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Patterns of positive selection in six Mammalian genomes.

Kosiol C, Vinar T, da Fonseca RR, Hubisz MJ, Bustamante CD, Nielsen R, Siepel A - PLoS Genet. (2008)

Bottom Line: The increased phylogenetic depth of this dataset results in substantially improved statistical power, and permits several new lineage- and clade-specific tests to be applied.A detailed analysis of Affymetrix exon array data indicated that PSGs are expressed at significantly lower levels, and in a more tissue-specific manner, than non-PSGs.Genes that are specifically expressed in the spleen, testes, liver, and breast are significantly enriched for PSGs, but no evidence was found for an enrichment for PSGs among brain-specific genes.

View Article: PubMed Central - PubMed

Affiliation: Department of Biological Statistics and Computational Biology, Cornell University, Ithaca, New York, United States of America.

ABSTRACT
Genome-wide scans for positively selected genes (PSGs) in mammals have provided insight into the dynamics of genome evolution, the genetic basis of differences between species, and the functions of individual genes. However, previous scans have been limited in power and accuracy owing to small numbers of available genomes. Here we present the most comprehensive examination of mammalian PSGs to date, using the six high-coverage genome assemblies now available for eutherian mammals. The increased phylogenetic depth of this dataset results in substantially improved statistical power, and permits several new lineage- and clade-specific tests to be applied. Of approximately 16,500 human genes with high-confidence orthologs in at least two other species, 400 genes showed significant evidence of positive selection (FDR<0.05), according to a standard likelihood ratio test. An additional 144 genes showed evidence of positive selection on particular lineages or clades. As in previous studies, the identified PSGs were enriched for roles in defense/immunity, chemosensory perception, and reproduction, but enrichments were also evident for more specific functions, such as complement-mediated immunity and taste perception. Several pathways were strongly enriched for PSGs, suggesting possible co-evolution of interacting genes. A novel Bayesian analysis of the possible "selection histories" of each gene indicated that most PSGs have switched multiple times between positive selection and nonselection, suggesting that positive selection is often episodic. A detailed analysis of Affymetrix exon array data indicated that PSGs are expressed at significantly lower levels, and in a more tissue-specific manner, than non-PSGs. Genes that are specifically expressed in the spleen, testes, liver, and breast are significantly enriched for PSGs, but no evidence was found for an enrichment for PSGs among brain-specific genes. This study provides additional evidence for widespread positive selection in mammalian evolution and new genome-wide insights into the functional implications of positive selection.

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Distributions of expression levels in PSGs (red) and non-PSGs (blue) for three tissue types.(A–C) Distributions as estimated from Affymetrix Human Exon 1.0 ST Array data by the RMA algorithm [88]. The other eight tissue types showed similar differences between PSGs and non-PSGs (Figure S7). (D) Distribution of degree of tissue bias in expression levels for PSGs (red) and non-PSGs (blue), as measured by the statistic τ[61] (Methods). An alternative measure of tissue bias (γ) showed a similar pattern.
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pgen-1000144-g005: Distributions of expression levels in PSGs (red) and non-PSGs (blue) for three tissue types.(A–C) Distributions as estimated from Affymetrix Human Exon 1.0 ST Array data by the RMA algorithm [88]. The other eight tissue types showed similar differences between PSGs and non-PSGs (Figure S7). (D) Distribution of degree of tissue bias in expression levels for PSGs (red) and non-PSGs (blue), as measured by the statistic τ[61] (Methods). An alternative measure of tissue bias (γ) showed a similar pattern.

Mentions: We examined the human mRNA expression levels of PSGs non-PSGs using public data from the Affymetrix Human Exon 1.0 ST Array, which contains probes for nearly all of our genes and permits accurate estimation of expression levels [60]. Our most striking finding was that PSGs show reduced expression levels in all of the 11 available tissues (breast, cerebellum, heart, kidney, liver, muscle, pancreas, prostate, spleen, testes, and thyroid; see Methods). In particular, a significantly smaller fraction of PSGs than of non-PSGs produce a hybridization signal above the background level for the array (P<4×10−4 in all tissues for PSGs defined by the all-branch test, one-sided FET). Moreover, among genes expressed above background, expression levels are significantly lower for PSGs than for non-PSGs (P<7×10−5 in all tissues, one-sided MWU test; Figures 5A–C). PSGs also show significantly greater tissue bias than non-PSGs, as measured by the statistic τ[61] (Figure 5D) or by an alternative statistic here denoted γ[17] (Methods). The differences in expression level and tissue bias between the two sets of genes do not appear to be explained by differences in false negative or false positive rates in the detection of positive selection, and the differences in expression level do not appear to be a consequence of the differences in tissue bias (Text S1). In addition, the observed differences remain if the genes that belong to strongly enriched GO categories (Table 2) are excluded, indicating they cannot be attributed to particular classes of PSGs known to have tissue-specific expression patterns, such as those involved in immunity or spermatogenesis. That expression levels are reduced in all tissues further suggests the existence of a general relationship between expression patterns and the likelihood of positive selection.


Patterns of positive selection in six Mammalian genomes.

Kosiol C, Vinar T, da Fonseca RR, Hubisz MJ, Bustamante CD, Nielsen R, Siepel A - PLoS Genet. (2008)

Distributions of expression levels in PSGs (red) and non-PSGs (blue) for three tissue types.(A–C) Distributions as estimated from Affymetrix Human Exon 1.0 ST Array data by the RMA algorithm [88]. The other eight tissue types showed similar differences between PSGs and non-PSGs (Figure S7). (D) Distribution of degree of tissue bias in expression levels for PSGs (red) and non-PSGs (blue), as measured by the statistic τ[61] (Methods). An alternative measure of tissue bias (γ) showed a similar pattern.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2483296&req=5

pgen-1000144-g005: Distributions of expression levels in PSGs (red) and non-PSGs (blue) for three tissue types.(A–C) Distributions as estimated from Affymetrix Human Exon 1.0 ST Array data by the RMA algorithm [88]. The other eight tissue types showed similar differences between PSGs and non-PSGs (Figure S7). (D) Distribution of degree of tissue bias in expression levels for PSGs (red) and non-PSGs (blue), as measured by the statistic τ[61] (Methods). An alternative measure of tissue bias (γ) showed a similar pattern.
Mentions: We examined the human mRNA expression levels of PSGs non-PSGs using public data from the Affymetrix Human Exon 1.0 ST Array, which contains probes for nearly all of our genes and permits accurate estimation of expression levels [60]. Our most striking finding was that PSGs show reduced expression levels in all of the 11 available tissues (breast, cerebellum, heart, kidney, liver, muscle, pancreas, prostate, spleen, testes, and thyroid; see Methods). In particular, a significantly smaller fraction of PSGs than of non-PSGs produce a hybridization signal above the background level for the array (P<4×10−4 in all tissues for PSGs defined by the all-branch test, one-sided FET). Moreover, among genes expressed above background, expression levels are significantly lower for PSGs than for non-PSGs (P<7×10−5 in all tissues, one-sided MWU test; Figures 5A–C). PSGs also show significantly greater tissue bias than non-PSGs, as measured by the statistic τ[61] (Figure 5D) or by an alternative statistic here denoted γ[17] (Methods). The differences in expression level and tissue bias between the two sets of genes do not appear to be explained by differences in false negative or false positive rates in the detection of positive selection, and the differences in expression level do not appear to be a consequence of the differences in tissue bias (Text S1). In addition, the observed differences remain if the genes that belong to strongly enriched GO categories (Table 2) are excluded, indicating they cannot be attributed to particular classes of PSGs known to have tissue-specific expression patterns, such as those involved in immunity or spermatogenesis. That expression levels are reduced in all tissues further suggests the existence of a general relationship between expression patterns and the likelihood of positive selection.

Bottom Line: The increased phylogenetic depth of this dataset results in substantially improved statistical power, and permits several new lineage- and clade-specific tests to be applied.A detailed analysis of Affymetrix exon array data indicated that PSGs are expressed at significantly lower levels, and in a more tissue-specific manner, than non-PSGs.Genes that are specifically expressed in the spleen, testes, liver, and breast are significantly enriched for PSGs, but no evidence was found for an enrichment for PSGs among brain-specific genes.

View Article: PubMed Central - PubMed

Affiliation: Department of Biological Statistics and Computational Biology, Cornell University, Ithaca, New York, United States of America.

ABSTRACT
Genome-wide scans for positively selected genes (PSGs) in mammals have provided insight into the dynamics of genome evolution, the genetic basis of differences between species, and the functions of individual genes. However, previous scans have been limited in power and accuracy owing to small numbers of available genomes. Here we present the most comprehensive examination of mammalian PSGs to date, using the six high-coverage genome assemblies now available for eutherian mammals. The increased phylogenetic depth of this dataset results in substantially improved statistical power, and permits several new lineage- and clade-specific tests to be applied. Of approximately 16,500 human genes with high-confidence orthologs in at least two other species, 400 genes showed significant evidence of positive selection (FDR<0.05), according to a standard likelihood ratio test. An additional 144 genes showed evidence of positive selection on particular lineages or clades. As in previous studies, the identified PSGs were enriched for roles in defense/immunity, chemosensory perception, and reproduction, but enrichments were also evident for more specific functions, such as complement-mediated immunity and taste perception. Several pathways were strongly enriched for PSGs, suggesting possible co-evolution of interacting genes. A novel Bayesian analysis of the possible "selection histories" of each gene indicated that most PSGs have switched multiple times between positive selection and nonselection, suggesting that positive selection is often episodic. A detailed analysis of Affymetrix exon array data indicated that PSGs are expressed at significantly lower levels, and in a more tissue-specific manner, than non-PSGs. Genes that are specifically expressed in the spleen, testes, liver, and breast are significantly enriched for PSGs, but no evidence was found for an enrichment for PSGs among brain-specific genes. This study provides additional evidence for widespread positive selection in mammalian evolution and new genome-wide insights into the functional implications of positive selection.

Show MeSH
Related in: MedlinePlus