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PubMed1988

Constitutional genetic markers of aging.

Constitutional genetic markers of aging can be defined as members of that subset of genes that modulate the times of onset and/or the rates of progression of one or more of the processes of aging, or the response of the target cells, tissues and organisms to a particular process. These genetic factors are classified into: (1) those that control changes in structure and function that may be universally expressed in aging organisms or that are expressed in large taxonomic groups of organisms ("public markers") and (2) those that control changes that are species specific or that reflect polymorphisms or mutations within a species ("private markers"). Both spontaneous and experimentally induced genetic variation can identify and characterize such genetic elements. Recommendations for implementing such a program of research include (1) particularization of the aging phenotype, (2) further development of nonmammalian models amenable to genetic analysis, (3) systematic search for relevant spontaneous mutations in Mus musculus, (4) utilization of recombinant inbred, chimeric, transgenic and interspecific mice and (5) investigations of genetic concomitants of speciation.

Aging↗
PubMed2006

Development of bioinformatics resources for display and analysis of copy number and other structural variants in the human genome.

The discovery of an abundance of copy number variants (CNVs; gains and losses of DNA sequences >1 kb) and other structural variants in the human genome is influencing the way research and diagnostic analyses are being designed and interpreted. As such, comprehensive databases with the most relevant information will be critical to fully understand the results and have impact in a diverse range of disciplines ranging from molecular biology to clinical genetics. Here, we describe the development of bioinformatics resources to facilitate these studies. The Database of Genomic Variants (http://projects.tcag.ca/variation/) is a comprehensive catalogue of structural variation in the human genome. The database currently contains 1,267 regions reported to contain copy number variation or inversions in apparently healthy human cases. We describe the current contents of the database and how it can serve as a resource for interpretation of array comparative genomic hybridization (array CGH) and other DNA copy imbalance data. We also present the structure of the database, which was built using a new data modeling methodology termed Cross-Referenced Tables (XRT). This is a generic and easy-to-use platform, which is strong in handling textual data and complex relationships. Web-based presentation tools have been built allowing publication of XRT data to the web immediately along with rapid sharing of files with other databases and genome browsers. We also describe a novel tool named eFISH (electronic fluorescence in situ hybridization) (http://projects.tcag.ca/efish/), a BLAST-based program that was developed to facilitate the choice of appropriate clones for FISH and CGH experiments, as well as interpretation of results in which genomic DNA probes are used in hybridization-based experiments.

Algorithms↗
PubMed2006

Variance component models for X-linked QTLs.

This paper discusses the theory and implementation of a model for mapping X-linked quantitative trait loci (QTL). As a result of X inactivation, a female's body is subdivided into a number of patches. In each patch one of her two X chromosomes is randomly switched off. This smooths the allelic contributions in a heterozygote and implies that females should show less trait variation than males for an X-linked trait. The latest version of the genetic analysis program Mendel incorporates a simple variance component version of this model. An application to head circumference in autistic children illustrates Mendel in action.

Analysis of Variance↗
PubMed2025

Large-scale admixture mapping in the All of Us Research Program improves the characterization of cross-population phenotypic differences.

Admixed individuals have largely been understudied in medical research due to their complex genetic ancestries. However, the consideration of admixture can help identify ancestry-enriched genetic associations, delineating some of the genetic underpinnings of cross-population phenotypic variation. To this end, we performed local ancestry inference within the All of Us Research Program to identify individuals with recent admixture between African (AFR) and European (EUR) populations (N=48,921). We identified evidence of local AFR ancestry enrichment at the HLA locus, suggestive of putative selection since admixture. Furthermore, we performed the largest admixture mapping (ADM) efforts in AFR-EUR Admixed individuals for 22 traits, identifying 71 associations between inferred local AFR ancestries and a trait. Variants from published GWAS could only account for 18 (25%) of the ADM associations, highlighting novel loci where ancestral haplotypes explained some phenotypic variation. Previous studies likely have not identified these loci due to the low availability of high-powered GWAS in populations genetically similar to AFR. One such loci was 9q21.33, associated with 1.4-fold risk of end-stage kidney disease (ESKD) for carriers of inferred local AFR ancestries at the region. This locus contains the gene SLC28A3, which has previously been linked to kidney function but has never been associated with cross-population ESKD prevalence differences. Together, our results expand upon the existing literature on phenotypic differences between populations, highlighting loci where genetic ancestries play a critical role in the genetic architecture of disease.

Journal Article↗
PubMed2003

Disease genes and intracellular protein networks.

By a computational approach we reconstructed genomic transcriptional profiles of 19 different adult human tissues, based on information on activity of 27,924 genes obtained from unbiased UniGene cDNA libraries. In each considered tissue, a small number of genes resulted highly expressed or "tissue specific." Distribution of gene expression levels in a tissue appears to follow a power law, thus suggesting a correspondence between transcriptional profile and "scale-free" topology of protein networks. The expression of 737 genes involved in Mendelian diseases was analyzed, compared with a large reference set of known human genes. Disease genes resulted significantly more expressed than expected. The possible correspondence of their products to important nodes of intracellular protein network is suggested. Auto-organization of the protein network, its stability in time in the differentiated state, and relationships with the degree of genetic variability at genome level are discussed.

Adult↗
PubMedDate not supplied

[Good practices for the study of hemoglobin].

Hemoglobinopathies have become a significant national health problem in France. The biologists have a pivotal role in the genetic diagnoses. Although sickle cell disease (SCD) is the most frequent abnormality found: not less than 200 new cases are observed each year at birth, many other globin gene variations are found in the various ethnic groups. Since 1995 a neonatal sickle cell screening program has been established for at risk newborns. This programme is supported by the "Association française de dépistage et prévention des handicaps de l'enfant" (AFDPHE). The characterization of hemoglobin genetic variations requires a comprehensive set of laboratory techniques for which we specify here main clinical and technical recommendations.

Blood Chemical Analysis↗
PubMed2004

Genetic stability of micropropagated almond plantlets, as assessed by RAPD and ISSR markers.

Almond shoots produced by axillary branching from clone VII derived from a seedling of cultivar Boa Casta were evaluated for somaclonal variation using randomly amplified polymorphic DNA (RAPD) and inter-simple sequence repeats (ISSR) analysis. To verify genetic stability we compared RAPD and ISSR patterns of plantlets obtained after 4 and 6 years of in vitro multiplication. A total of 64 RAPD and 10 ISSR primers gave 326 distinct and reproducible band classes, monomorphic across all 22 plantlets analysed. Thus, a total of 7,172 bands were generated, exhibiting homogeneous RAPD and ISSR patterns for the plantlets tested. These results suggest that the culture conditions used for axillary branching proliferation are appropriate for clonal propagation of almond clone VII, as they do not seem to interfere with the integrity of the regenerated plantlets. These results allowed us to establish the use of axillary branching plantlets (mother-plants) as internal controls for the analysis of somaclonal variation of shoots regenerated from other in vitro culture processes performed with clone VII (adventitious regeneration, regeneration from meristem culture, virus sanitation programs and genetic engineering).

Agriculture↗
PubMed2005

Genetic parameters of fertility in two lines of rabbits with different reproductive potential.

A Bayesian analysis with a threshold model was performed for fertility defined as a binary trait (1 = successful mating, 0 = unsuccessful mating) in two populations of rabbits of different reproductive potential and different genetic origin: Line P selected for litter size and Line C selected for growth rate. There were 20,793 records of natural mating (86.2% successful) in Line C between 1983 and 2003, and 17,548 records (80.5% successful) in Line P, between 1992 and 2003. Data related to 5,388 and 3,848 females and 1,021 and 685 males in Lines C and P, respectively. The pedigree included 6,409 and 4,533 individuals in Lines C and P, respectively. The binary response was modeled under a probit approach. The model for the latent variable included male and female additive genetic effects, male and female permanent environmental effects, and the year-season and physiological status of the female (nulliparous, multiparous lactating, or multiparous nonlactating) as systematic effects. Means (standard deviation in parentheses) of the estimated marginal posterior distribution (EMPD) of male heritability were 0.013 (0.006) and 0.010 (0.008) in Lines C and P, respectively, and those of EMPD of female heritability were 0.056 (0.013) and 0.062 (0.018) in Lines C and P, respectively. Means of the EMPD of the proportion of the phenotypic variance due to environmental male and female effects were, respectively, 0.031 (0.007) and 0.128 (0.018) in Line C and 0.053 (0.010) and 0.231 (0.024) in Line P. Means (standard deviations in parentheses) of the EMPD of genetic correlation between male and female fertility were 0.733 (0.197) in Line C and 0.434 (0.381) in Line P. The posterior distribution of genetic correlations presents a huge dispersion, and the estimates should be taken with caution because of the almost negligible estimate of the male genetic component. Results indicate that little genetic variation exists for female fertility, and practically none for male fertility. It would, therefore, be possible to improve reproductive performance by including female fertility in a breeding program, but response to selection would be very small.

Animals↗
PubMed2006

Genetic and other contributions to alcohol intake in rhesus macaques (Macaca mulatta).

BACKGROUND: The etiology of alcoholism and alcohol abuse, like many other complex diseases, is heterogeneous and multifactorial. Numerous studies demonstrate a genetic contribution to variation in the expression of alcohol-related disorders in humans. Over the past decade, nonhuman primates have emerged as a valuable model for some aspects of human alcohol abuse because of their phylogenetic proximity to humans. Long-term, longitudinal studies of rhesus macaques (Macaca mulatta) have provided much insight into environmental influences, especially early life experiences, on alcohol consumption and behavior patterns that characterize alcohol intake later in life. It is not known, however, whether there is a genetic component as well to the variation seen in alcohol consumption in rhesus macaques. A significant genetic component to variation in alcohol consumption in rhesus macaques would show for the first time that like humans, for nonhuman primates additive genetic influences are important. Moreover, their use as a model for alcohol-related disorders in humans would have even greater relevance and utility for designing experiments incorporating the expanding molecular genetics field, and allow researchers to investigate the interaction among the known environmental influences and various genotypes. METHODS: In this study, we investigate factors contributing to variation in alcohol consumption of 156 rhesus macaques collected over 10 years when subjects were adolescent in age, belonging to a single extended pedigree, with each cohort receiving identical early rearing backgrounds and subsequent treatments. To measure alcohol consumption each animal was provided unfettered simultaneous access both to an aspartame-sweetened 8.4% (v/v) alcohol-water solution, the aspartame-sweetened vehicle, and to water for 1 hour each day during the early afternoon between 13:00 and 15:00 in their home cages for a period of 5 to 7 weeks. We use multiple regression to identify factors that significantly affect alcohol consumption among these animals and a maximum likelihood program (ASReml) that, controlling for the significant factors, estimates the genetic contribution to the variance in alcohol consumption. RESULTS: Multiple regression analysis identified test cohort and rearing environment as contributing to 57 and 2%, respectively, of the total variance in alcohol consumption. Of the remaining 41% of the variance about half (19.8%) was attributable to additive genetic effects using a maximum likelihood program. CONCLUSION: This study demonstrates that, as in humans, there are additive genetic factors that contribute to variation in alcohol consumption in rhesus macaques, with other nongenetic factors accounting for substantial portions of the variance in alcohol consumption, Our findings show the presence of an additive genetic component and suggest the potential utility of the nonhuman primate as a molecular genetics tool for understanding alcohol abuse and alcoholism.

Alcohol Drinking↗
PubMed2004

Evaluation of the ARMD1 locus on 1q25-31 in patients with age-related maculopathy: genetic variation in laminin genes and in exon 104 of HEMICENTIN-1.

The age-related maculopathy (ARM) genetics program at Columbia University utilizes comprehensive genetic analysis of candidate genes in large case-control studies to determine genotypes associated with the ARM complex trait. Genes encoding laminins, a class of extracellular matrix proteins, represent attractive candidates for two reasons. First, the presence of laminins in the basal lamina of the retinal pigment epithelium (RPE), Bruch's membrane, and choriocapillaris suggests a possible role in the pathophysiology of ARM. Second, three laminin genes, LAMC1, LAMC2, and LAMB3, are located in the 1q25-31 region, within the previously mapped ARMD1 locus. The entire open reading frame of the three laminin genes was screened for variants by denaturing high-performance liquid chromatography (DHPLC) and direct sequencing in at least 92, and up to 368 ARM patients and matched unaffected controls. Sixty-nine sequence variants were detected in the 69 exons of the LAMC1, LAMC2, and LAMB3 genes. Screening of exon 104 of the recently proposed ARMD1 gene, HEMICENTIN-1, residing in the 1q25-31 locus, did not detect the suggested causal variant, Q5345R, in 632 study subjects. Overall, we did not find statistically significant differences in the frequency of variants between ARM-affected individuals and age-matched controls. Four rare, non-synonymous, variants were detected in single cases of ARM patients. Our data on relatively limited numbers of study subjects do not suggest a significant role for genetic variation in the three laminin genes and in exon 104 of HEMICENTIN-1 in predisposing individuals to ARM. However, as in many instances in similar studies, involvement of rare amino acid-changing variants in a fraction of ARM cannot be ruled out.

Aged↗
PubMed2005

Chromatography paper strip sampling of enteric adenoviruses type 40 and 41 positive stool specimens.

BACKGROUND: The enteric subgroup F adenoviruses type 40 (Ad40) and 41 (Ad41) are the second most important cause of acute infantile gastroenteritis after rotaviruses. Repeated community outbreaks have been associated with antigenic changes among the Ad40 and Ad41 strains due to host immune pressure. Therefore large field epidemiological surveys and studies on the genetic variations in different isolates of Ad40 and Ad41 are important for disease control programs, the design of efficient diagnostic kits and vaccines against subgroup F adenoviruses. A novel method using sodium dodecyl sulphate SDS/EDTA-pretreated chromatography paper strips was evaluated for the collection, storage and shipping of Ad40/41 contaminated stool samples. RESULTS: This study shows that adenoviral DNA can be successfully detected in the filter strips by PCR after four months storage at -20 degrees C, 4 degrees C, room temperature (20-25 degrees C) and 37 degrees C. Furthermore no adenoviral infectivity was observed upon contact with the SDS/EDTA-pretreated strips. CONCLUSIONS: Collecting, storing and transporting adenovirus type 40 and 41 positive stool samples on SDS/EDTA-pretreated chromatography filter strips is a convenient, biosafe and cost effective method for studying new genome variants and monitoring spread of enteric adenovirus strains during outbreaks.

Adenoviridae↗
PubMed2006

Short communication: genetic correlation between test-day electrical conductivity of milk and mastitis.

Electrical conductivity (EC) of milk is an indicator of mastitis. If EC shows genetic variation and is genetically correlated to mastitis, it could be used in a breeding program that includes selection for improved mastitis resistance. In this study, daily records of EC and mastitis from about 1,500 Holstein cows were analyzed. A bivariate animal model was used for estimation of (co)variance components, including fixed effects of age of calving, herd-test-day, and days in milk, in addition to random additive genetic effects and permanent environmental effects. For EC, the estimated heritability was moderate (0.22 to 0.39), whereas for mastitis, the heritability was low (0.013). The genetic correlation between EC and mastitis was estimated to be 0.75, and genetic improvement of mastitis resistance should be feasible through selection for reduced EC.

Analysis of Variance↗
PubMed1981

Genetically controlled enzymatic variation in a southern, biracial, semi-rural community: the Bogalusa heart study.

Caucasian and Afro-American schoolchildren participating in a community-based cardiovascular screening program in Bogalusa, Louisiana are characterized with respect to phenotypic and allelic frequencies at 10 enzymatic and 3 nonenzymatic polymorphic loci. Biracial gene frequencies in Bogalusa are compared with those reported for other populations of similar ethnic composition. Intra- and interracial genetic distances within and between the racial subpopulations of Bogalusa and Seattle, Washington are compared. While the comparisons do not support the concept that northern, urban blacks have more Caucasian admixture than blacks residing in the rural South, they do suggest microdifferentiation of the two white populations.

Alleles↗
PubMed1989

Intraspecific genetic variability in mitochondrial DNA of the screwworm fly (Cochliomyia hominivorax).

Mitochondrial DNA variability has been analyzed in the primary screwworm fly (Cochliomyia hominivorax) using restriction endonuclease fragment patterns and restriction site mapping. A total of 30 different screwworm lines originating from Texas to Costa Rica and the Island of Jamaica was examined using 15 restriction endonucleases. Eleven of the restriction enzymes revealed polymorphism and yielded 16 mitochondrial genotypes or haplotypes. Two of the haplotypes were widely distributed, haplotype 1 being found scattered across southern Mexico and haplotype 2 along the west coast of Mexico. Haplotype 1 also appeared paired with several other haplotypes in mixed lines that were most likely the result of collecting an egg mass to which more than one female had contributed or to some form of contamination by haplotype 1 after introduction into the laboratory. These lines became fixed before single insects were examined and thus it is impossible to rule out heteroplasmy. The other 14 haplotypes were found in only a single locale and 12 of these were found in only one line. The average sequence diversity among 27 mainland lines was about 0.5%. The two Jamaican lines and one east coast mainland line differed from the others by greater than 2%. The pattern of geographical distribution, a small number of apparently recurring haplotypes and a substantial number (75%) of the haplotypes unique, bears similarities to patterns observed in other insects such as Drosophila. The high frequency of unique genotypes in southern Mexico suggests a population with a very reduced gene flow, which may have had a positive effect on the sterile male release control program.

Animals↗
PubMed2001

Metabonomic characterization of genetic variations in toxicological and metabolic responses using probabilistic neural networks.

Current emphasis on efficient screening of novel therapeutic agents in toxicological studies has resulted in the evaluation of novel analytical technologies, including genomic (transcriptomic) and proteomic approaches. We have shown that high-resolution 1H NMR spectroscopy of biofluids and tissues coupled with appropriate chemometric analysis can also provide complementary data for use in in vivo toxicological screening of drugs. Metabonomics concerns the quantitative analysis of the dynamic multiparametric metabolic response of living systems to pathophysiological stimuli or genetic modification [Nicholson, J. K., Lindon, J. C., and Holmes, E. (1999) Xenobiotica 11, 1181-1189]. In this study, we have used 1H NMR spectroscopy to characterize the time-related changes in the urinary metabolite profiles of laboratory rats treated with 13 model toxins and drugs which predominantly target liver or kidney. These 1H NMR spectra were data-reduced and subsequently analyzed using a probabilistic neural network (PNN) approach. The methods encompassed a database of 1310 samples, of which 583 comprised a training set for the neural network, with the remaining 727 (independent cases) employed as a test set for validation. Using these techniques, the 13 classes of toxicity, together with the variations associated with strain, were distinguishable to >90%. Analysis of the 1H NMR spectral data by multilayer perceptron networks and principal components analysis gave a similar but less accurate classification than PNN analysis. This study has highlighted the value of probabilistic neural networks in developing accurate NMR-based metabonomic models for the prediction of xenobiotic-induced toxicity in experimental animals and indicates possible future uses in accelerated drug discovery programs. Furthermore, the sensitivity of this tool to strain differences may prove to be useful in investigating the genetic variation of metabolic responses and for assessing the validity of specific animal models.

Animals↗
PubMed2005

LOVD: easy creation of a locus-specific sequence variation database using an "LSDB-in-a-box" approach.

The completion of the human genome project has initiated, as well as provided the basis for, the collection and study of all sequence variation between individuals. Direct access to up-to-date information on sequence variation is currently provided most efficiently through web-based, gene-centered, locus-specific databases (LSDBs). We have developed the Leiden Open (source) Variation Database (LOVD) software approaching the "LSDB-in-a-Box" idea for the easy creation and maintenance of a fully web-based gene sequence variation database. LOVD is platform-independent and uses PHP and MySQL open source software only. The basic gene-centered and modular design of the database follows the recommendations of the Human Genome Variation Society (HGVS) and focuses on the collection and display of DNA sequence variations. With minimal effort, the LOVD platform is extendable with clinical data. The open set-up should both facilitate and promote functional extension with scripts written by the community. The LOVD software is freely available from the Leiden Muscular Dystrophy pages (www.DMD.nl/LOVD/). To promote the use of LOVD, we currently offer curators the possibility to set up an LSDB on our Leiden server.

Computational Biology↗
PubMed2006

Myocardial beta1-adrenergic receptor polymorphisms affect functional recovery after ischemic injury.

Association studies suggest beta(1)-adrenergic receptor (beta(1)-AR) polymorphisms are disease modifiers in heart failure. The Arg389 variant has increased coupling to G(s) in transfected cells and evokes enhanced ventricular function in transgenic mice. Here, we assessed the differential effects of the human Gly389 and Arg389 beta(1)-AR polymorphisms on myocardial recovery after ischemic injury. Function was studied in transgenic mice with cardiac-specific expression of either human Gly389 or Arg389 beta(1)-AR at baseline and after 20 min of ex vivo ischemia and reperfusion (I/R). In 3-mo-old mice of either genotype, there was poor recovery after I/R (approximately 38% vs. approximately 68% for nontransgenic). Paradoxically, at 6 mo of age, functional recovery remained severely depressed in Gly389 hearts (approximately 32%) but was similar to nontransgenic for Arg389 hearts (approximately 60%). In Arg389 hearts, agonist-promoted adenylyl cyclase activities were depressed by approximately 35% at 6 mo of age, and G protein-coupled receptor kinase (GRK) activity was increased by approximately twofold compared with Gly389. Furthermore, I/R evoked an approximately threefold increase in ERK2 phosphorylation in Arg389 but an approximately twofold decrease in Gly389 hearts. Individually, these changes have been shown to mitigate I/R injury; thus the Arg389-beta(1)-AR uniquely evokes specialized pathways that act to protect against I/R injury. The improved recovery of function after I/R in Arg389 hearts relative to Gly389 appears to be due to an adaptive multimechanism program with allele-specific alterations in receptor signaling, GRK activity, and ERK2. Thus genetic variation of the human beta(1)-AR may play a role in cardiac functional recovery after ischemic injury.

Aging↗