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Evidence of convergent evolution in humans and macaques supports an adaptive role for copy number variation of the β-defensin-2 gene.

Ottolini B, Hornsby MJ, Abujaber R, MacArthur JA, Badge RM, Schwarzacher T, Albertson DG, Bevins CL, Solnick JV, Hollox EJ - Genome Biol Evol (2014)

Bottom Line: Remarkably, we found that the structure of the CNV is different between primates, with distinct mutational origins and CNV boundaries defined by retroviral long terminal repeat elements.In addition, the rhesus macaque gene has been subject to divergent positive selection at the amino acid level following its initial duplication event between 3 and 9.5 Ma, suggesting adaptation of this gene as the macaque successfully colonized novel environments outside Africa.Therefore, the molecular phenotype of β-defensin-2 CNV has undergone convergent evolution, and this gene shows evidence of adaptation at the amino acid level in rhesus macaques.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics, University of Leicester, United Kingdom.

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Analysis of CNV of β-defensin regions in humans and rhesus macaque. (A) Human. The correlation of each individual arrayCGH probe with the copy number of 68 samples estimated by PRT is shown as the track r2cn. Also shown are β-defensin genes mapping to the region, segmental duplications as defined by Bailey et al. (2001), and genomic position. The red arrows indicate the copy number variable repeat (322 kb). (B) Rhesus macaque. The correlation of each individual arrayCGH probe with the copy number of 16 samples estimated by PRT and ddPCR is shown as the track r2cn. Also shown are Ref-Seq genes in the region, including the DEFB4 ortholog DEFB2L. Location of the putative ortholog of the other human β-defensins mapping to this region is shown in supplementary table S2, Supplementary Material online.
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evu236-F1: Analysis of CNV of β-defensin regions in humans and rhesus macaque. (A) Human. The correlation of each individual arrayCGH probe with the copy number of 68 samples estimated by PRT is shown as the track r2cn. Also shown are β-defensin genes mapping to the region, segmental duplications as defined by Bailey et al. (2001), and genomic position. The red arrows indicate the copy number variable repeat (322 kb). (B) Rhesus macaque. The correlation of each individual arrayCGH probe with the copy number of 16 samples estimated by PRT and ddPCR is shown as the track r2cn. Also shown are Ref-Seq genes in the region, including the DEFB4 ortholog DEFB2L. Location of the putative ortholog of the other human β-defensins mapping to this region is shown in supplementary table S2, Supplementary Material online.

Mentions: Because the human β-defensin CNV block is embedded within repeat-rich regions REPP and REPD, methods that identify CNV regions based on the transition from normal diploid copy number to variable copy number are unlikely to be effective. Instead, in order to test the extent of the human β-defensin CNV contiguous block, we calculated the squared correlation coefficient (r2) pairwise between the log2ratio for each aCGH probe and the β-defensin copy number determined by triplex PRT, across all 68 samples. PRT is a form of quantitative PCR where test and reference loci are amplified using the same pair of primers designed on a dispersed, divergent, repeat (Aldhous et al. 2010). The rationale behind this approach is that intensity values from aCGH probes that are measuring the same CNV as the PRT will, on average, be strongly correlated with copy number measured by PRT, across a large number of samples. Conversely, those intensity values from aCGH probes outside the CNV region measured by PRT will not be strongly correlated with copy number measured by PRT. Importantly, this last tenet holds whether the aCGH probes map to a diploid non-CNV region or a more complex CNV unrelated to the CNV measured by the PRT. These r2 values were plotted against the two assembled β-defensin repeats present in the human reference genome and showed a contiguous region of 322 kb where the log2ratio of the aCGH probes is correlated with the β-defensin copy number (fig. 1a). This region includes the defensin genes DEFB4, DEFB103, DEFB104, DEFB105, DEFB106, and DEFB107 as expected, as well the sperm-associated glycoprotein SPAG11 and the proline rich 23 domain containing one gene (PRR23D1). SPAG11 is related to the β-defensin genes, and is both antimicrobial and necessary for the initiation of sperm maturation (Horsten et al. 2004; Zhou et al. 2004). PRR23D1 is transcribed and predicted to encode a protein, as yet of unknown function. Other human PRR23 family members (PRR23A, PRR23B, and PRR23C) are testis-specific genes, according to the RNA sequencing (RNA-Seq) data provided by Illumina BodyMap 2, strongly suggesting that this family has a role in the male reproductive system.Fig. 1.—


Evidence of convergent evolution in humans and macaques supports an adaptive role for copy number variation of the β-defensin-2 gene.

Ottolini B, Hornsby MJ, Abujaber R, MacArthur JA, Badge RM, Schwarzacher T, Albertson DG, Bevins CL, Solnick JV, Hollox EJ - Genome Biol Evol (2014)

Analysis of CNV of β-defensin regions in humans and rhesus macaque. (A) Human. The correlation of each individual arrayCGH probe with the copy number of 68 samples estimated by PRT is shown as the track r2cn. Also shown are β-defensin genes mapping to the region, segmental duplications as defined by Bailey et al. (2001), and genomic position. The red arrows indicate the copy number variable repeat (322 kb). (B) Rhesus macaque. The correlation of each individual arrayCGH probe with the copy number of 16 samples estimated by PRT and ddPCR is shown as the track r2cn. Also shown are Ref-Seq genes in the region, including the DEFB4 ortholog DEFB2L. Location of the putative ortholog of the other human β-defensins mapping to this region is shown in supplementary table S2, Supplementary Material online.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4255768&req=5

evu236-F1: Analysis of CNV of β-defensin regions in humans and rhesus macaque. (A) Human. The correlation of each individual arrayCGH probe with the copy number of 68 samples estimated by PRT is shown as the track r2cn. Also shown are β-defensin genes mapping to the region, segmental duplications as defined by Bailey et al. (2001), and genomic position. The red arrows indicate the copy number variable repeat (322 kb). (B) Rhesus macaque. The correlation of each individual arrayCGH probe with the copy number of 16 samples estimated by PRT and ddPCR is shown as the track r2cn. Also shown are Ref-Seq genes in the region, including the DEFB4 ortholog DEFB2L. Location of the putative ortholog of the other human β-defensins mapping to this region is shown in supplementary table S2, Supplementary Material online.
Mentions: Because the human β-defensin CNV block is embedded within repeat-rich regions REPP and REPD, methods that identify CNV regions based on the transition from normal diploid copy number to variable copy number are unlikely to be effective. Instead, in order to test the extent of the human β-defensin CNV contiguous block, we calculated the squared correlation coefficient (r2) pairwise between the log2ratio for each aCGH probe and the β-defensin copy number determined by triplex PRT, across all 68 samples. PRT is a form of quantitative PCR where test and reference loci are amplified using the same pair of primers designed on a dispersed, divergent, repeat (Aldhous et al. 2010). The rationale behind this approach is that intensity values from aCGH probes that are measuring the same CNV as the PRT will, on average, be strongly correlated with copy number measured by PRT, across a large number of samples. Conversely, those intensity values from aCGH probes outside the CNV region measured by PRT will not be strongly correlated with copy number measured by PRT. Importantly, this last tenet holds whether the aCGH probes map to a diploid non-CNV region or a more complex CNV unrelated to the CNV measured by the PRT. These r2 values were plotted against the two assembled β-defensin repeats present in the human reference genome and showed a contiguous region of 322 kb where the log2ratio of the aCGH probes is correlated with the β-defensin copy number (fig. 1a). This region includes the defensin genes DEFB4, DEFB103, DEFB104, DEFB105, DEFB106, and DEFB107 as expected, as well the sperm-associated glycoprotein SPAG11 and the proline rich 23 domain containing one gene (PRR23D1). SPAG11 is related to the β-defensin genes, and is both antimicrobial and necessary for the initiation of sperm maturation (Horsten et al. 2004; Zhou et al. 2004). PRR23D1 is transcribed and predicted to encode a protein, as yet of unknown function. Other human PRR23 family members (PRR23A, PRR23B, and PRR23C) are testis-specific genes, according to the RNA sequencing (RNA-Seq) data provided by Illumina BodyMap 2, strongly suggesting that this family has a role in the male reproductive system.Fig. 1.—

Bottom Line: Remarkably, we found that the structure of the CNV is different between primates, with distinct mutational origins and CNV boundaries defined by retroviral long terminal repeat elements.In addition, the rhesus macaque gene has been subject to divergent positive selection at the amino acid level following its initial duplication event between 3 and 9.5 Ma, suggesting adaptation of this gene as the macaque successfully colonized novel environments outside Africa.Therefore, the molecular phenotype of β-defensin-2 CNV has undergone convergent evolution, and this gene shows evidence of adaptation at the amino acid level in rhesus macaques.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics, University of Leicester, United Kingdom.

Show MeSH