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A simple method for estimating the strength of natural selection on overlapping genes.

ABSTRACT: Overlapping genes, where one DNA sequence codes for two proteins with different reading frames, are not uncommon in viruses and cellular organisms. Estimating the direction and strength of natural selection acting on overlapping genes is important for understanding their functionality, origin, evolution, maintenance, and potential interaction. However, the standard methods for estimating synonymous (dS) and nonsynonymous (dN) nucleotide substitution rates are inapplicable here because a nucleotide change can be simultaneously synonymous and nonsynonymous when both reading frames involved are considered. We have developed a simple method that can estimate dN/dS and test for the action of natural selection in each relevant reading frame of the overlapping genes. Our method is an extension of the modified Nei-Gojobori method previously developed for nonoverlapping genes. We confirmed the reliability of our method using extensive computer simulation. Applying this method, we studied the longest human sense-antisense overlapping gene pair, LRRC8E and ENSG00000214248. Although LRRC8E (leucine-rich repeat containing eight family, member E) is known to regulate cell size, the function of ENSG00000214248 is unknown. Our analysis revealed purifying selection on ENSG00000214248 and suggested that it originated in the common ancestor of bony vertebrates.

SUBMITTER: Wei X

PROVIDER: S-EPMC4316641 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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A simple method for estimating the strength of natural selection on overlapping genes.

Wei Xinzhu X Zhang Jianzhi J

Genome biology and evolution 20141231 1

Overlapping genes, where one DNA sequence codes for two proteins with different reading frames, are not uncommon in viruses and cellular organisms. Estimating the direction and strength of natural selection acting on overlapping genes is important for understanding their functionality, origin, evolution, maintenance, and potential interaction. However, the standard methods for estimating synonymous (dS) and nonsynonymous (dN) nucleotide substitution rates are inapplicable here because a nucleoti ...[more]

PMID: 25552532

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Project description:Neutral mutations may hitchhike to high frequency when they are situated close to sites under positive selection, generating local reductions in genetic diversity. This process is thought to be an important determinant of levels of genomic variation in natural populations. The size of genome regions affected by genetic hitchhiking is expected to be dependent on the strength of selection, but there is little empirical data supporting this prediction. Here, we compare microsatellite variation around two drug resistance genes (chloroquine resistance transporter (pfcrt), chromosome 7, and dihydrofolate reductase (dhfr), chromosome 4) in malaria parasite populations exposed to strong (Thailand) or weak selection (Laos) by anti-malarial drugs. In each population, we examined the point mutations underlying resistance and length variation at 22 (chromosome 4) or 25 (chromosome 7) microsatellite markers across these chromosomes. All parasites from Thailand carried the K76T mutation in pfcrt conferring resistance to chloroquine (CQ) and 2-4 mutations in dhfr conferring resistance to pyrimethamine. By contrast, we found both wild-type and resistant alleles at both genes in Laos. There were dramatic differences in the extent of hitchhiking in the two countries. The size of genome regions affected was smaller in Laos than in Thailand. We observed significant reduction in variation relative to sensitive parasites for 34-64 kb (2-4 cM) in Laos on chromosome 4, compared with 98-137 kb (6-8 cM) in Thailand. Similarly, on chromosome 7, we observed reduced variation for 34-69 kb (2-4 cM) around pfcrt in Laos, but for 195-268 kb (11-16 cM) in Thailand. Reduction in genetic variation was also less extreme in Laos than in Thailand. Most loci were monomorphic in a 12 kb region surrounding both genes on resistant chromosomes from Thailand, whereas in Laos, even loci immediately proximal to selective sites showed some variation on resistant chromosomes. Finally, linkage disequilibrium (LD) decayed more rapidly around resistant pfcrt and dhfr alleles from Laos than from Thailand. These results demonstrate that different realizations of the same selective sweeps may vary considerably in size and shape, in a manner broadly consistent with selection history. From a practical perspective, genomic regions containing resistance genes may be most effectively located by genome-wide association in populations exposed to strong drug selection. However, the lower levels of LD surrounding resistance alleles in populations under weak selection may simplify identification of functional mutations.

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A simple method for estimating the strength of natural selection on overlapping genes.

Publications

A simple method for estimating the strength of natural selection on overlapping genes.

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