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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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Related in: MedlinePlus

Structural analysis of the HAVCR1 gene.At top is a graph showing the domain structure of the gene and corresponding Bayes Empirical Bayes [83] posterior probabilities (PP) of positive selection, based on our six-species alignments, with sites predicted to be under positive selection (PP>0.95) in red. At bottom right is a structural diagram (based on the structure of the IgV domain of the mouse gene) showing the interaction between two receptors that have been implicated in the regulation of HAVCR1's immune function. It is thought that clustering of receptors within the same cell surface might facilitate phosphorylation of the cytoplasmic tail, and that interaction between receptors from different cells might be a mechanism for B–T cell adhesion [91]. Predicted residue 39 falls within the region of these receptors, very near residue 37, which directly interacts with the opposite receptor (according to the available mouse structure). In addition, predicted residues 54 and 56 are adjacent to the virus-binding surface (shown in pink), as defined by a polymorphism in macaque [91]. Interestingly, the residue that falls between them (55) appears to be critical for virus-binding at the homologous loop in the CEA coronavirus receptor [91]. Residue 75 in the IgV domain also shows evidence of positive selection (PP>0.90, shown in orange) but its function is unknown.
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pgen-1000144-g003: Structural analysis of the HAVCR1 gene.At top is a graph showing the domain structure of the gene and corresponding Bayes Empirical Bayes [83] posterior probabilities (PP) of positive selection, based on our six-species alignments, with sites predicted to be under positive selection (PP>0.95) in red. At bottom right is a structural diagram (based on the structure of the IgV domain of the mouse gene) showing the interaction between two receptors that have been implicated in the regulation of HAVCR1's immune function. It is thought that clustering of receptors within the same cell surface might facilitate phosphorylation of the cytoplasmic tail, and that interaction between receptors from different cells might be a mechanism for B–T cell adhesion [91]. Predicted residue 39 falls within the region of these receptors, very near residue 37, which directly interacts with the opposite receptor (according to the available mouse structure). In addition, predicted residues 54 and 56 are adjacent to the virus-binding surface (shown in pink), as defined by a polymorphism in macaque [91]. Interestingly, the residue that falls between them (55) appears to be critical for virus-binding at the homologous loop in the CEA coronavirus receptor [91]. Residue 75 in the IgV domain also shows evidence of positive selection (PP>0.90, shown in orange) but its function is unknown.

Mentions: Several gene families of the immunoglobulin superfamily (“immunoglobulin mediated immune response,” P = 1.1×10−7) show particularly strong enrichments for PSGs. For example, five of the six SIGLEC genes included in our analysis are under positive selection (see [34]). A detailed examination of one immunoglobulin gene for which structural information was available—a cell-surface receptor for hepatitis A and other viruses called HAVCR1 (LRT P = 6.9×10−9)—revealed several sites under positive selection in its N-terminal V-like immunoglobulin (IgV) domain. Three of these sites correspond to regions of the protein believed to play critical roles in binding to viruses or in regulating the immune function of the gene (Figure 3). In addition to its role in viral defense, HAVCR1 is a key player in the hygiene hypothesis explaining the increase in allergies and asthma [35]. It also interacts with IgA (CD79A; P = 5.4×10−9), whose deficiency is associated with increased susceptibility to autoimmune and allergic diseases [36].


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)

Structural analysis of the HAVCR1 gene.At top is a graph showing the domain structure of the gene and corresponding Bayes Empirical Bayes [83] posterior probabilities (PP) of positive selection, based on our six-species alignments, with sites predicted to be under positive selection (PP>0.95) in red. At bottom right is a structural diagram (based on the structure of the IgV domain of the mouse gene) showing the interaction between two receptors that have been implicated in the regulation of HAVCR1's immune function. It is thought that clustering of receptors within the same cell surface might facilitate phosphorylation of the cytoplasmic tail, and that interaction between receptors from different cells might be a mechanism for B–T cell adhesion [91]. Predicted residue 39 falls within the region of these receptors, very near residue 37, which directly interacts with the opposite receptor (according to the available mouse structure). In addition, predicted residues 54 and 56 are adjacent to the virus-binding surface (shown in pink), as defined by a polymorphism in macaque [91]. Interestingly, the residue that falls between them (55) appears to be critical for virus-binding at the homologous loop in the CEA coronavirus receptor [91]. Residue 75 in the IgV domain also shows evidence of positive selection (PP>0.90, shown in orange) but its function is unknown.
© Copyright Policy
Related In: Results  -  Collection

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

pgen-1000144-g003: Structural analysis of the HAVCR1 gene.At top is a graph showing the domain structure of the gene and corresponding Bayes Empirical Bayes [83] posterior probabilities (PP) of positive selection, based on our six-species alignments, with sites predicted to be under positive selection (PP>0.95) in red. At bottom right is a structural diagram (based on the structure of the IgV domain of the mouse gene) showing the interaction between two receptors that have been implicated in the regulation of HAVCR1's immune function. It is thought that clustering of receptors within the same cell surface might facilitate phosphorylation of the cytoplasmic tail, and that interaction between receptors from different cells might be a mechanism for B–T cell adhesion [91]. Predicted residue 39 falls within the region of these receptors, very near residue 37, which directly interacts with the opposite receptor (according to the available mouse structure). In addition, predicted residues 54 and 56 are adjacent to the virus-binding surface (shown in pink), as defined by a polymorphism in macaque [91]. Interestingly, the residue that falls between them (55) appears to be critical for virus-binding at the homologous loop in the CEA coronavirus receptor [91]. Residue 75 in the IgV domain also shows evidence of positive selection (PP>0.90, shown in orange) but its function is unknown.
Mentions: Several gene families of the immunoglobulin superfamily (“immunoglobulin mediated immune response,” P = 1.1×10−7) show particularly strong enrichments for PSGs. For example, five of the six SIGLEC genes included in our analysis are under positive selection (see [34]). A detailed examination of one immunoglobulin gene for which structural information was available—a cell-surface receptor for hepatitis A and other viruses called HAVCR1 (LRT P = 6.9×10−9)—revealed several sites under positive selection in its N-terminal V-like immunoglobulin (IgV) domain. Three of these sites correspond to regions of the protein believed to play critical roles in binding to viruses or in regulating the immune function of the gene (Figure 3). In addition to its role in viral defense, HAVCR1 is a key player in the hygiene hypothesis explaining the increase in allergies and asthma [35]. It also interacts with IgA (CD79A; P = 5.4×10−9), whose deficiency is associated with increased susceptibility to autoimmune and allergic diseases [36].

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