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Prevalence of multinucleotide replacements in evolution of primates and Drosophila.

Terekhanova NV, Bazykin GA, Neverov A, Kondrashov AS, Seplyarskiy VB - Mol. Biol. Evol. (2013)

Bottom Line: The plurality of MNRs affect nearby nucleotides, so that at least six times as many DNRs affect two adjacent nucleotide sites than sites 10 nucleotides apart.Still, approximately 60% of DNRs, and approximately 90% of TNRs, span distances more than two (or three) nucleotides.The prevalence of MNRs matches that is observed in data on de novo mutations and is also observed in the regions with the lowest sequence conservation, suggesting that MNRs mainly have mutational origin; however, epistatic selection and/or gene conversion may also play a role.

View Article: PubMed Central - PubMed

Affiliation: Department of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Moscow, Russia.

ABSTRACT
Evolution of sequences mostly involves independent changes at different sites. However, substitutions at neighboring sites may co-occur as multinucleotide replacement events (MNRs). Here, we compare noncoding sequences of several species of primates, and of three species of Drosophila fruit flies, in a phylogenetic analysis of the replacements that occurred between species at nearby nucleotide sites. Both in primates and in Drosophila, the frequency of single-nucleotide replacements is substantially elevated within 10 nucleotides from other replacements that occurred on the same lineage but not on another lineage. The data imply that dinucleotide replacements (DNRs) affecting sites at distances of up to 10 nucleotides from each other are responsible for 2.3% of single-nucleotide replacements in primate genomes and for 5.6% in Drosophila genomes. Among these DNRs, 26% and 69%, respectively, are in fact parts of replacements of three or more trinucleotide replacements (TNRs). The plurality of MNRs affect nearby nucleotides, so that at least six times as many DNRs affect two adjacent nucleotide sites than sites 10 nucleotides apart. Still, approximately 60% of DNRs, and approximately 90% of TNRs, span distances more than two (or three) nucleotides. MNRs make a major contribution to the observed clustering of substitutions: In the human-chimpanzee comparison, DNRs are responsible for 50% of cases when two nearby replacements are observed on the human lineage, and TNRs are responsible for 83% of cases when three replacements at three immediately adjacent sites are observed on the human lineage. The prevalence of MNRs matches that is observed in data on de novo mutations and is also observed in the regions with the lowest sequence conservation, suggesting that MNRs mainly have mutational origin; however, epistatic selection and/or gene conversion may also play a role.

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Inferring the frequencies of DNRs (A,B) and of TNRs (C–E). The schematic phylogenetic tree at the left represents, from top to bottom, the two sister species, focal and proxy, and the outgroup; the adjacent horizontal lines represent multiple sequence alignments for the corresponding species. (A,B) The frequencies of substitutions on the focal lineage are measured within the set of sites (vertical ovals), such that another substitution (vertical line) is observed at distance k from them on the proxy (A) or on the focal (B) lineage (dd(k) and sd(k), respectively). (C,D) The frequencies of pairs of substitutions on the focal lineage are measured within the set of sites (pairs of vertical ovals at distances l from each other), such that another substitution (vertical line) is observed at distance k from them on the proxy (A) or the focal (B) lineage (dt(k,l) and st(k,l), respectively). E, five scenarios that can give rise to three adjacent substitutions on the same lineage, from top to bottom: three distinct mutations; two distinct mutations (an arc connects positions involved in an MNR), one being a DNR involving the second and the third, the first and the second, or the first and the third of the three nucleotides; and one TNR.
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mst036-F1: Inferring the frequencies of DNRs (A,B) and of TNRs (C–E). The schematic phylogenetic tree at the left represents, from top to bottom, the two sister species, focal and proxy, and the outgroup; the adjacent horizontal lines represent multiple sequence alignments for the corresponding species. (A,B) The frequencies of substitutions on the focal lineage are measured within the set of sites (vertical ovals), such that another substitution (vertical line) is observed at distance k from them on the proxy (A) or on the focal (B) lineage (dd(k) and sd(k), respectively). (C,D) The frequencies of pairs of substitutions on the focal lineage are measured within the set of sites (pairs of vertical ovals at distances l from each other), such that another substitution (vertical line) is observed at distance k from them on the proxy (A) or the focal (B) lineage (dt(k,l) and st(k,l), respectively). E, five scenarios that can give rise to three adjacent substitutions on the same lineage, from top to bottom: three distinct mutations; two distinct mutations (an arc connects positions involved in an MNR), one being a DNR involving the second and the third, the first and the second, or the first and the third of the three nucleotides; and one TNR.

Mentions: To estimate the fraction α of single-nucleotide replacements that occurred as part of an MNR, we use a phylogenetic approach (fig. 1). In each analysis, we consider a trio of species, including the “focal” species (Homo sapiens or Drosophila melanogaster), a “proxy” sister species, and an outgroup. Using the outgroup to infer the ancestral state, we then consider the replacements that have occurred either on the focal or on the proxy lineage since their divergence from their last common ancestor. The logic of the analysis is as follows. Replacements on different lineages may occur only as independent events; conversely, multiple nearby replacements on the same lineage may occur either as independent events or as MNRs. Therefore, to calculate the rate of DNRs αd(k), we compare the conditional frequencies of substitutions on the focal lineage, given another substitution that has occurred at distance k nucleotides on the focal lineage (sd(k)) or on the proxy lineage (dd(k)):Fig. 1.


Prevalence of multinucleotide replacements in evolution of primates and Drosophila.

Terekhanova NV, Bazykin GA, Neverov A, Kondrashov AS, Seplyarskiy VB - Mol. Biol. Evol. (2013)

Inferring the frequencies of DNRs (A,B) and of TNRs (C–E). The schematic phylogenetic tree at the left represents, from top to bottom, the two sister species, focal and proxy, and the outgroup; the adjacent horizontal lines represent multiple sequence alignments for the corresponding species. (A,B) The frequencies of substitutions on the focal lineage are measured within the set of sites (vertical ovals), such that another substitution (vertical line) is observed at distance k from them on the proxy (A) or on the focal (B) lineage (dd(k) and sd(k), respectively). (C,D) The frequencies of pairs of substitutions on the focal lineage are measured within the set of sites (pairs of vertical ovals at distances l from each other), such that another substitution (vertical line) is observed at distance k from them on the proxy (A) or the focal (B) lineage (dt(k,l) and st(k,l), respectively). E, five scenarios that can give rise to three adjacent substitutions on the same lineage, from top to bottom: three distinct mutations; two distinct mutations (an arc connects positions involved in an MNR), one being a DNR involving the second and the third, the first and the second, or the first and the third of the three nucleotides; and one TNR.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3649671&req=5

mst036-F1: Inferring the frequencies of DNRs (A,B) and of TNRs (C–E). The schematic phylogenetic tree at the left represents, from top to bottom, the two sister species, focal and proxy, and the outgroup; the adjacent horizontal lines represent multiple sequence alignments for the corresponding species. (A,B) The frequencies of substitutions on the focal lineage are measured within the set of sites (vertical ovals), such that another substitution (vertical line) is observed at distance k from them on the proxy (A) or on the focal (B) lineage (dd(k) and sd(k), respectively). (C,D) The frequencies of pairs of substitutions on the focal lineage are measured within the set of sites (pairs of vertical ovals at distances l from each other), such that another substitution (vertical line) is observed at distance k from them on the proxy (A) or the focal (B) lineage (dt(k,l) and st(k,l), respectively). E, five scenarios that can give rise to three adjacent substitutions on the same lineage, from top to bottom: three distinct mutations; two distinct mutations (an arc connects positions involved in an MNR), one being a DNR involving the second and the third, the first and the second, or the first and the third of the three nucleotides; and one TNR.
Mentions: To estimate the fraction α of single-nucleotide replacements that occurred as part of an MNR, we use a phylogenetic approach (fig. 1). In each analysis, we consider a trio of species, including the “focal” species (Homo sapiens or Drosophila melanogaster), a “proxy” sister species, and an outgroup. Using the outgroup to infer the ancestral state, we then consider the replacements that have occurred either on the focal or on the proxy lineage since their divergence from their last common ancestor. The logic of the analysis is as follows. Replacements on different lineages may occur only as independent events; conversely, multiple nearby replacements on the same lineage may occur either as independent events or as MNRs. Therefore, to calculate the rate of DNRs αd(k), we compare the conditional frequencies of substitutions on the focal lineage, given another substitution that has occurred at distance k nucleotides on the focal lineage (sd(k)) or on the proxy lineage (dd(k)):Fig. 1.

Bottom Line: The plurality of MNRs affect nearby nucleotides, so that at least six times as many DNRs affect two adjacent nucleotide sites than sites 10 nucleotides apart.Still, approximately 60% of DNRs, and approximately 90% of TNRs, span distances more than two (or three) nucleotides.The prevalence of MNRs matches that is observed in data on de novo mutations and is also observed in the regions with the lowest sequence conservation, suggesting that MNRs mainly have mutational origin; however, epistatic selection and/or gene conversion may also play a role.

View Article: PubMed Central - PubMed

Affiliation: Department of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Moscow, Russia.

ABSTRACT
Evolution of sequences mostly involves independent changes at different sites. However, substitutions at neighboring sites may co-occur as multinucleotide replacement events (MNRs). Here, we compare noncoding sequences of several species of primates, and of three species of Drosophila fruit flies, in a phylogenetic analysis of the replacements that occurred between species at nearby nucleotide sites. Both in primates and in Drosophila, the frequency of single-nucleotide replacements is substantially elevated within 10 nucleotides from other replacements that occurred on the same lineage but not on another lineage. The data imply that dinucleotide replacements (DNRs) affecting sites at distances of up to 10 nucleotides from each other are responsible for 2.3% of single-nucleotide replacements in primate genomes and for 5.6% in Drosophila genomes. Among these DNRs, 26% and 69%, respectively, are in fact parts of replacements of three or more trinucleotide replacements (TNRs). The plurality of MNRs affect nearby nucleotides, so that at least six times as many DNRs affect two adjacent nucleotide sites than sites 10 nucleotides apart. Still, approximately 60% of DNRs, and approximately 90% of TNRs, span distances more than two (or three) nucleotides. MNRs make a major contribution to the observed clustering of substitutions: In the human-chimpanzee comparison, DNRs are responsible for 50% of cases when two nearby replacements are observed on the human lineage, and TNRs are responsible for 83% of cases when three replacements at three immediately adjacent sites are observed on the human lineage. The prevalence of MNRs matches that is observed in data on de novo mutations and is also observed in the regions with the lowest sequence conservation, suggesting that MNRs mainly have mutational origin; however, epistatic selection and/or gene conversion may also play a role.

Show MeSH