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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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Data phylogenetic structure. The phylogenetic tree of the five VSG triplets considered in our study. A total of 15 VSG sequences from the antigen gene archive of African trypanosomes were extracted from the VSG database (http://www.vsgdb.net) and multiply aligned by CLUSTALw. The close relatedness between genes within the same triplet suggests recent divergence from a common ancestor.
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mss166-F1: Data phylogenetic structure. The phylogenetic tree of the five VSG triplets considered in our study. A total of 15 VSG sequences from the antigen gene archive of African trypanosomes were extracted from the VSG database (http://www.vsgdb.net) and multiply aligned by CLUSTALw. The close relatedness between genes within the same triplet suggests recent divergence from a common ancestor.

Mentions: We examined a VSG data set consisting of five triplets of high-identity VSG genes, from the antigen gene archive of African trypanosomes (fig. 1). The 15 genes were obtained from the trypanosome VSG database (http://www.vsgdb.net), with the members of each triplet being 1) Tb927.5.5260, Tb09.160.0100, Tb11.38.0005; 2) Tb09.244.1860, Tb11.57.0027, Tb09.244.0130; 3) Tb927.3.400, Tb08.27P2.680, Tb09.244. 0900; 4) Tb09.244.1850, Tb09.244.0 140, Tb11.57.0026; and 5) Tb09.v2.0430, Tb09.v4.0178, Tb927.6.5210. In the chronic stages of trypanosome infection, such highly related genes can recombine with expressed genes and form novel mosaic genes that can sustain parasite antigenic variation. Given the importance of N-domain hypervariability in determining the epitopes essential for antigenic variation of this parasite, our analysis is restricted to the N-domain encoding regions of these genes (supplementary material SI1, Supplementary Material online, for details). The pairwise alignments used in the analysis were performed by CLUSTALW (Thompson et al. 1994), aligning the three genes of each triplet separately and subsequently retaining only the N-domain encoding regions, comprising ∼1,050 nucleotides on average. Pairwise nucleotide identity within the same triplet ranges between 80% and 90%, whereas gene comparisons across triplets display a much lower identity of approximately 50%. Because we are interested in understanding the evolutionary processes that diversify high-identity gene pairs, we consider only pairwise alignments within the same triplet (3 pairs per triplet), thus obtaining a total of 15 pairwise alignments.Fig. 1.


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)

Data phylogenetic structure. The phylogenetic tree of the five VSG triplets considered in our study. A total of 15 VSG sequences from the antigen gene archive of African trypanosomes were extracted from the VSG database (http://www.vsgdb.net) and multiply aligned by CLUSTALw. The close relatedness between genes within the same triplet suggests recent divergence from a common ancestor.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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

mss166-F1: Data phylogenetic structure. The phylogenetic tree of the five VSG triplets considered in our study. A total of 15 VSG sequences from the antigen gene archive of African trypanosomes were extracted from the VSG database (http://www.vsgdb.net) and multiply aligned by CLUSTALw. The close relatedness between genes within the same triplet suggests recent divergence from a common ancestor.
Mentions: We examined a VSG data set consisting of five triplets of high-identity VSG genes, from the antigen gene archive of African trypanosomes (fig. 1). The 15 genes were obtained from the trypanosome VSG database (http://www.vsgdb.net), with the members of each triplet being 1) Tb927.5.5260, Tb09.160.0100, Tb11.38.0005; 2) Tb09.244.1860, Tb11.57.0027, Tb09.244.0130; 3) Tb927.3.400, Tb08.27P2.680, Tb09.244. 0900; 4) Tb09.244.1850, Tb09.244.0 140, Tb11.57.0026; and 5) Tb09.v2.0430, Tb09.v4.0178, Tb927.6.5210. In the chronic stages of trypanosome infection, such highly related genes can recombine with expressed genes and form novel mosaic genes that can sustain parasite antigenic variation. Given the importance of N-domain hypervariability in determining the epitopes essential for antigenic variation of this parasite, our analysis is restricted to the N-domain encoding regions of these genes (supplementary material SI1, Supplementary Material online, for details). The pairwise alignments used in the analysis were performed by CLUSTALW (Thompson et al. 1994), aligning the three genes of each triplet separately and subsequently retaining only the N-domain encoding regions, comprising ∼1,050 nucleotides on average. Pairwise nucleotide identity within the same triplet ranges between 80% and 90%, whereas gene comparisons across triplets display a much lower identity of approximately 50%. Because we are interested in understanding the evolutionary processes that diversify high-identity gene pairs, we consider only pairwise alignments within the same triplet (3 pairs per triplet), thus obtaining a total of 15 pairwise alignments.Fig. 1.

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