprise the third largest superfamily that occupy approximately 2% of the human genome. They encode regulatory enzymes that control a vast variety of cellular processes through phosphorylation of their protein substrates. Expression of PK genes is subject to complex transcriptional regulation which is not fully understood.

Principal findings: Our comparative analysis demonstrates that genomic organization of regulatory PK genes differs from organization of other protein coding genes. PK genes occupy larger genomic loci, have longer introns, spacer regions, and encode larger proteins. The primary transcript length of PK genes, similar to other protein coding genes, inversely correlates with gene expression level and expression breadth, which is likely due to the necessity to reduce metabolic costs of transcription for abundant messages. On average, PK genes evolve slower than other protein coding genes. Breadth of PK expression negatively correlates with rate of non-synonymous substitutions in protein coding regions. This rate is lower for high expression and ubiquitous PKs, relative to low expression PKs, and correlates with divergence in untranslated regions. Conversely, rate of silent mutations is uniform in different PK groups, indicating that differing rates of non-synonymous substitutions reflect variations in selective pressure. Brain and testis employ a considerable number of tissue-specific PKs, indicating high complexity of phosphorylation-dependent regulatory network in these organs. There are considerable differences in genomic organization between PKs up-regulated in the testis and brain. PK genes up-regulated in the highly proliferative testicular tissue are fast evolving and small, with short introns and transcribed regions. In contrast, genes up-regulated in the minimally proliferative nervous tissue carry long introns, extended transcribed regions, and evolve slowly.

Conclusions/significance: PK genomic architecture, the size of gene functional domains and evolutionary rates correlate with the pattern of gene expression. Structure and evolutionary divergence of tissue-specific PK genes is related to the proliferative activity of the tissue where these genes are predominantly expressed. Our data provide evidence that physiological requirements for transcription intensity, ubiquitous expression, and tissue-specific regulation shape gene structure and affect rates of evolution.

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Related in: MedlinePlus

RNA secondary structures in the vicinity of the start codon.A. Profiles of nucleotide base pairing in the vicinity of the start codon for abundant and rare PK transcripts. Nucleotide positions are shown relative to translation start codon. B. Examples of predicted local secondary structures in the vicinity of the start codon for an abundant PK transcript (VRK1, NM_003384) and a rare PK transcript (MYLK4, NM_001012418). Start codons are shown in blue.
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pone-0003599-g006: RNA secondary structures in the vicinity of the start codon.A. Profiles of nucleotide base pairing in the vicinity of the start codon for abundant and rare PK transcripts. Nucleotide positions are shown relative to translation start codon. B. Examples of predicted local secondary structures in the vicinity of the start codon for an abundant PK transcript (VRK1, NM_003384) and a rare PK transcript (MYLK4, NM_001012418). Start codons are shown in blue.

Mentions: It was shown earlier that selection may be operating in the protein coding regions on most variable synonymous positions to maintain a more stable and ordered mRNA secondary structures [30]. To evaluate secondary structures in 5′UTRs, we computationally “folded” sequences of mature PK transcripts. In agreement with the results of transcriptome-wide analysis of mammalian mRNA folding, we found that secondary structures are frequently formed in PK transcripts between UTRs and CDSs in the vicinity of the start and stop codons (Figure S4). Sequences immediately upstream from the start codon have strong hybridization affinity to the N-terminal coding sequences, thus promoting formation of local hairpin structures where the start codon is positioned at the end of a hairpin in a relaxed loop (Figure 6). This type of secondary structure was facilitated by the enhanced GC-content in the N-terminal protein coding regions, and was observed in both abundant and rare transcripts. However, thermodynamic stability of these characteristic hairpin structures was significantly higher for abundant PK transcripts, than for rare transcripts (p<10−5).


Expression patterns of protein kinases correlate with gene architecture and evolutionary rates.

Ogurtsov AY, Mariño-Ramírez L, Johnson GR, Landsman D, Shabalina SA, Spiridonov NA - PLoS ONE (2008)

RNA secondary structures in the vicinity of the start codon.A. Profiles of nucleotide base pairing in the vicinity of the start codon for abundant and rare PK transcripts. Nucleotide positions are shown relative to translation start codon. B. Examples of predicted local secondary structures in the vicinity of the start codon for an abundant PK transcript (VRK1, NM_003384) and a rare PK transcript (MYLK4, NM_001012418). Start codons are shown in blue.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2572838&req=5

pone-0003599-g006: RNA secondary structures in the vicinity of the start codon.A. Profiles of nucleotide base pairing in the vicinity of the start codon for abundant and rare PK transcripts. Nucleotide positions are shown relative to translation start codon. B. Examples of predicted local secondary structures in the vicinity of the start codon for an abundant PK transcript (VRK1, NM_003384) and a rare PK transcript (MYLK4, NM_001012418). Start codons are shown in blue.
Mentions: It was shown earlier that selection may be operating in the protein coding regions on most variable synonymous positions to maintain a more stable and ordered mRNA secondary structures [30]. To evaluate secondary structures in 5′UTRs, we computationally “folded” sequences of mature PK transcripts. In agreement with the results of transcriptome-wide analysis of mammalian mRNA folding, we found that secondary structures are frequently formed in PK transcripts between UTRs and CDSs in the vicinity of the start and stop codons (Figure S4). Sequences immediately upstream from the start codon have strong hybridization affinity to the N-terminal coding sequences, thus promoting formation of local hairpin structures where the start codon is positioned at the end of a hairpin in a relaxed loop (Figure 6). This type of secondary structure was facilitated by the enhanced GC-content in the N-terminal protein coding regions, and was observed in both abundant and rare transcripts. However, thermodynamic stability of these characteristic hairpin structures was significantly higher for abundant PK transcripts, than for rare transcripts (p<10−5).

Bottom Line: The primary transcript length of PK genes, similar to other protein coding genes, inversely correlates with gene expression level and expression breadth, which is likely due to the necessity to reduce metabolic costs of transcription for abundant messages.Structure and evolutionary divergence of tissue-specific PK genes is related to the proliferative activity of the tissue where these genes are predominantly expressed.Our data provide evidence that physiological requirements for transcription intensity, ubiquitous expression, and tissue-specific regulation shape gene structure and affect rates of evolution.

View Article: PubMed Central - PubMed

Affiliation: National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, Maryland, USA.

ABSTRACT

Background: Protein kinase (PK) genes comprise the third largest superfamily that occupy approximately 2% of the human genome. They encode regulatory enzymes that control a vast variety of cellular processes through phosphorylation of their protein substrates. Expression of PK genes is subject to complex transcriptional regulation which is not fully understood.

Principal findings: Our comparative analysis demonstrates that genomic organization of regulatory PK genes differs from organization of other protein coding genes. PK genes occupy larger genomic loci, have longer introns, spacer regions, and encode larger proteins. The primary transcript length of PK genes, similar to other protein coding genes, inversely correlates with gene expression level and expression breadth, which is likely due to the necessity to reduce metabolic costs of transcription for abundant messages. On average, PK genes evolve slower than other protein coding genes. Breadth of PK expression negatively correlates with rate of non-synonymous substitutions in protein coding regions. This rate is lower for high expression and ubiquitous PKs, relative to low expression PKs, and correlates with divergence in untranslated regions. Conversely, rate of silent mutations is uniform in different PK groups, indicating that differing rates of non-synonymous substitutions reflect variations in selective pressure. Brain and testis employ a considerable number of tissue-specific PKs, indicating high complexity of phosphorylation-dependent regulatory network in these organs. There are considerable differences in genomic organization between PKs up-regulated in the testis and brain. PK genes up-regulated in the highly proliferative testicular tissue are fast evolving and small, with short introns and transcribed regions. In contrast, genes up-regulated in the minimally proliferative nervous tissue carry long introns, extended transcribed regions, and evolve slowly.

Conclusions/significance: PK genomic architecture, the size of gene functional domains and evolutionary rates correlate with the pattern of gene expression. Structure and evolutionary divergence of tissue-specific PK genes is related to the proliferative activity of the tissue where these genes are predominantly expressed. Our data provide evidence that physiological requirements for transcription intensity, ubiquitous expression, and tissue-specific regulation shape gene structure and affect rates of evolution.

Show MeSH
Related in: MedlinePlus