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PubMed2002

One gene and one outcome? No way.

The world of molecular diagnostics is undergoing major change because of both technical advances and the availability of rapidly expanding genetic databases generated by the study of human genomics. These resources comprise an extraordinary opportunity to decipher the biological importance of genetic aberrations, and link our understanding with clinical utility. The challenge lies in sorting through the information and developing effective strategies to advance molecular diagnostics.

Genetic Markers↗
PubMed2026

Genetic Research on Cardiac Channelopathies in African and African-Descent Populations: A Scoping Review.

Cardiac channelopathies are inherited arrhythmias that can lead to sudden cardiac death. Despite Africa's extensive genomic diversity, African and African-descent populations remain underrepresented in genetic research, creating gaps in variant interpretation and clinical care. This scoping review aims to map the extent, range, and nature of genetic research on cardiac channelopathies in these populations and to identify key geographic, thematic, and methodological gaps. Using the Joanna Briggs Institute scoping review methodology and the Population-Concept-Context framework, systematic searches in PubMed, Embase, and Web of Science identified original human studies on cardiac channelopathies with genetic data. Extracted variables included study characteristics, populations, types of channelopathies, and reported genes and variants. Forty-four studies met the inclusion criteria. Most studies originated from the United States and South Africa, while West, Central, and East Africa were largely underrepresented. US Black individuals and South African individuals of continental African or African-descended ancestry (excluding populations of European descent such as Cape Afrikaner people) were the most studied groups, with other continental African groups rarely included. Long QT syndrome was the predominant focus, and SCN5A, KCNQ1, and KCNH2 were the most frequently analyzed genes. Many of the genetic variants discussed remained of uncertain significance due to limited functional validation and the underrepresentation of African genomes in reference databases. Genetic research on cardiac channelopathies in populations of African ancestry is limited, restricting variant interpretation, counseling, and risk prediction. Broader African inclusion, expanded gene screening, and functional studies are essential to improve diagnostics and promote equity in genomic medicine.

Humans↗
PubMed2002

Analysis of DNA polymorphism at HLA-A locus by PCR amplification with sequence specific oligonucleotide probe in Chinese Han and Uygur populations.

To determine HLA-A genetic polymorphism in Chinese populations and establish ethnic genetic database, 165 Han and 162 Uygur subjects were investigated with a non-isotopic and sensitive method PCR-SSOP. 22 alleles were identified in Han with the most frequent allele being HLA-A * 1101 (19.7%), followed by * 0201 (12.72%). Also, 22 alleles were identified in Uygur with * 2407 (17.90%) being the most frequent one and the frequencies of following alleles: * 0201, * 0101, * 3301 were higher than 10%. HLA-A * 0203, * 0205, * 0210, * 0302, * 2403 and * 3302 were only detected in Han; meanwhile * 0205, * 0211, * 2301, * 2502, * 68012 and * 6802 were only in Uygur. According to Hardy-Weinberg equilibrium, each allele showed no significant (P > 0.05) deviation between the expected frequency and the observed one. Heterozygosity (H), discrimination power (DP) and probability of paternity exclusion (EPP) of HLA-A locus from Han nationality were computed to be 0.9029, 0.9776 and 0.8592; and those from Uygur as 0.9063, 0.9379 and 0.7885. These results suggest that HLA-A DNA polymorphism and the database of two Chinese populations have useful applications in processing forensic casework (as personal identification, paternity test), tracing population migration and genetic diagnosis.

Alleles↗
PubMed1999

Crooked tail (Cd) models human folate-responsive neural tube defects.

Genetic correlation of human neural tube defects (NTDs) with NTD genes identified in mouse may unravel predisposing complex traits for assessment of individual risk and treatment in clinical settings. Folic acid (FA) can reduce the recurrence of NTDs in human populations by as much as 50-70%, though the mechanism of this rescue is unknown. We examined whether Crooked tail ( Cd ), a mouse strain prone to exencephaly, could provide a genetic animal model for folate-responsive NTDs. The Cd locus was localized to a 0.2 cM interval of the Mouse Genome Database genetic map, identifying tightly linked markers for genotyping prior to phenotypic expression. In a controlled diet study, Cd was found to mimic closely the clinical response to FA. FA supplementation reduced the recurrence risk of Cd exencephaly by as much as 55%. This rescue was dose dependent and did not require subjects to be inherently folate deficient. Like the female predominance of NTDs in humans, female Cd embryos were most likely to display exencephaly and were more responsive than males to the FA rescue. Importantly, FA supplementation shifted the severity of Cd phenotypic expression from early embryonic lethality to longer survival, and reduced the incidence of NTDs. The Cd locus is distinct from the known genes associated with neurulation defects, and isolation of this gene will assist identification of biochemical, genetic and gender-dependent factors contributing to folate-responsive NTDs.

Animals↗
PubMed2026

A Case Report of a Pedigree with Distal Hereditary Motor Neuropathy Caused by a Homozygous c.1124G>A Variant an the /*9Vaccinia-Related Kinase 1 Gene.

This study aimed to analyze the clinical phenotypes, neurophysiological characteristics, and pathogenicity of gene variants in a pedigree with distal hereditary motor neuropathy (dHMN) caused by VRK1 variants, and to provide evidence to support clinical diagnosis and genetic counseling for this disease. We report a Chinese consanguineous family with dHMN caused by a homozygous c.1124G>A variant in the VRK1 gene. Clinical and electrophysiological data of the proband were collected. Whole-exome sequencing (WES) and validation by Sanger sequencing were performed to identify the variant site, and pathogenicity interpretation was conducted in accordance with American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines. The proband was a 24-year-old male who presented with 2 years of progressive weakness and atrophy of the distal lower limbs, accompanied by slender upper limbs and no sensory disturbance. Electrophysiological examination showed decreased compound muscle action potential (CMAP) amplitude in motor nerves of both upper and lower limbs, indicating peripheral neurogenic damage, while sensory nerve conduction was normal. Genetic testing detected a homozygous c.1124G>A (p.Trp375Ter) variant in the VRK1 gene. His parents and elder sisters were heterozygous carriers, and the pedigree conformed to autosomal recessive inheritance. According to ACMG guidelines, this variant was classified as pathogenic (evidence: PVS1, PM2, PP1). The homozygous VRK1 c.1124G>A variant causes adult-onset dHMN, rather than pontocerebellar hypoplasia type 1A (PCH1A) as annotated in some genetic databases. This pedigree presents distinctive phenotypes, including slender upper limbs and diffusely decreased CMAP amplitudes in both upper and lower limbs, thereby expanding the clinical and genetic spectrum of VRK1-related dHMN in the Chinese population.

Humans↗
PubMed2002

Mapping public policy on genetics.

The mapping of the human genome and related advances in genetics are stimulating the development of public policies on genetics. Certain notions that currently prevail in public policy development overall--including the importance of protecting privacy of information, an interest in cost-effectiveness, and the power of the anecdote--will help determine the future of public policy on genetics. Information areas affected include discrimination by insurers and employers, confidentiality, genetic databanks, genetic testing in law enforcement, and court-ordered genetic testing in civil cases. Service issues address clinical standards, insurance benefits, allocation of resources, and screening of populations at risk. Supply issues encompass funding of research and clinical positions. Likely government actions include, among others: (1) Requiring individual consent for the disclosure of personal information, except when such consent would impose inordinate costs; (2) licensing genetic databases; (3) allowing courts to use personal information in cases where a refusal to use such information would offend the public; (4) mandating health insurers to pay for cost-effective genetic services; (5) funding pharmaceutical research to develop tailored products to prevent or treat diseases; and (6) funding training programs.

Attitude↗
PubMed1999

Clinical and genetic heterogeneity in autosomal dominant cataract.

AIMS: To determine the different morphologies of autosomal dominant cataract (ADC), assess the intra- and interfamilial variation in cataract morphology, and undertake a genetic linkage study to identify loci for genes causing ADC and detect the underlying mutation. METHODS: Patients were recruited from the ocular genetic database at Moorfields Eye Hospital. All individuals underwent an eye examination with particular attention to the lens including anterior segment photography where possible. Blood samples were taken for DNA extraction and genetic linkage analysis was carried out using polymorphic microsatellite markers. RESULTS: 292 individuals from 16 large pedigrees with ADC were examined, of whom 161 were found to be affected. The cataract phenotypes could all be described as one of the eight following morphologies-anterior polar, posterior polar, nuclear, lamellar, coralliform, blue dot (cerulean), cortical, and pulverulent. The phenotypes varied in severity but the morphology was consistent within each pedigree, except in those affected by the pulverulent cataract, which showed considerable intrafamilial variation. Positive linkage was obtained in five families; in two families linkage was demonstrated to new loci and in three families linkage was demonstrated to previously described loci. In one of the families the underlying mutation was isolated. Exclusion data were obtained on five families. CONCLUSIONS: Although there is considerable clinical heterogeneity in ADC, the phenotype is usually consistent within families. There is extensive genetic heterogeneity and specific cataract phenotypes appear to be associated with mutations at more than one chromosome locus. In cases where the genetic mutation has been identified the molecular biology and clinical phenotype are closely associated.

Adolescent↗
PubMed1998

Novel COL7A1 mutations in dystrophic forms of epidermolysis bullosa.

Mutations in the type VII collagen gene (COL7A1) have been shown to underlie different variants of dystrophic epidermolysis bullosa (DEB). Examination of the genetic database indicates that most of the mutations are family specific, with few recurrent mutations. To facilitate further refinement of genotype/phenotype correlations in DEB, we have examined a cohort of nine families with DEB (seven recessively and two dominantly inherited) by a mutation detection strategy based on polymerase chain reaction amplification of COL7A1 genomic sequences, followed by heteroduplex scanning and direct nucleotide sequencing. The results revealed 16 allelic mutations, 11 of them being novel, previously unpublished. The genetic information was also used for prenatal testing in a family at risk for recurrence of a severe, Hallopeau-Siemens type of RDEB. These data contribute to the expanding database of COL7A1 mutations in DEB.

Adult↗
PubMed2001

The adaptive evolution database (TAED).

BACKGROUND: The Master Catalog is a collection of evolutionary families, including multiple sequence alignments, phylogenetic trees and reconstructed ancestral sequences, for all protein-sequence modules encoded by genes in GenBank. It can therefore support large-scale genomic surveys, of which we present here The Adaptive Evolution Database (TAED). In TAED, potential examples of positive adaptation are identified by high values for the normalized ratio of nonsynonymous to synonymous nucleotide substitution rates (KA/KS values) on branches of an evolutionary tree between nodes representing reconstructed ancestral sequences. RESULTS: Evolutionary trees and reconstructed ancestral sequences were extracted from the Master Catalog for every subtree containing proteins from the Chordata only or the Embryophyta only. Branches with high KA/KS values were identified. These represent candidate episodes in the history of the protein family when the protein may have undergone positive selection, where the mutant form conferred more fitness than the ancestral form. Such episodes are frequently associated with change in function. An unexpectedly large number of families (between 10% and 20% of those families examined) were found to have at least one branch with high KA/KS values above arbitrarily chosen cut-offs (1 and 0.6). Most of these survived a robustness test and were collected into TAED. CONCLUSIONS: TAED is a raw resource for bioinformaticists interested in data mining and for experimental evolutionists seeking candidate examples of adaptive evolution for further experimental study. It can be expanded to include other evolutionary information (for example changes in gene regulation or splicing) placed in a phylogenetic perspective.

Adaptation, Physiological↗
PubMed2000

A new pentaplex PCR system for forensic casework analysis.

In 1998 the Federal Criminal Police Office of Germany (BKA) established a central genetic database of offenders and suspects to facilitate comparisons with biological samples from future criminal offences. The five obligatory short tandem repeat (STR) loci in this database (TH01, SE33, vWA, FGA and D21S11) were co-amplified in a new PCR pentaplex analysing system together with the sex-specific locus amelogenin. Due to overlapping fragment sizes, amplification products were fluorescent dye-labelled with different colours, separated by electrophoresis and detected directly using the ABI PRISM 310 Genetic Analyzer. Reproducible and reliable results were obtained from as low as 125 pg template DNA, indicating high specificity and sensitivity of the assay. Environmental studies and enzymatic digest with DNase I revealed an excellent stability of the pentaplex system with typeable results even in cases of partially degraded DNA. Complete and reproducible DNA typing was possible in blood-stain mixtures with the minor component as low as 10%. Mean stutter peak intensities were analysed for all loci and ranged from 2.7 +/- 0.8% (TH01) to 10.6 +/- 1.6% (vWA) of the main signal intensity. Allele frequencies were determined in a North Bavarian population sample (n = 121). The combination of five systems resulted in a mean exclusion chance of 99.86% and a power of discrimination of 99.999996%. No deviation from Hardy-Weinberg equilibrium could be found.

Alleles↗
PubMed2001

The forensic DNA implications of genetic differentiation between endogamous communities.

In many indigenous minority populations, and among migrants from Asian and African populations now resident in western Europe, North America and Australia, there is a strong tradition of endogamy and a preference for consanguineous unions. These marriage practices can result in F(ST) values greatly in excess of the maximum value (0.01) currently recommended for forensic DNA purposes under guidelines established by the National Research Council (NRC) of the USA. To examine the possible extent of deviation from this accepted norm, three co-resident Pakistani communities were studied using 10 autosomal dinucleotide markers and six tetranucleotide markers on the Y-chromosome. The mean population subdivision coefficient (FST) value was 0.13 for the autosomal loci, and Y-chromosome loci exhibited even stronger differentiation with unique alleles identified in all three communities. The data indicate that even when sub-populations are virtually indistinguishable in terms of anthropology, geography, ethnicity or culture, they may still exhibit major genetic differentiation. Where significant population stratification is known to exist, more detailed genetic databases should be developed for forensic DNA purposes, based on reference data from each of the appropriate sub-populations and not on random or combined samples.

Consanguinity↗
PubMed2000

Selecting protein targets for structural genomics of Pyrobaculum aerophilum: validating automated fold assignment methods by using binary hypothesis testing.

Three-dimensional protein folds were assigned to all ORFs of the recently sequenced genome of the hyperthermophilic archaeon Pyrobaculum aerophilum. Binary hypothesis testing was used to estimate a confidence level for each assignment. A separate test was conducted to assign a probability for whether each sequence has a novel fold-i.e., one that is not yet represented in the experimental database of known structures. Of the 2,130 predicted nontransmembrane proteins in this organism, 916 matched a fold at a cumulative 90% confidence level, and 245 could be assigned at a 99% confidence level. Likewise, 286 proteins were predicted to have a previously unobserved fold with a 90% confidence level, and 14 at a 99% confidence level. These statistically based tools are combined with homology searches against the Online Mendelian Inheritance in Man (OMIM) human genetics database and other protein databases for the selection of attractive targets for crystallographic or NMR structure determination. Results of these studies have been collated and placed at http://www.doe-mbi.ucla.edu/people/parag/P A_HOME/, the University of California, Los Angeles-Department of Energy Pyrobaculum aerophilum web site.

Algorithms↗
PubMed2000

Unusual polymorphisms in human immunodeficiency virus type 1 associated with nonprogressive infection.

Factors accounting for long-term nonprogression may include infection with an attenuated strain of human immunodeficiency virus type 1 (HIV-1), genetic polymorphisms in the host, and virus-specific immune responses. In this study, we examined eight individuals with nonprogressing or slowly progressing HIV-1 infection, none of whom were homozygous for host-specific polymorphisms (CCR5-Delta32, CCR2-64I, and SDF-1-3'A) which have been associated with slower disease progression. HIV-1 was recovered from seven of the eight, and recovered virus was used for sequencing the full-length HIV-1 genome; full-length HIV-1 genome sequences from the eighth were determined following amplification of viral sequences directly from peripheral blood mononuclear cells (PBMC). Longitudinal studies of one individual with HIV-1 that consistently exhibited a slow/low growth phenotype revealed a single amino acid deletion in a conserved region of the gp41 transmembrane protein that was not seen in any of 131 envelope sequences in the Los Alamos HIV-1 sequence database. Genetic analysis also revealed that five of the eight individuals harbored HIV-1 with unusual 1- or 2-amino-acid deletions in the Gag sequence compared to subgroup B Gag consensus sequences. These deletions in Gag have either never been observed previously or are extremely rare in the database. Three individuals had deletions in Nef, and one had a 4-amino-acid insertion in Vpu. The unusual polymorphisms in Gag, Env, and Nef described here were also found in stored PBMC samples taken 3 to 11 years prior to, or in one case 4 years subsequent to, the time of sampling for the original sequencing. In all, seven of the eight individuals exhibited one or more unusual polymorphisms; a total of 13 unusual polymorphisms were documented in these seven individuals. These polymorphisms may have been present from the time of initial infection or may have appeared in response to immune surveillance or other selective pressures. Our results indicate that unusual, difficult-to-revert polymorphisms in HIV-1 can be found associated with slow progression or nonprogression in a majority of such cases.

Amino Acid Sequence↗
PubMed2025

Influence of ADRB2 variants on bronchodilator response and asthma control in a mixed population.

OBJECTIVE: Given that b2 agonists constitute the primary treatment for asthma and that treatment response varies as a result of polymorphisms in the ADRB2 gene, we sought to investigate the associations between ADRB2 gene variants and bronchodilator response (BDR) in asthma patients. METHODS: A genetic database comprising 813 individuals was analyzed for variants in the ADRB2 gene. A longitudinal analysis of severe asthma patients was performed to evaluate changes in BDR over time. RESULTS: The rs1042713, rs1042714, and rs1042717 variants were associated with age-related changes in BDR in patients with severe asthma. The G allele (rs1042714) and the A allele (rs1042717) were associated with uncontrolled asthma, with carriers of the G46/G79/A252 alleles showing a higher risk of difficult-to-control asthma. Notably, no association was found between these variants and ADRB2 expression levels. CONCLUSIONS: Our findings suggest that a genetic panel including ADRB2 variants, as well as age-related differences in BDR, is a useful complementary tool in asthma management.

Humans↗
PubMed1999

Population genetic data on loci LDLR, GYPA, HBGG, D7S8 and GC in the Bangkok population compared with rural Thais from Trat province.

Prior to the introduction of any DNA marker as a tool for person identification and paternity test in certain ethnic groups, a population genetic database should be constructed. Using multiplex primers in single tube polymerase chain amplification, 5 loci of unrelated genes in the PM Amplitype kit (Perkin Elmer) were studied in two Thai population groups: 228 DNA samples were extracted from blood collected at the Borai rural area in Trat province; another 123 DNA samples were collected at the outpatient clinic, Department of Forensic Medicine, King Chulalongkorn Memorial Hospital, Bangkok. Analysis of alleles and genotypes was performed after reversed dot blot hybridization of PCR products to allelic sequence specific probes immobilized on the membrane strip followed by nonradioisotopic detection according to the manufacturer's protocol. Population genetic statistic parameters including discrimination power (DP), the probability of matching (PM), power of exclusion for trio (PE trio) and typical paternity index (PI typical) were computed. Both Thai population groups showed no significant deviation from the Hardy Weinberg Expectation (HWE). The combined DP of all 5 loci in the PM Amplitype markers was 0.993636 for rural Thais and 0.994409 for Thais from Bangkok. The combined PM for rural Thais and those living in Bangkok was 0.006364 and 0.005591, respectively. The combined PE trio was 0.696825 and 0.698875 in both Thai population groups and the combined PI typical values were < 1.0. In conclusion, person identification using PM Amplitype DNA markers was efficient and satisfactory within certain limits. Hence, the application of PM Amplitype DNA markers for paternity tests should be cautiously considered and applied in combination with other parameters.

Alleles↗
PubMed2002

Regulatory context is a crucial part of gene function.

Information about the time and place of gene transcription, which until recently was only possible by extensive experimental analysis, can now be predicted through in silico analysis. Using the human RANTES/CCL5 promoter, we show that organizational features of promoters derived from promoter sequences contain information about the spatial and temporal 'functional context' of expression.

Animals↗
PubMed2002

Comparison of the small molecule metabolic enzymes of Escherichia coli and Saccharomyces cerevisiae.

The comparison of the small molecule metabolism pathways in Escherichia coli and Saccharomyces cerevisiae (yeast) shows that 271 enzymes are common to both organisms. These common enzymes involve 384 gene products in E. coli and 390 in yeast, which are between one half and two thirds of the gene products of small molecule metabolism in E. coli and yeast, respectively. The arrangement and family membership of the domains that form all or part of 374 E. coli sequences and 343 yeast sequences was determined. Of these, 70% consist entirely of homologous domains, and 20% have homologous domains linked to other domains that are unique to E. coli, yeast, or both. Over two thirds of the enzymes common to the two organisms have sequence identities between 30% and 50%. The remaining groups include 13 clear cases of nonorthologous displacement. Our calculations show that at most one half to two thirds of the gene products involved in small molecule metabolism are common to E. coli and yeast. We have shown that the common core of 271 enzymes has been largely conserved since the separation of prokaryotes and eukaryotes, including modifications for regulatory purposes, such as gene fusion and changes in the number of isozymes in one of the two organisms. Only one fifth of the common enzymes have nonhomologous domains between the two organisms. Around the common core very different extensions have been made to small molecule metabolism in the two organisms.

Databases, Genetic↗