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Patterns of evolutionary constraints on genes in humans.

De S, Lopez-Bigas N, Teichmann SA - BMC Evol. Biol. (2008)

Bottom Line: A strong or even moderate change in constraints in functional regions, for example in coding regions, can have significant evolutionary consequences.Focussing on groups of genes in functional categories, we find that transcription factors contain a significant excess of nonsynonymous base-positions that are conserved in other mammals but changed in human, while immunity related genes harbour mutations at base-positions that evolve rapidly in all mammals including humans due to strong preference for advantageous alleles.While recent studies have identified genes under positive selection in humans, our approach identifies evolutionary constraints on Gene Ontology groups identifying changes in humans relative to some of the other mammals.

View Article: PubMed Central - HTML - PubMed

Affiliation: MRC Laboratory of Molecular Biology, Hills Road, Cambridge, CB2 2QH, UK. sde@mrc-lmb.cam.ac.uk

ABSTRACT

Background: Different regions in a genome evolve at different rates depending on structural and functional constraints. Some genomic regions are highly conserved during metazoan evolution, while other regions may evolve rapidly, either in all species or in a lineage-specific manner. A strong or even moderate change in constraints in functional regions, for example in coding regions, can have significant evolutionary consequences.

Results: Here we discuss a novel framework, 'BaseDiver', to classify groups of genes in humans based on the patterns of evolutionary constraints on polymorphic positions in their coding regions. Comparing the nucleotide-level divergence among mammals with the extent of deviation from the ancestral base in the human lineage, we identify patterns of evolutionary pressure on nonsynonymous base-positions in groups of genes belonging to the same functional category. Focussing on groups of genes in functional categories, we find that transcription factors contain a significant excess of nonsynonymous base-positions that are conserved in other mammals but changed in human, while immunity related genes harbour mutations at base-positions that evolve rapidly in all mammals including humans due to strong preference for advantageous alleles. Genes involved in olfaction also evolve rapidly in all mammals, and in humans this appears to be due to weak negative selection.

Conclusion: While recent studies have identified genes under positive selection in humans, our approach identifies evolutionary constraints on Gene Ontology groups identifying changes in humans relative to some of the other mammals.

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(A) A cartoon representation of the DNA-binding domain of ZNF228 (green) in contact with DNA (orange). The nonsynonymous SNP (rs2722722, H484Y) is shown in blue. The complex was modelled based on a homologus structure (1MEY, chain C) taken from the Protein Data Bank (B) Summary of information about nonsynonymous SNPs observed in DNA-binding domains of known and putative transcription factors.
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Figure 4: (A) A cartoon representation of the DNA-binding domain of ZNF228 (green) in contact with DNA (orange). The nonsynonymous SNP (rs2722722, H484Y) is shown in blue. The complex was modelled based on a homologus structure (1MEY, chain C) taken from the Protein Data Bank (B) Summary of information about nonsynonymous SNPs observed in DNA-binding domains of known and putative transcription factors.

Mentions: Lineage-specific changes in constraints on functionally important positions may have a significant impact, which may not always be identified by a conventional scan for positive selection. While, for the majority of the proteins, a lack of structural data prevents us from identifying the physicochemical consequences of individual polymorphisms, we can highlight several potentially interesting instances. For example, ZNF228 (ENSP00000346305) a Kruppel-like C2H2 zinc finger transcription factor expressed mainly in heart and haematopoietic tissue has a low (<1) dN/dS ratio with chimpanzee, but harbours three SNPs in the DNA binding domain. One of them (rs2722722: H484Y) is probably in contact with DNA, as an equivalent residue in a homologous structure shares a large interface area with DNA (1MEY:C19; area = 47.1 Å2) as shown in Figure 4A. The nucleotide position is fairly conserved in mammals (GERP score: -0.81) but has been subject to selection in humans as apparent from the high derived allele frequency (DAF ∈ 0.5 – 0.75) in all four HapMap populations and high linkage disequilibrium (LD) value (>1.4) in Asian and European populations [22]. A list of nonsynonymous polymorphisms in DNA-binding domains of genes in Cluster I, which can potentially influence DNA-binding properties, is given in Figure 4B. Experimental characterization could reveal the functional consequences of these polymorphisms in humans.


Patterns of evolutionary constraints on genes in humans.

De S, Lopez-Bigas N, Teichmann SA - BMC Evol. Biol. (2008)

(A) A cartoon representation of the DNA-binding domain of ZNF228 (green) in contact with DNA (orange). The nonsynonymous SNP (rs2722722, H484Y) is shown in blue. The complex was modelled based on a homologus structure (1MEY, chain C) taken from the Protein Data Bank (B) Summary of information about nonsynonymous SNPs observed in DNA-binding domains of known and putative transcription factors.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2587479&req=5

Figure 4: (A) A cartoon representation of the DNA-binding domain of ZNF228 (green) in contact with DNA (orange). The nonsynonymous SNP (rs2722722, H484Y) is shown in blue. The complex was modelled based on a homologus structure (1MEY, chain C) taken from the Protein Data Bank (B) Summary of information about nonsynonymous SNPs observed in DNA-binding domains of known and putative transcription factors.
Mentions: Lineage-specific changes in constraints on functionally important positions may have a significant impact, which may not always be identified by a conventional scan for positive selection. While, for the majority of the proteins, a lack of structural data prevents us from identifying the physicochemical consequences of individual polymorphisms, we can highlight several potentially interesting instances. For example, ZNF228 (ENSP00000346305) a Kruppel-like C2H2 zinc finger transcription factor expressed mainly in heart and haematopoietic tissue has a low (<1) dN/dS ratio with chimpanzee, but harbours three SNPs in the DNA binding domain. One of them (rs2722722: H484Y) is probably in contact with DNA, as an equivalent residue in a homologous structure shares a large interface area with DNA (1MEY:C19; area = 47.1 Å2) as shown in Figure 4A. The nucleotide position is fairly conserved in mammals (GERP score: -0.81) but has been subject to selection in humans as apparent from the high derived allele frequency (DAF ∈ 0.5 – 0.75) in all four HapMap populations and high linkage disequilibrium (LD) value (>1.4) in Asian and European populations [22]. A list of nonsynonymous polymorphisms in DNA-binding domains of genes in Cluster I, which can potentially influence DNA-binding properties, is given in Figure 4B. Experimental characterization could reveal the functional consequences of these polymorphisms in humans.

Bottom Line: A strong or even moderate change in constraints in functional regions, for example in coding regions, can have significant evolutionary consequences.Focussing on groups of genes in functional categories, we find that transcription factors contain a significant excess of nonsynonymous base-positions that are conserved in other mammals but changed in human, while immunity related genes harbour mutations at base-positions that evolve rapidly in all mammals including humans due to strong preference for advantageous alleles.While recent studies have identified genes under positive selection in humans, our approach identifies evolutionary constraints on Gene Ontology groups identifying changes in humans relative to some of the other mammals.

View Article: PubMed Central - HTML - PubMed

Affiliation: MRC Laboratory of Molecular Biology, Hills Road, Cambridge, CB2 2QH, UK. sde@mrc-lmb.cam.ac.uk

ABSTRACT

Background: Different regions in a genome evolve at different rates depending on structural and functional constraints. Some genomic regions are highly conserved during metazoan evolution, while other regions may evolve rapidly, either in all species or in a lineage-specific manner. A strong or even moderate change in constraints in functional regions, for example in coding regions, can have significant evolutionary consequences.

Results: Here we discuss a novel framework, 'BaseDiver', to classify groups of genes in humans based on the patterns of evolutionary constraints on polymorphic positions in their coding regions. Comparing the nucleotide-level divergence among mammals with the extent of deviation from the ancestral base in the human lineage, we identify patterns of evolutionary pressure on nonsynonymous base-positions in groups of genes belonging to the same functional category. Focussing on groups of genes in functional categories, we find that transcription factors contain a significant excess of nonsynonymous base-positions that are conserved in other mammals but changed in human, while immunity related genes harbour mutations at base-positions that evolve rapidly in all mammals including humans due to strong preference for advantageous alleles. Genes involved in olfaction also evolve rapidly in all mammals, and in humans this appears to be due to weak negative selection.

Conclusion: While recent studies have identified genes under positive selection in humans, our approach identifies evolutionary constraints on Gene Ontology groups identifying changes in humans relative to some of the other mammals.

Show MeSH