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The impact of mutation and gene conversion on the local diversification of antigen genes in African trypanosomes.

Gjini E, Haydon DT, Barry JD, Cobbold CA - Mol. Biol. Evol. (2012)

Bottom Line: We find that diversifying gene conversion events with lower-identity partners occur at least five times less frequently than point mutations on variant surface glycoprotein (VSG) pairs, and the average imported conversion tract is between 14 and 25 nucleotides long.However, because of the high diversity introduced by gene conversion, the two processes have almost equal impact on the per-nucleotide rate of sequence diversification between VSG subfamily members.We are able to disentangle the most likely locations of point mutations and conversions on each aligned gene pair.

View Article: PubMed Central - PubMed

Affiliation: School of Mathematics and Statistics, College of Science and Engineering, University of Glasgow, Glasgow, United Kingdom. egjini@igc.gulbenkian.pt

ABSTRACT
Patterns of genetic diversity in parasite antigen gene families hold important information about their potential to generate antigenic variation within and between hosts. The evolution of such gene families is typically driven by gene duplication, followed by point mutation and gene conversion. There is great interest in estimating the rates of these processes from molecular sequences for understanding the evolution of the pathogen and its significance for infection processes. In this study, a series of models are constructed to investigate hypotheses about the nucleotide diversity patterns between closely related gene sequences from the antigen gene archive of the African trypanosome, the protozoan parasite causative of human sleeping sickness in Equatorial Africa. We use a hidden Markov model approach to identify two scales of diversification: clustering of sequence mismatches, a putative indicator of gene conversion events with other lower-identity donor genes in the archive, and at a sparser scale, isolated mismatches, likely arising from independent point mutations. In addition to quantifying the respective probabilities of occurrence of these two processes, our approach yields estimates for the gene conversion tract length distribution and the average diversity contributed locally by conversion events. Model fitting is conducted using a Bayesian framework. We find that diversifying gene conversion events with lower-identity partners occur at least five times less frequently than point mutations on variant surface glycoprotein (VSG) pairs, and the average imported conversion tract is between 14 and 25 nucleotides long. However, because of the high diversity introduced by gene conversion, the two processes have almost equal impact on the per-nucleotide rate of sequence diversification between VSG subfamily members. We are able to disentangle the most likely locations of point mutations and conversions on each aligned gene pair.

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Related in: MedlinePlus

Model diagrams. The four models differ in the assumptions they make about the nature of the evolutionary processes (depicted by line type) and the divergence time between the compared sequences (depicted by line length). Model 1 assumes point mutation and conversion are governed by the same parameters on all gene pairs, and each pair within a triplet shares the same “age” with other pairs. Model 2 assumes distinct triplet-specific probabilities of genetic processes, and it allows for triplet-specific conversion length distribution and conversion mismatch density. Model 3 assumes the processes occur universally at equal rates across triplets, including conversion length distribution and mismatch density; however, the divergence time of each triplet may be different. Model 4 assumes equal process rates across gene pairs, but it allows for within-triplet variation in divergence time.
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mss166-F2: Model diagrams. The four models differ in the assumptions they make about the nature of the evolutionary processes (depicted by line type) and the divergence time between the compared sequences (depicted by line length). Model 1 assumes point mutation and conversion are governed by the same parameters on all gene pairs, and each pair within a triplet shares the same “age” with other pairs. Model 2 assumes distinct triplet-specific probabilities of genetic processes, and it allows for triplet-specific conversion length distribution and conversion mismatch density. Model 3 assumes the processes occur universally at equal rates across triplets, including conversion length distribution and mismatch density; however, the divergence time of each triplet may be different. Model 4 assumes equal process rates across gene pairs, but it allows for within-triplet variation in divergence time.

Mentions: We construct different models to investigate competing hypotheses on the same data set. Each model is based on different assumptions about the origin of differences across aligned pairs (fig. 2). In the following, we present results for four models that we consider most relevant and biologically plausible:


The impact of mutation and gene conversion on the local diversification of antigen genes in African trypanosomes.

Gjini E, Haydon DT, Barry JD, Cobbold CA - Mol. Biol. Evol. (2012)

Model diagrams. The four models differ in the assumptions they make about the nature of the evolutionary processes (depicted by line type) and the divergence time between the compared sequences (depicted by line length). Model 1 assumes point mutation and conversion are governed by the same parameters on all gene pairs, and each pair within a triplet shares the same “age” with other pairs. Model 2 assumes distinct triplet-specific probabilities of genetic processes, and it allows for triplet-specific conversion length distribution and conversion mismatch density. Model 3 assumes the processes occur universally at equal rates across triplets, including conversion length distribution and mismatch density; however, the divergence time of each triplet may be different. Model 4 assumes equal process rates across gene pairs, but it allows for within-triplet variation in divergence time.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC3472502&req=5

mss166-F2: Model diagrams. The four models differ in the assumptions they make about the nature of the evolutionary processes (depicted by line type) and the divergence time between the compared sequences (depicted by line length). Model 1 assumes point mutation and conversion are governed by the same parameters on all gene pairs, and each pair within a triplet shares the same “age” with other pairs. Model 2 assumes distinct triplet-specific probabilities of genetic processes, and it allows for triplet-specific conversion length distribution and conversion mismatch density. Model 3 assumes the processes occur universally at equal rates across triplets, including conversion length distribution and mismatch density; however, the divergence time of each triplet may be different. Model 4 assumes equal process rates across gene pairs, but it allows for within-triplet variation in divergence time.
Mentions: We construct different models to investigate competing hypotheses on the same data set. Each model is based on different assumptions about the origin of differences across aligned pairs (fig. 2). In the following, we present results for four models that we consider most relevant and biologically plausible:

Bottom Line: We find that diversifying gene conversion events with lower-identity partners occur at least five times less frequently than point mutations on variant surface glycoprotein (VSG) pairs, and the average imported conversion tract is between 14 and 25 nucleotides long.However, because of the high diversity introduced by gene conversion, the two processes have almost equal impact on the per-nucleotide rate of sequence diversification between VSG subfamily members.We are able to disentangle the most likely locations of point mutations and conversions on each aligned gene pair.

View Article: PubMed Central - PubMed

Affiliation: School of Mathematics and Statistics, College of Science and Engineering, University of Glasgow, Glasgow, United Kingdom. egjini@igc.gulbenkian.pt

ABSTRACT
Patterns of genetic diversity in parasite antigen gene families hold important information about their potential to generate antigenic variation within and between hosts. The evolution of such gene families is typically driven by gene duplication, followed by point mutation and gene conversion. There is great interest in estimating the rates of these processes from molecular sequences for understanding the evolution of the pathogen and its significance for infection processes. In this study, a series of models are constructed to investigate hypotheses about the nucleotide diversity patterns between closely related gene sequences from the antigen gene archive of the African trypanosome, the protozoan parasite causative of human sleeping sickness in Equatorial Africa. We use a hidden Markov model approach to identify two scales of diversification: clustering of sequence mismatches, a putative indicator of gene conversion events with other lower-identity donor genes in the archive, and at a sparser scale, isolated mismatches, likely arising from independent point mutations. In addition to quantifying the respective probabilities of occurrence of these two processes, our approach yields estimates for the gene conversion tract length distribution and the average diversity contributed locally by conversion events. Model fitting is conducted using a Bayesian framework. We find that diversifying gene conversion events with lower-identity partners occur at least five times less frequently than point mutations on variant surface glycoprotein (VSG) pairs, and the average imported conversion tract is between 14 and 25 nucleotides long. However, because of the high diversity introduced by gene conversion, the two processes have almost equal impact on the per-nucleotide rate of sequence diversification between VSG subfamily members. We are able to disentangle the most likely locations of point mutations and conversions on each aligned gene pair.

Show MeSH
Related in: MedlinePlus