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Article ; Online: Genome-wide oscillations in G + C density and sequence conservation.

Moqtaderi, Zarmik / Brown, Susan / Bender, Welcome

2021 Volume 31, Issue 11, Page(s) 2050–2057

Abstract: Eukaryotic genomes typically show a uniform G + C content among chromosomes, but on smaller scales ... many species have a G + C density that fluctuates with a characteristic wavelength. This oscillation is evident ... oscillate in phase with G + C content, with conserved regions having higher G + C. Loci with large ...

Abstract	Eukaryotic genomes typically show a uniform G + C content among chromosomes, but on smaller scales, many species have a G + C density that fluctuates with a characteristic wavelength. This oscillation is evident in many insect species, with wavelengths ranging between 700 bp and 4 kb. Measures of evolutionary conservation oscillate in phase with G + C content, with conserved regions having higher G + C. Loci with large regulatory regions show more regular oscillations; coding sequences and heterochromatic regions show little or no oscillation. There is little oscillation in vertebrate genomes in regions with densely distributed mobile repetitive elements. However, species with few repeats show oscillation in both G + C density and sequence conservation. These oscillations may reflect optimal spacing of
MeSH term(s)	Base Sequence ; Biological Evolution ; Conserved Sequence/genetics ; Evolution, Molecular ; Genome ; Regulatory Sequences, Nucleic Acid ; Repetitive Sequences, Nucleic Acid
Language	English
Publishing date	2021-10-14
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1284872-4
ISSN	1549-5469 ; 1088-9051 ; 1054-9803
ISSN (online)	1549-5469
ISSN	1088-9051 ; 1054-9803
DOI	10.1101/gr.274332.120
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Article ; Online: Biochemical phenotype and its relationship to treatment in 16 individuals with PCCB c.1606A > G (p.Asn536Asp) variant propionic acidemia.

Wenger, Olivia / Brown, Miraides / Smith, Brandon / Chowdhury, Devyani / Crosby, Andrew H / Baple, Emma L / Yoder, Mark / Laxen, William / Tortorelli, Silvia / Strauss, Kevin A

Molecular genetics and metabolism

2020 Volume 131, Issue 3, Page(s) 316–324

Abstract: ... individuals homozygous for PCCB c.1606A > G (p.Asn536Asp) variant PA participated in a two-week suspension ... from all subjects. We characterized the baseline biochemical phenotype of untreated PCCB c.1606A > G homozygotes and ... measures or cardiac outcomes. Treatment of PCCB c.1606A > G homozygotes with protein restriction ...

Abstract	Propionic acidemia (PA) is caused by inherited deficiency of mitochondrial propionyl-CoA carboxylase (PCC) and results in significant neurodevelopmental and cardiac morbidity. However, relationships among therapeutic intervention, biochemical markers, and disease progression are poorly understood. Sixteen individuals homozygous for PCCB c.1606A > G (p.Asn536Asp) variant PA participated in a two-week suspension of therapy. Standard metabolic markers (plasma amino acids, blood spot methylcitrate, plasma/urine acylcarnitines, urine organic acids) were obtained before and after stopping treatment. These same markers were obtained in sixteen unaffected siblings. Echocardiography and electrocardiography were obtained from all subjects. We characterized the baseline biochemical phenotype of untreated PCCB c.1606A > G homozygotes and impact of treatment on PCC deficiency biomarkers. Therapeutic regimens varied widely. Suspension of therapy did not significantly alter branched chain amino acid levels, their alpha-ketoacid derivatives, or urine ketones. Carnitine supplementation significantly increased urine propionylcarnitine and its ratio to total carnitine. Methylcitrate blood spot and urine levels did not correlate with other biochemical measures or cardiac outcomes. Treatment of PCCB c.1606A > G homozygotes with protein restriction, prescription formula, and/or various dietary supplements has a limited effect on core biomarkers of PCC deficiency. These patients require further longitudinal study with standardized approaches to better understand the relationship between biomarkers and disease burden.
MeSH term(s)	Acids/blood ; Acids/urine ; Adolescent ; Adult ; Amino Acids/blood ; Amino Acids/urine ; Biomarkers/blood ; Biomarkers/urine ; Carbon-Carbon Ligases/blood ; Carbon-Carbon Ligases/genetics ; Carbon-Carbon Ligases/urine ; Carnitine/blood ; Carnitine/urine ; Child ; Child, Preschool ; Echocardiography ; Female ; Heart/diagnostic imaging ; Heart/physiopathology ; Humans ; Male ; Mitochondria/genetics ; Mitochondria/metabolism ; Mutation/genetics ; Neurodevelopmental Disorders/blood ; Neurodevelopmental Disorders/diagnostic imaging ; Neurodevelopmental Disorders/genetics ; Neurodevelopmental Disorders/urine ; Organic Chemicals/blood ; Organic Chemicals/urine ; Phenotype ; Propionic Acidemia/blood ; Propionic Acidemia/diagnostic imaging ; Propionic Acidemia/genetics ; Propionic Acidemia/urine ; Young Adult
Chemical Substances	Acids ; Amino Acids ; Biomarkers ; Organic Chemicals ; Carbon-Carbon Ligases (EC 6.4.-) ; PCCB protein, human (EC 6.4.-) ; Carnitine (S7UI8SM58A)
Language	English
Publishing date	2020-10-03
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1418518-0
ISSN	1096-7206 ; 1096-7192
ISSN (online)	1096-7206
ISSN	1096-7192
DOI	10.1016/j.ymgme.2020.09.006
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Article ; Online: Phospholipase C epsilon links G protein-coupled receptor activation to inflammatory astrocytic responses.

Dusaban, Stephanie S / Purcell, Nicole H / Rockenstein, Edward / Masliah, Eliezer / Cho, Min Kyung / Smrcka, Alan V / Brown, Joan Heller

Proceedings of the National Academy of Sciences of the United States of America

2013 Volume 110, Issue 9, Page(s) 3609–3614

Abstract: ... can activate G protein-coupled receptors (GPCRs) on astrocytes. We postulated that GPCRs that couple to Ras ...

Abstract	Neuroinflammation plays a major role in the pathophysiology of diseases of the central nervous system, and the role of astroglial cells in this process is increasingly recognized. Thrombin and the lysophospholipids lysophosphatidic acid and sphingosine 1-phosphate (S1P) are generated during injury and can activate G protein-coupled receptors (GPCRs) on astrocytes. We postulated that GPCRs that couple to Ras homolog gene family, member A (RhoA) induce inflammatory gene expression in astrocytes through the small GTPase responsive phospholipase Cε (PLCε). Using primary astrocytes from wild-type and PLCε knockout mice, we demonstrate that 1-h treatment with thrombin or S1P increases cyclooxygenase 2 (COX-2) mRNA levels ∼10-fold and that this requires PLCε. Interleukin-6 and interleukin-1β mRNA levels are also increased in a PLCε-dependent manner. Thrombin, lysophosphatidic acid, and S1P increase COX-2 protein expression through a mechanism involving RhoA, catalytically active PLCε, sustained activation of protein kinase D (PKD), and nuclear translocation of NF-κB. Endogenous ligands that are released from astrocytes in an in vitro wounding assay also induce COX-2 expression through a PLCε- and NF-κB-dependent pathway. Additionally, in vivo stab wound injury activates PKD and induces COX-2 and other inflammatory genes in WT but not in PLCε knockout mouse brain. Thus, PLCε links GPCRs to sustained PKD activation, providing a means for GPCR ligands that couple to RhoA to induce NF-κB signaling and promote neuroinflammation.
MeSH term(s)	Animals ; Astrocytes/drug effects ; Astrocytes/enzymology ; Astrocytes/pathology ; Cyclooxygenase 2/metabolism ; Enzyme Activation/drug effects ; Inflammation/enzymology ; Inflammation/pathology ; Lysophospholipids/pharmacology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Models, Biological ; NF-kappa B/metabolism ; Phosphoinositide Phospholipase C/metabolism ; Protein Kinase C/metabolism ; Receptors, G-Protein-Coupled/metabolism ; Sphingosine/analogs & derivatives ; Sphingosine/pharmacology ; Thrombin/pharmacology ; Wound Healing/drug effects
Chemical Substances	Lysophospholipids ; NF-kappa B ; Receptors, G-Protein-Coupled ; sphingosine 1-phosphate (26993-30-6) ; Ptgs2 protein, mouse (EC 1.14.99.-) ; Cyclooxygenase 2 (EC 1.14.99.1) ; protein kinase D (EC 2.7.10.-) ; Protein Kinase C (EC 2.7.11.13) ; Phosphoinositide Phospholipase C (EC 3.1.4.11) ; phospholipase C epsilon (EC 3.1.4.11) ; Thrombin (EC 3.4.21.5) ; Sphingosine (NGZ37HRE42) ; lysophosphatidic acid (PG6M3969SG)
Language	English
Publishing date	2013-02-11
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.1217355110
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Article ; Online: Multifactorial likelihood assessment of BRCA1 and BRCA2 missense variants confirms that BRCA1:c.122A>G(p.His41Arg) is a pathogenic mutation.

Whiley, Phillip J / Parsons, Michael T / Leary, Jennifer / Tucker, Kathy / Warwick, Linda / Dopita, Belinda / Thorne, Heather / Lakhani, Sunil R / Goldgar, David E / Brown, Melissa A / Spurdle, Amanda B

PloS one

2014 Volume 9, Issue 1, Page(s) e86836

Abstract: ... in aberrant mRNA transcripts predicted to encode truncated proteins. The BRCA1:c.122A>G(p.His41Arg) RING ... were considered to be pathogenic (Class 5). BRCA1:c.4484G> C(p.Arg1495Thr) was shown to result ...

Abstract	Rare exonic, non-truncating variants in known cancer susceptibility genes such as BRCA1 and BRCA2 are problematic for genetic counseling and clinical management of relevant families. This study used multifactorial likelihood analysis and/or bioinformatically-directed mRNA assays to assess pathogenicity of 19 BRCA1 or BRCA2 variants identified following patient referral to clinical genetic services. Two variants were considered to be pathogenic (Class 5). BRCA1:c.4484G> C(p.Arg1495Thr) was shown to result in aberrant mRNA transcripts predicted to encode truncated proteins. The BRCA1:c.122A>G(p.His41Arg) RING-domain variant was found from multifactorial likelihood analysis to have a posterior probability of pathogenicity of 0.995, a result consistent with existing protein functional assay data indicating lost BARD1 binding and ubiquitin ligase activity. Of the remaining variants, seven were determined to be not clinically significant (Class 1), nine were likely not pathogenic (Class 2), and one was uncertain (Class 3).These results have implications for genetic counseling and medical management of families carrying these specific variants. They also provide additional multifactorial likelihood variant classifications as reference to evaluate the sensitivity and specificity of bioinformatic prediction tools and/or functional assay data in future studies.
MeSH term(s)	Alternative Splicing/genetics ; BRCA1 Protein/genetics ; BRCA2 Protein/genetics ; Computational Biology ; Exons/genetics ; Genetic Predisposition to Disease ; Humans ; Likelihood Functions ; Multifactorial Inheritance/genetics ; Mutation, Missense/genetics ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; Reproducibility of Results ; Sequence Deletion/genetics
Chemical Substances	BRCA1 Protein ; BRCA2 Protein ; RNA, Messenger
Language	English
Publishing date	2014-01-28
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0086836
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Article: Identification of a C/G polymorphism in the promoter region of the BRCA1 gene and its use as a marker for rapid detection of promoter deletions.

Catteau, A / Xu, C F / Brown, M A / Hodgson, S / Greenman, J / Mathew, C G / Dunning, A M / Solomon, E

British journal of cancer

1999 Volume 79, Issue 5-6, Page(s) 759–763

Abstract: ... mutations were detected; however, a new polymorphism consisting of a C-to-G base change within the beta ... previously been shown not to be associated with breast or ovarian cancer. This indicates that the C/G ... promoter was identified, with the frequency of the G allele being 0.34. Close to complete ...

Abstract	Reduced expression of BRCA1 has been implicated in sporadic breast cancer, although the mechanisms underlying this phenomenon remain unclear. To determine whether regulatory mutations could account for the reduced expression, we screened the promoter region by sequencing in 20 patients with sporadic disease. No mutations were detected; however, a new polymorphism consisting of a C-to-G base change within the beta-promoter was identified, with the frequency of the G allele being 0.34. Close to complete linkage disequilibrium was found between this marker and the Pro871 Leu polymorphism, situated in exon 11, which has previously been shown not to be associated with breast or ovarian cancer. This indicates that the C/G polymorphism is also unlikely to play a role in either disease. However, the strength of linkage disequilibrium between these markers permitted their use for rapid screening for genomic deletions within BRCA1. A series of 214 cases with familial breast cancer were analysed using this approach; 88/214 were heterozygous for the promoter polymorphism, thereby excluding a deletion in this region. Among the remaining patients, one hemizygous case reflecting a promoter deletion was successfully identified. Therefore, this study indicates that deletions within the beta-promoter region of BRCA1 are an uncommon event in familial breast cancer. Furthermore, it suggests that mutations within the BRCA1 promoter are unlikely to account for the reported decreased expression of BRCA1 in sporadic disease.
MeSH term(s)	Adenocarcinoma/genetics ; Adult ; Age of Onset ; Base Sequence ; Breast Neoplasms/genetics ; Cytosine ; DNA/blood ; DNA, Neoplasm/genetics ; Family ; Female ; Genes, BRCA1 ; Genetic Markers ; Genotype ; Guanine ; Humans ; Male ; Ovarian Neoplasms/genetics ; Polymorphism, Genetic ; Promoter Regions, Genetic ; Reference Values ; Sequence Deletion ; United Kingdom ; Whites/genetics
Chemical Substances	DNA, Neoplasm ; Genetic Markers ; Guanine (5Z93L87A1R) ; Cytosine (8J337D1HZY) ; DNA (9007-49-2)
Language	English
Publishing date	1999-02
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80075-2
ISSN	1532-1827 ; 0007-0920
ISSN (online)	1532-1827
ISSN	0007-0920
DOI	10.1038/sj.bjc.6690122
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Article: An analogue of adenine that forms an "A:T" base pair of comparable stability to G:C.

Booth, James / Cummins, W Jon / Brown, Tom

Chemical communications (Cambridge, England)

2004 , Issue 19, Page(s) 2208–2209

Abstract: ... into oligodeoxynucleotides. D:T has similar thermodynamic stability to G:C and is a stable analogue of A:T. ...

Abstract	The heterocyclic base 7-aminopropargyl-7-deaza-2,6-diaminopurine (D) has been incorporated into oligodeoxynucleotides. D:T has similar thermodynamic stability to G:C and is a stable analogue of A:T.
MeSH term(s)	Adenine/analogs & derivatives ; Adenine/chemistry ; Base Pairing ; Base Sequence ; Cytosine/chemistry ; Guanine/chemistry ; Nucleic Acid Conformation ; Thermodynamics ; Thymine/chemistry
Chemical Substances	Guanine (5Z93L87A1R) ; Cytosine (8J337D1HZY) ; Adenine (JAC85A2161) ; Thymine (QR26YLT7LT)
Language	English
Publishing date	2004-10-07
Publishing country	England
Document type	Journal Article
ZDB-ID	1472881-3
ISSN	1364-548X ; 1359-7345 ; 0009-241X
ISSN (online)	1364-548X
ISSN	1359-7345 ; 0009-241X
DOI	10.1039/b409155h
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Article: A depot lepromin test and B. C. G. vaccination.

BROWN, J A K / STONE, M M

Lancet (London, England)

2003 Volume 1, Issue 7086, Page(s) 1260–1262

MeSH term(s)	BCG Vaccine/pharmacology ; Humans ; Lepromin ; Leprosy/immunology ; Mycobacterium bovis ; Vaccination
Chemical Substances	BCG Vaccine ; Lepromin (11006-67-0)
Language	English
Publishing date	2003-03-17
Publishing country	England
Document type	Journal Article
ZDB-ID	3306-6
ISSN	1474-547X ; 0140-6736 ; 0023-7507
ISSN (online)	1474-547X
ISSN	0140-6736 ; 0023-7507
DOI	10.1016/s0140-6736(59)91235-8
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Article ; Online: Multifactorial likelihood assessment of BRCA1 and BRCA2 missense variants confirms that BRCA1:c.122A>G(p.His41Arg) is a pathogenic mutation.

Phillip J Whiley / Michael T Parsons / Jennifer Leary / Kathy Tucker / Linda Warwick / Belinda Dopita / Heather Thorne / Sunil R Lakhani / David E Goldgar / Melissa A Brown / Amanda B Spurdle

PLoS ONE, Vol 9, Iss 1, p e

2014 Volume 86836

Abstract	Rare exonic, non-truncating variants in known cancer susceptibility genes such as BRCA1 and BRCA2 are problematic for genetic counseling and clinical management of relevant families. This study used multifactorial likelihood analysis and/or bioinformatically-directed mRNA assays to assess pathogenicity of 19 BRCA1 or BRCA2 variants identified following patient referral to clinical genetic services. Two variants were considered to be pathogenic (Class 5). BRCA1:c.4484G> C(p.Arg1495Thr) was shown to result in aberrant mRNA transcripts predicted to encode truncated proteins. The BRCA1:c.122A>G(p.His41Arg) RING-domain variant was found from multifactorial likelihood analysis to have a posterior probability of pathogenicity of 0.995, a result consistent with existing protein functional assay data indicating lost BARD1 binding and ubiquitin ligase activity. Of the remaining variants, seven were determined to be not clinically significant (Class 1), nine were likely not pathogenic (Class 2), and one was uncertain (Class 3).These results have implications for genetic counseling and medical management of families carrying these specific variants. They also provide additional multifactorial likelihood variant classifications as reference to evaluate the sensitivity and specificity of bioinformatic prediction tools and/or functional assay data in future studies.
Keywords	Medicine ; R ; Science ; Q
Subject code	572
Language	English
Publishing date	2014-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
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Article: The crystal structure of d(G-G-G-G-C-C-C-C). A model for poly(dG).poly(dC).

McCall, M / Brown, T / Kennard, O

Journal of molecular biology

1985 Volume 183, Issue 3, Page(s) 385–396

Abstract: The structure of the DNA oligomer d(G-G-G-G-C-C-C-C) has been determined at a resolution of 2.5 ... groups on the DNA are hydrated, and 106 ordered solvent molecules have been found. The two d(G-G-G-G).d(C ... by applying a simple rotation and translation to each of the unmodified d(G-G-G-G).d(C-C-C-C) units. Detailed ...

Abstract	The structure of the DNA oligomer d(G-G-G-G-C-C-C-C) has been determined at a resolution of 2.5 A by single-crystal X-ray methods. There are two strands in the asymmetric unit, and these coil about each other to form a right-handed double-helix of the A-type with Watson-Crick hydrogen bonds between base-pairs. The helix has a shallow minor groove and a deep, water-filled major groove; almost all exposed functional groups on the DNA are hydrated, and 106 ordered solvent molecules have been found. The two d(G-G-G-G).d(C-C-C-C) segments in the octamer exhibit similar and uniform structures, but there is a slight discontinuity at the GpC step between them. A recurring feature of the structure is the overlap of adjacent guanine bases in each GpG step, with the five-membered ring of one guanine stacking on the six-membered ring of its neighbour. There is little or no overlap between adjacent cytosine rings. Conformational parameters for these GpG steps are compared with those from other single-crystal X-ray analyses. In general, GpG steps exhibit high slide, low roll and variable twist. Models for poly(dG).poly(dC) were generated by applying a simple rotation and translation to each of the unmodified d(G-G-G-G).d(C-C-C-C) units. Detailed features of these models are shown to be compatible with various assays of poly(dG).poly(dC) in solution, and are useful in understanding the polymorphic behaviour of this sequence under a variety of experimental conditions.
MeSH term(s)	Chemical Phenomena ; Chemistry ; Macromolecular Substances ; Models, Molecular ; Oligodeoxyribonucleotides ; Oligonucleotides ; Polydeoxyribonucleotides ; X-Ray Diffraction
Chemical Substances	Macromolecular Substances ; Oligodeoxyribonucleotides ; Oligonucleotides ; Polydeoxyribonucleotides ; oligodeoxycytidylic acid ; oligodeoxyguanylic acid ; poly(dG).poly(dC) (25512-84-9)
Language	English
Publishing date	1985-06-05
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80229-3
ISSN	1089-8638 ; 0022-2836
ISSN (online)	1089-8638
ISSN	0022-2836
DOI	10.1016/0022-2836(85)90009-9
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Article: Structural features and hydration of d(C-G-C-G-A-A-T-T-A-G-C-G); a double helix containing two G.A mispairs.

Hunter, W N / Brown, T / Kennard, O

Journal of biomolecular structure & dynamics

1986 Volume 4, Issue 2, Page(s) 173–191

Abstract: ... interactions and hydration are presented and compared with those of the parent compound d(C-G-C-G-A-A-T-T-C-G-C ... two G.A mismatched base pairs. The purine-purine mismatches have guanine in the usual anti orientation ... G). ...

Abstract	Single crystal X-ray diffraction techniques have been used to characterise the molecular structure of the title compound to 2.5A resolution. The structure consists of ten standard Watson-Crick base pairs and two G.A mismatched base pairs. The purine-purine mismatches have guanine in the usual anti orientation with respect to the sugar and adenine in syn orientation. There are two hydrogen bonds formed between the mismatch bases, N-1 and O-6 of guanine with N-7 and N-6 of adenine respectively. The bulky purine-purine mismatches are accommodated with minor perturbation of the sugar-phosphate backbone. There is a slight improvement in base pair overlap at the mismatch sites. Details of the backbone conformation, base stacking interactions and hydration are presented and compared with those of the parent compound d(C-G-C-G-A-A-T-T-C-G-C-G).
MeSH term(s)	Base Composition ; Crystallization ; DNA ; Genetic Variation ; Hot Temperature ; Hydrogen Bonding ; Nucleic Acid Conformation ; Water
Chemical Substances	Water (059QF0KO0R) ; DNA (9007-49-2)
Language	English
Publishing date	1986-10
Publishing country	England
Document type	Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	49157-3
ISSN	1538-0254 ; 0739-1102
ISSN (online)	1538-0254
ISSN	0739-1102
DOI	10.1080/07391102.1986.10506338
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