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Evolutionary analyses of KCNQ1 and HERG voltage-gated potassium channel sequences reveal location-specific susceptibility and augmented chemical severities of arrhythmogenic mutations.

Jackson HA, Accili EA - BMC Evol. Biol. (2008)

Bottom Line: Using evolutionary analyses, AAMs in HERG and KCNQ1 were preferentially found at evolutionarily conserved sites and unevenly distributed among functionally conserved domains.Unlike nsSNPs, AAMs preferentially locate to evolutionarily conserved, and functionally important, sites and regions within HERG and KCNQ1, and are chemically more severe than changes which occur in evolution.Expected chemical severity may contribute to the overrepresentation of certain residues in AAMs, as well as to evolutionary change.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Cellular and Physiological Sciences, Faculty of Medicine, University of British Columbia, Vancouver, BC, V6T 1Z3, Canada. hajacks@interchange.ubc.ca

ABSTRACT

Background: Mutations in HERG and KCNQ1 potassium channels have been associated with Long QT syndrome and atrial fibrillation, and more recently with sudden infant death syndrome and sudden unexplained death. In other proteins, disease-associated amino acid mutations have been analyzed according to the chemical severity of the changes and the locations of the altered amino acids according to their conservation over metazoan evolution. Here, we present the first such analysis of arrhythmia-associated mutations (AAMs) in the HERG and KCNQ1 potassium channels.

Results: Using evolutionary analyses, AAMs in HERG and KCNQ1 were preferentially found at evolutionarily conserved sites and unevenly distributed among functionally conserved domains. Non-synonymous single nucleotide polymorphisms (nsSNPs) are under-represented at evolutionarily conserved sites in HERG, but distribute randomly in KCNQ1. AAMs are chemically more severe, according to Grantham's Scale, than changes observed in evolution and their severity correlates with the expected chemical severity of the involved codon. Expected chemical severity of a given amino acid also correlates with its relative contribution to arrhythmias. At evolutionarily variable sites, the chemical severity of the changes is also correlated with the expected chemical severity of the involved codon.

Conclusion: Unlike nsSNPs, AAMs preferentially locate to evolutionarily conserved, and functionally important, sites and regions within HERG and KCNQ1, and are chemically more severe than changes which occur in evolution. Expected chemical severity may contribute to the overrepresentation of certain residues in AAMs, as well as to evolutionary change.

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Arrhythmia-associated mutations in HERG and KCNQ1 are overrepresented at evolutionarily conserved and slowly evolving sites. a) Counts of observed (white bars) and expected (black bars) numbers of AAMs at amino acid sites in HERG and KCNQ1 which have undergone different numbers of substitutions among species (see methods). Because of a low number of expected mutations in the more variable positions, the X2 statistic was also calculated for pooled data with two bins, 0 and 1+, with 1 degree of freedom. The number of disease mutations observed at completely conserved sites (0-class) in both HERG and KCNQ1 is significantly higher than by chance alone: HERG, X2(5 df) = 37.41, p < 0.001 or X2(1 df) = 34.65, p < 0.001; KCNQ1, X2(5 df) = 50.45, p < 0.001 or X2(1 df) = 49.37, p < 0.001. b) Counts of observed and expected numbers of non-synonymous single nucleotide polymorphisms (nsSNPs). In HERG, fewer nsSNPs occur at completely conserved sites than expected by chance alone (X2(5 df) = 22.94, p < 0.001 or X2(1 df) = 10.07, p < 0.05) whereas in KCNQ1, the distribution is not significantly different from the expected count of neutral variation (X2(5 df) = 1.04, p > 0.05). c) Data were pooled to account for low numbers of expected AAMs at variable sites and significance was confirmed. The distribution of AAMs was significantly different than what would be expected by random chance for both HERG (X2(7 df) = 26.10, p < 0.001 or X2(1 df) = 14.17, p < 0.001) and KCNQ1 (X2(7 df) = 34.74, p < 0.001 or X2(1 df) = 18.15, p < 0.001).
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Figure 3: Arrhythmia-associated mutations in HERG and KCNQ1 are overrepresented at evolutionarily conserved and slowly evolving sites. a) Counts of observed (white bars) and expected (black bars) numbers of AAMs at amino acid sites in HERG and KCNQ1 which have undergone different numbers of substitutions among species (see methods). Because of a low number of expected mutations in the more variable positions, the X2 statistic was also calculated for pooled data with two bins, 0 and 1+, with 1 degree of freedom. The number of disease mutations observed at completely conserved sites (0-class) in both HERG and KCNQ1 is significantly higher than by chance alone: HERG, X2(5 df) = 37.41, p < 0.001 or X2(1 df) = 34.65, p < 0.001; KCNQ1, X2(5 df) = 50.45, p < 0.001 or X2(1 df) = 49.37, p < 0.001. b) Counts of observed and expected numbers of non-synonymous single nucleotide polymorphisms (nsSNPs). In HERG, fewer nsSNPs occur at completely conserved sites than expected by chance alone (X2(5 df) = 22.94, p < 0.001 or X2(1 df) = 10.07, p < 0.05) whereas in KCNQ1, the distribution is not significantly different from the expected count of neutral variation (X2(5 df) = 1.04, p > 0.05). c) Data were pooled to account for low numbers of expected AAMs at variable sites and significance was confirmed. The distribution of AAMs was significantly different than what would be expected by random chance for both HERG (X2(7 df) = 26.10, p < 0.001 or X2(1 df) = 14.17, p < 0.001) and KCNQ1 (X2(7 df) = 34.74, p < 0.001 or X2(1 df) = 18.15, p < 0.001).

Mentions: A greater proportion of AAMs are found at evolutionarily conserved sites, and a smaller proportion are found at variable sites, than would be expected by an underlying neutral process (Figure 3a). Using X2 analysis, the difference between the distributions of observed and expected disease mutations were statistically significant in both channels, even when only the numbers of disease harboring sites were analyzed (ruling out an effect of multiple mutations at highly mutable sites) or when data were pooled to account for low numbers of expected disease mutations in higher variability classes (data not shown). In KCNQ1, nsSNPs distribute randomly but, in HERG, they were significantly underrepresented at completely conserved sites and overabundant at variable positions (Figure 3b).


Evolutionary analyses of KCNQ1 and HERG voltage-gated potassium channel sequences reveal location-specific susceptibility and augmented chemical severities of arrhythmogenic mutations.

Jackson HA, Accili EA - BMC Evol. Biol. (2008)

Arrhythmia-associated mutations in HERG and KCNQ1 are overrepresented at evolutionarily conserved and slowly evolving sites. a) Counts of observed (white bars) and expected (black bars) numbers of AAMs at amino acid sites in HERG and KCNQ1 which have undergone different numbers of substitutions among species (see methods). Because of a low number of expected mutations in the more variable positions, the X2 statistic was also calculated for pooled data with two bins, 0 and 1+, with 1 degree of freedom. The number of disease mutations observed at completely conserved sites (0-class) in both HERG and KCNQ1 is significantly higher than by chance alone: HERG, X2(5 df) = 37.41, p < 0.001 or X2(1 df) = 34.65, p < 0.001; KCNQ1, X2(5 df) = 50.45, p < 0.001 or X2(1 df) = 49.37, p < 0.001. b) Counts of observed and expected numbers of non-synonymous single nucleotide polymorphisms (nsSNPs). In HERG, fewer nsSNPs occur at completely conserved sites than expected by chance alone (X2(5 df) = 22.94, p < 0.001 or X2(1 df) = 10.07, p < 0.05) whereas in KCNQ1, the distribution is not significantly different from the expected count of neutral variation (X2(5 df) = 1.04, p > 0.05). c) Data were pooled to account for low numbers of expected AAMs at variable sites and significance was confirmed. The distribution of AAMs was significantly different than what would be expected by random chance for both HERG (X2(7 df) = 26.10, p < 0.001 or X2(1 df) = 14.17, p < 0.001) and KCNQ1 (X2(7 df) = 34.74, p < 0.001 or X2(1 df) = 18.15, p < 0.001).
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Figure 3: Arrhythmia-associated mutations in HERG and KCNQ1 are overrepresented at evolutionarily conserved and slowly evolving sites. a) Counts of observed (white bars) and expected (black bars) numbers of AAMs at amino acid sites in HERG and KCNQ1 which have undergone different numbers of substitutions among species (see methods). Because of a low number of expected mutations in the more variable positions, the X2 statistic was also calculated for pooled data with two bins, 0 and 1+, with 1 degree of freedom. The number of disease mutations observed at completely conserved sites (0-class) in both HERG and KCNQ1 is significantly higher than by chance alone: HERG, X2(5 df) = 37.41, p < 0.001 or X2(1 df) = 34.65, p < 0.001; KCNQ1, X2(5 df) = 50.45, p < 0.001 or X2(1 df) = 49.37, p < 0.001. b) Counts of observed and expected numbers of non-synonymous single nucleotide polymorphisms (nsSNPs). In HERG, fewer nsSNPs occur at completely conserved sites than expected by chance alone (X2(5 df) = 22.94, p < 0.001 or X2(1 df) = 10.07, p < 0.05) whereas in KCNQ1, the distribution is not significantly different from the expected count of neutral variation (X2(5 df) = 1.04, p > 0.05). c) Data were pooled to account for low numbers of expected AAMs at variable sites and significance was confirmed. The distribution of AAMs was significantly different than what would be expected by random chance for both HERG (X2(7 df) = 26.10, p < 0.001 or X2(1 df) = 14.17, p < 0.001) and KCNQ1 (X2(7 df) = 34.74, p < 0.001 or X2(1 df) = 18.15, p < 0.001).
Mentions: A greater proportion of AAMs are found at evolutionarily conserved sites, and a smaller proportion are found at variable sites, than would be expected by an underlying neutral process (Figure 3a). Using X2 analysis, the difference between the distributions of observed and expected disease mutations were statistically significant in both channels, even when only the numbers of disease harboring sites were analyzed (ruling out an effect of multiple mutations at highly mutable sites) or when data were pooled to account for low numbers of expected disease mutations in higher variability classes (data not shown). In KCNQ1, nsSNPs distribute randomly but, in HERG, they were significantly underrepresented at completely conserved sites and overabundant at variable positions (Figure 3b).

Bottom Line: Using evolutionary analyses, AAMs in HERG and KCNQ1 were preferentially found at evolutionarily conserved sites and unevenly distributed among functionally conserved domains.Unlike nsSNPs, AAMs preferentially locate to evolutionarily conserved, and functionally important, sites and regions within HERG and KCNQ1, and are chemically more severe than changes which occur in evolution.Expected chemical severity may contribute to the overrepresentation of certain residues in AAMs, as well as to evolutionary change.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Cellular and Physiological Sciences, Faculty of Medicine, University of British Columbia, Vancouver, BC, V6T 1Z3, Canada. hajacks@interchange.ubc.ca

ABSTRACT

Background: Mutations in HERG and KCNQ1 potassium channels have been associated with Long QT syndrome and atrial fibrillation, and more recently with sudden infant death syndrome and sudden unexplained death. In other proteins, disease-associated amino acid mutations have been analyzed according to the chemical severity of the changes and the locations of the altered amino acids according to their conservation over metazoan evolution. Here, we present the first such analysis of arrhythmia-associated mutations (AAMs) in the HERG and KCNQ1 potassium channels.

Results: Using evolutionary analyses, AAMs in HERG and KCNQ1 were preferentially found at evolutionarily conserved sites and unevenly distributed among functionally conserved domains. Non-synonymous single nucleotide polymorphisms (nsSNPs) are under-represented at evolutionarily conserved sites in HERG, but distribute randomly in KCNQ1. AAMs are chemically more severe, according to Grantham's Scale, than changes observed in evolution and their severity correlates with the expected chemical severity of the involved codon. Expected chemical severity of a given amino acid also correlates with its relative contribution to arrhythmias. At evolutionarily variable sites, the chemical severity of the changes is also correlated with the expected chemical severity of the involved codon.

Conclusion: Unlike nsSNPs, AAMs preferentially locate to evolutionarily conserved, and functionally important, sites and regions within HERG and KCNQ1, and are chemically more severe than changes which occur in evolution. Expected chemical severity may contribute to the overrepresentation of certain residues in AAMs, as well as to evolutionary change.

Show MeSH
Related in: MedlinePlus