scholarly journals Molecular genetic aetiology of general cognitive function is enriched in evolutionarily conserved regions

2016 ◽  
Vol 6 (12) ◽  
pp. e980-e980 ◽  
Author(s):  
W D Hill ◽  
◽  
G Davies ◽  
S E Harris ◽  
S P Hagenaars ◽  
...  
Keyword(s):  
Cognitive Function ◽  
Molecular Genetic ◽  
Conserved Regions ◽  
Evolutionarily Conserved

scholarly journals Molecular genetic aetiology of general cognitive function is enriched in evolutionarily conserved regions

2016 ◽  
Author(s):  
W. D. Hill ◽  
G. Davies ◽  
S. E Harris ◽  
S. P. Hagenaars ◽  
D. C. Liewald ◽  
...  
Keyword(s):  
Cognitive Function ◽  
Genome Wide Association Study ◽  
Molecular Genetic ◽  
Genetic Correlations ◽  
Pleiotropic Effect ◽  
Nucleotide Polymorphisms ◽  
Genetic Associations ◽  
Conserved Regions ◽  
Disease States ◽  
Genome Wide

AbstractDifferences in general cognitive function have been shown to be partly heritable and to show genetic correlations with a several psychiatric and physical disease states. However, to date few single nucleotide polymorphisms (SNPs) have demonstrated genome-wide significance, hampering efforts aimed at determining which genetic variants are most important for cognitive function and which regions drive the genetic associations between cognitive function and disease states. Here, we combine multiple large genome-wide association study (GWAS) data sets, from the CHARGE cognitive consortium and UK Biobank, to partition the genome into 52 functional annotations and an additional 10 annotations describing tissue-specific histone marks. Using stratified linkage disequilibrium score regression we show that, in two measures of cognitive function, SNPs associated with cognitive function cluster in regions of the genome that are under evolutionary negative selective pressure. These conserved regions contained ~2.6% of the SNPs from each GWAS but accounted for ~ 40% of the SNP-based heritability. The results suggest that the search for causal variants associated with cognitive function, and those variants that exert a pleiotropic effect between cognitive function and health, will be facilitated by examining these enriched regions.

scholarly journals NLIP and HAD-like Domains of Pah1 and Lipin 1 Phosphatidate Phosphatases Are Essential for Their Catalytic Activities

Molecules ◽  
2021 ◽  
Vol 26 (18) ◽  
pp. 5470
Author(s):  
Wei-Hsin Hsu ◽  
Yi-Hao Huang ◽  
Pin-Ru Chen ◽  
Lu-Sheng Hsieh
Keyword(s):  
Catalytic Activity ◽  
Intrinsically Disordered Proteins ◽  
Protein Solubility ◽  
Disordered Proteins ◽  
Haloacid Dehalogenase ◽  
Catalytic Activities ◽  
Intrinsically Disordered ◽  
Conserved Regions ◽  
Evolutionarily Conserved ◽  
Lipin 1

Saccharomyces cerevisiae Pah1 phosphatidate phosphatase (PAP) catalyzes the dephosphorylation of phosphatidate to yield diacylglycerol, controlling phospholipids and triacylglycerol metabolisms. Pah1 and human Lipin 1 are intrinsically disordered proteins with 56% and 43% unfolded regions, respectively. Truncation analysis of the conserved and non-conserved regions showed that N- and C-conserved regions are essential for the catalytic activity of Pah1. PAP activities can be detected in the conserved N-terminal Lipin (NLIP) domain and C-terminal Lipin (CLIP)/haloacid dehalogenase (HAD)-like domain of Pah1 and Lipin 1, suggesting that the evolutionarily conserved domains are essential for the catalytic activity. The removal of disordered hydrophilic regions drastically reduced the protein solubility of Pah1. Thioredoxin is an efficient fusion protein for production of soluble NLIP–HAD recombinant proteins in Escherichia coli.

scholarly journals A Molecular Genetic Dissection of the Evolutionarily Conserved N Terminus of Yeast Rad52

Genetics ◽  
2002 ◽  
Vol 161 (2) ◽  
pp. 549-562
Author(s):  
Uffe H Mortensen ◽  
Naz Erdeniz ◽  
Qi Feng ◽  
Rodney Rothstein
Keyword(s):  
Dna Damage ◽  
Amino Acid ◽  
Dna Binding ◽  
Molecular Genetic ◽  
Mitotic Recombination ◽  
Amino Acid Residues ◽  
Γ Irradiation ◽  
Evolutionarily Conserved ◽  
N Terminus ◽  
Γ Ray

Abstract Rad52 is a DNA-binding protein that stimulates the annealing of complementary single-stranded DNA. Only the N terminus of Rad52 is evolutionarily conserved; it contains the core activity of the protein, including its DNA-binding activity. To identify amino acid residues that are important for Rad52 function(s), we systematically replaced 76 of 165 amino acid residues in the N terminus with alanine. These substitutions were examined for their effects on the repair of γ-ray-induced DNA damage and on both interchromosomal and direct repeat heteroallelic recombination. This analysis identified five regions that are required for efficient γ-ray damage repair or mitotic recombination. Two regions, I and II, also contain the classic mutations, rad52-2 and rad52-1, respectively. Interestingly, four of the five regions contain mutations that impair the ability to repair γ-ray-induced DNA damage yet still allow mitotic recombinants to be produced at rates that are similar to or higher than those obtained with wild-type strains. In addition, a new class of separation-of-function mutation that is only partially deficient in the repair of γ-ray damage, but exhibits decreased mitotic recombination similar to rad52 null strains, was identified. These results suggest that Rad52 protein acts differently on lesions that occur spontaneously during the cell cycle than on those induced by γ-irradiation.

scholarly journals Genetic and Functional Interaction of Evolutionarily Conserved Regions of the Prp18 Protein and the U5 snRNA

2005 ◽  
Vol 25 (6) ◽  
pp. 2107-2116 ◽  
Author(s):  
Dagmar Bačíková ◽  
David S. Horowitz
Keyword(s):  
Functional Relationship ◽  
Mrna Splicing ◽  
Second Step ◽  
Functional Interaction ◽  
Synthetic Lethal ◽  
Conserved Regions ◽  
Evolutionarily Conserved ◽  
Conserved Region ◽  
Relationship Of ◽  
U5 Snrna

ABSTRACT Both the Prp18 protein and the U5 snRNA function in the second step of pre-mRNA splicing. We identified suppressors of mutant prp18 alleles in the gene for the U5 snRNA (SNR7). The suppressors' U5 snRNAs have either a U4-to-A or an A8-to-C mutation in the evolutionarily invariant loop 1 of U5. Suppression is specific for prp18 alleles that encode proteins with mutations in a highly conserved region of Prp18 which forms an unstructured loop in crystals of Prp18. The snr7 suppressors partly restored the pre-mRNA splicing activity that was lost in the prp18 mutants. The close functional relationship of Prp18 and U5 is emphasized by the finding that two snr7 alleles, U5A and U6A, are dominant synthetic lethal with prp18 alleles. Our results support the idea that Prp18 and the U5 snRNA act in concert during the second step of pre-mRNA splicing and suggest a model in which the conserved loop of Prp18 acts to stabilize the interaction of loop 1 of the U5 snRNA with the splicing intermediates.

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