Limits...
Human gephyrin is encompassed within giant functional noncoding yin-yang sequences.

Climer S, Templeton AR, Zhang W - Nat Commun (2015)

Bottom Line: Its specific function is intricately regulated and its aberrant activities have been observed for a number of human diseases.The gephyrin yin-yang pair consists of 284 divergent nucleotide states and both variants vary drastically from their mutual ancestral haplotype, suggesting rapid evolution.This discovery holds potential to deepen our understanding of variable human-specific regulation of gephyrin while providing clues for rapid evolutionary events and allelic migrations buried within human history.

View Article: PubMed Central - PubMed

Affiliation: Department of Computer Science and Engineering, Washington University, St Louis, Missouri 63130, USA.

ABSTRACT
Gephyrin is a highly conserved gene that is vital for the organization of proteins at inhibitory receptors, molybdenum cofactor biosynthesis and other diverse functions. Its specific function is intricately regulated and its aberrant activities have been observed for a number of human diseases. Here we report a remarkable yin-yang haplotype pattern encompassing gephyrin. Yin-yang haplotypes arise when a stretch of DNA evolves to present two disparate forms that bear differing states for nucleotide variations along their lengths. The gephyrin yin-yang pair consists of 284 divergent nucleotide states and both variants vary drastically from their mutual ancestral haplotype, suggesting rapid evolution. Several independent lines of evidence indicate strong positive selection on the region and suggest these high-frequency haplotypes represent two distinct functional mechanisms. This discovery holds potential to deepen our understanding of variable human-specific regulation of gephyrin while providing clues for rapid evolutionary events and allelic migrations buried within human history.

No MeSH data available.


Related in: MedlinePlus

Yin-yang haplotypes(Best viewed in color, high-resolution image available online as Supplementary Fig. 3.) Upper panel: Yin-yang region with color-coded genes and positions in kb. Lower panel: Genotypes for the yin-yang haplotypes. The first column of matrices represents the ‘yin’ bloc identified in the analysis of the GIH, LWK, MKK, and TSI populations. The middle column represents the ‘yin’ bloc from the CEU, CHB, JPT, and YRI analysis. The last column represents the available yin-yang SNPs for each of the three additional HapMap populations: ASW, CHD, and MEX. For each matrix, each column represents a SNP and each row represents an individual (rows are rearranged to place similar individuals near each other). Color-coded bars at top of the first two columns indicate SNP positions by matching the gene color from the top panel. Dark blue indicates homozygote for SNP allele in the bloc, red for homozygote for alternate allele, light blue for heterozygote, and white for missing data. A solid dark blue horizontal line represents an individual that possesses two yin haplotypes and a solid red line represents a yang homozygote. Percentages of individuals that are homozygotes or heterozygotes for the yin and yang haplotypes are shown on the right side of each matrix. Yin (blue) and yang (red) haplotype frequencies are shown in pie chart above each matrix, with white indicating the percentage of haplotypes that are not 100% yin nor 100% yang.
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Figure 1: Yin-yang haplotypes(Best viewed in color, high-resolution image available online as Supplementary Fig. 3.) Upper panel: Yin-yang region with color-coded genes and positions in kb. Lower panel: Genotypes for the yin-yang haplotypes. The first column of matrices represents the ‘yin’ bloc identified in the analysis of the GIH, LWK, MKK, and TSI populations. The middle column represents the ‘yin’ bloc from the CEU, CHB, JPT, and YRI analysis. The last column represents the available yin-yang SNPs for each of the three additional HapMap populations: ASW, CHD, and MEX. For each matrix, each column represents a SNP and each row represents an individual (rows are rearranged to place similar individuals near each other). Color-coded bars at top of the first two columns indicate SNP positions by matching the gene color from the top panel. Dark blue indicates homozygote for SNP allele in the bloc, red for homozygote for alternate allele, light blue for heterozygote, and white for missing data. A solid dark blue horizontal line represents an individual that possesses two yin haplotypes and a solid red line represents a yang homozygote. Percentages of individuals that are homozygotes or heterozygotes for the yin and yang haplotypes are shown on the right side of each matrix. Yin (blue) and yang (red) haplotype frequencies are shown in pie chart above each matrix, with white indicating the percentage of haplotypes that are not 100% yin nor 100% yang.

Mentions: Overall, the three blocs found by the two analyses capture a single yin-yang haplotype pair. The three blocs possess 226 SNPs in common and span across 284 unique SNPs overall (Supplementary Dataset 1). We define this yin-yang pair using these 284 highly correlated SNPs. (See Supplementary Note 1 and Supplementary Fig. 1 for description of an additional bloc corresponding to the yang haplotype for the first analysis.) This yin-yang pair is located on 14q23.3, encompassing gephyrin (GPHN) and extending beyond by ~300 kb upstream and downstream of gephyrin (Fig. 1). Interestingly, all of the divergent markers appear within introns, long non-coding RNA, or intergenic regions. As illustrated by the color coded bar above the first two columns of matrices in Fig. 1, few SNPs are downstream from gephyrin (2.7%, 3.4%, and 5.1% for the 255-, 264-, and 257-SNP blocs, respectively) and none lie within MPP5. About one-fifth of the SNPs lie upstream from gephyrin (19.2%, 18.6%, and 20.6%) and all three blocs include the same eight SNPs within the long non-coding RNA, LINC00238. Most of the SNPs lie within non-coding regions of gephyrin (78.0%, 78.0%, and 74.3%).


Human gephyrin is encompassed within giant functional noncoding yin-yang sequences.

Climer S, Templeton AR, Zhang W - Nat Commun (2015)

Yin-yang haplotypes(Best viewed in color, high-resolution image available online as Supplementary Fig. 3.) Upper panel: Yin-yang region with color-coded genes and positions in kb. Lower panel: Genotypes for the yin-yang haplotypes. The first column of matrices represents the ‘yin’ bloc identified in the analysis of the GIH, LWK, MKK, and TSI populations. The middle column represents the ‘yin’ bloc from the CEU, CHB, JPT, and YRI analysis. The last column represents the available yin-yang SNPs for each of the three additional HapMap populations: ASW, CHD, and MEX. For each matrix, each column represents a SNP and each row represents an individual (rows are rearranged to place similar individuals near each other). Color-coded bars at top of the first two columns indicate SNP positions by matching the gene color from the top panel. Dark blue indicates homozygote for SNP allele in the bloc, red for homozygote for alternate allele, light blue for heterozygote, and white for missing data. A solid dark blue horizontal line represents an individual that possesses two yin haplotypes and a solid red line represents a yang homozygote. Percentages of individuals that are homozygotes or heterozygotes for the yin and yang haplotypes are shown on the right side of each matrix. Yin (blue) and yang (red) haplotype frequencies are shown in pie chart above each matrix, with white indicating the percentage of haplotypes that are not 100% yin nor 100% yang.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4380243&req=5

Figure 1: Yin-yang haplotypes(Best viewed in color, high-resolution image available online as Supplementary Fig. 3.) Upper panel: Yin-yang region with color-coded genes and positions in kb. Lower panel: Genotypes for the yin-yang haplotypes. The first column of matrices represents the ‘yin’ bloc identified in the analysis of the GIH, LWK, MKK, and TSI populations. The middle column represents the ‘yin’ bloc from the CEU, CHB, JPT, and YRI analysis. The last column represents the available yin-yang SNPs for each of the three additional HapMap populations: ASW, CHD, and MEX. For each matrix, each column represents a SNP and each row represents an individual (rows are rearranged to place similar individuals near each other). Color-coded bars at top of the first two columns indicate SNP positions by matching the gene color from the top panel. Dark blue indicates homozygote for SNP allele in the bloc, red for homozygote for alternate allele, light blue for heterozygote, and white for missing data. A solid dark blue horizontal line represents an individual that possesses two yin haplotypes and a solid red line represents a yang homozygote. Percentages of individuals that are homozygotes or heterozygotes for the yin and yang haplotypes are shown on the right side of each matrix. Yin (blue) and yang (red) haplotype frequencies are shown in pie chart above each matrix, with white indicating the percentage of haplotypes that are not 100% yin nor 100% yang.
Mentions: Overall, the three blocs found by the two analyses capture a single yin-yang haplotype pair. The three blocs possess 226 SNPs in common and span across 284 unique SNPs overall (Supplementary Dataset 1). We define this yin-yang pair using these 284 highly correlated SNPs. (See Supplementary Note 1 and Supplementary Fig. 1 for description of an additional bloc corresponding to the yang haplotype for the first analysis.) This yin-yang pair is located on 14q23.3, encompassing gephyrin (GPHN) and extending beyond by ~300 kb upstream and downstream of gephyrin (Fig. 1). Interestingly, all of the divergent markers appear within introns, long non-coding RNA, or intergenic regions. As illustrated by the color coded bar above the first two columns of matrices in Fig. 1, few SNPs are downstream from gephyrin (2.7%, 3.4%, and 5.1% for the 255-, 264-, and 257-SNP blocs, respectively) and none lie within MPP5. About one-fifth of the SNPs lie upstream from gephyrin (19.2%, 18.6%, and 20.6%) and all three blocs include the same eight SNPs within the long non-coding RNA, LINC00238. Most of the SNPs lie within non-coding regions of gephyrin (78.0%, 78.0%, and 74.3%).

Bottom Line: Its specific function is intricately regulated and its aberrant activities have been observed for a number of human diseases.The gephyrin yin-yang pair consists of 284 divergent nucleotide states and both variants vary drastically from their mutual ancestral haplotype, suggesting rapid evolution.This discovery holds potential to deepen our understanding of variable human-specific regulation of gephyrin while providing clues for rapid evolutionary events and allelic migrations buried within human history.

View Article: PubMed Central - PubMed

Affiliation: Department of Computer Science and Engineering, Washington University, St Louis, Missouri 63130, USA.

ABSTRACT
Gephyrin is a highly conserved gene that is vital for the organization of proteins at inhibitory receptors, molybdenum cofactor biosynthesis and other diverse functions. Its specific function is intricately regulated and its aberrant activities have been observed for a number of human diseases. Here we report a remarkable yin-yang haplotype pattern encompassing gephyrin. Yin-yang haplotypes arise when a stretch of DNA evolves to present two disparate forms that bear differing states for nucleotide variations along their lengths. The gephyrin yin-yang pair consists of 284 divergent nucleotide states and both variants vary drastically from their mutual ancestral haplotype, suggesting rapid evolution. Several independent lines of evidence indicate strong positive selection on the region and suggest these high-frequency haplotypes represent two distinct functional mechanisms. This discovery holds potential to deepen our understanding of variable human-specific regulation of gephyrin while providing clues for rapid evolutionary events and allelic migrations buried within human history.

No MeSH data available.


Related in: MedlinePlus