Dataset Information

Sequences conserved by selection across mouse and human malaria species.

ABSTRACT:

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Little is known, either experimentally or computationally, about the genomic sequence features that regulate malaria genes. A sequence conservation analysis of the malaria species P. falciparum, P. berghei, P. yoelii, and P. chabaudi could significantly advance knowledge of malaria gene regulation.

Results

We computationally identify intergenic sequences conserved beyond neutral expectations, using a conservation algorithm that accounts for the strong compositional biases in malaria genomes. We first quantify the composition-specific divergence at silent positions in coding sequence. Using this as a background, we examine gene 5' regions, identifying 610 blocks conserved far beyond neutral expectations across the three mouse malariae, and 81 blocks conserved as strongly across all four species (p < 10(-6)). Detailed analysis of these blocks indicates that only a minor fraction are likely to be previously unknown coding sequences. Analogous noncoding conserved blocks have been shown to regulate adjacent genes in other phylogenies, making the predicted blocks excellent candidates for novel regulatory functions. We also find three potential transcription factor binding motifs which exhibit strong conservation and overrepresentation among the rodent malariae.

Conclusion

A broader finding of our analysis is that less malaria intergenic sequence has been conserved by selection than in yeast or vertebrate genomes. This supports the hypothesis that transcriptional regulation is simpler in malaria than other eukaryotic species. We have built a public database containing all sequence alignments and functional predictions, and we expect this to be a valuable resource to the malaria research community.

SUBMITTER: Imamura H

PROVIDER: S-EPMC2174483 | biostudies-literature | 2007 Oct

REPOSITORIES: biostudies-literature

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Publications

Sequences conserved by selection across mouse and human malaria species.

Imamura Hideo H Persampieri Jason H JH Chuang Jeffrey H JH

BMC genomics 20071015

<h4>Unlabelled</h4>Little is known, either experimentally or computationally, about the genomic sequence features that regulate malaria genes. A sequence conservation analysis of the malaria species P. falciparum, P. berghei, P. yoelii, and P. chabaudi could significantly advance knowledge of malaria gene regulation.<h4>Results</h4>We computationally identify intergenic sequences conserved beyond neutral expectations, using a conservation algorithm that accounts for the strong compositional bias ...[more]

PMID: 17937810

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Project description:Comparison of polymorphism at synonymous and non-synonymous sites in protein-coding DNA can provide evidence for selective constraint. Non-coding DNA that forms part of the regulatory landscape presents more of a challenge since there is not such a clear-cut distinction between sites under stronger and weaker selective constraint. Here, we consider putative regulatory elements termed Conserved Non-coding Elements (CNEs) defined by their high level of sequence identity across all vertebrates. Some mutations in these regions have been implicated in developmental disorders; we analyse CNE polymorphism data to investigate whether such deleterious effects are widespread in humans. Single nucleotide variants from the HapMap and 1000 Genomes Projects were mapped across nearly 2000 CNEs. In the 1000 Genomes data we find a significant excess of rare derived alleles in CNEs relative to coding sequences; this pattern is absent in HapMap data, apparently obscured by ascertainment bias. The distribution of polymorphism within CNEs is not uniform; we could identify two categories of sites by exploiting deep vertebrate alignments: stretches that are non-variant, and those that have at least one substitution. The conserved category has fewer polymorphic sites and a greater excess of rare derived alleles, which can be explained by a large proportion of sites under strong purifying selection within humans--higher than that for non-synonymous sites in most protein coding regions, and comparable to that at the strongly conserved trans-dev genes. Conversely, the more evolutionarily labile CNE sites have an allele frequency distribution not significantly different from non-synonymous sites. Future studies should exploit genome-wide re-sequencing to obtain better coverage in selected non-coding regions, given the likelihood that mutations in evolutionarily conserved enhancer sequences are deleterious. Discovery pipelines should validate non-coding variants to aid in identifying causal and risk-enhancing variants in complex disorders, in contrast to the current focus on exome sequencing.

Dataset Information

Sequences conserved by selection across mouse and human malaria species.

Unlabelled

Results

Conclusion

Publications

Sequences conserved by selection across mouse and human malaria species.

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