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PubMed1986

Association of amino levulinate dehydratase levels and ferrochelatase inhibition in childhood lead exposure.

The basis for the clinical variation in response to lead exposure in children is not well understood. We studied selected children from a large lead screening program in whom elevation of red cell protoporphyrin concentration (a measure of inhibition of the enzyme ferrochelatase) was markedly above or below average for a given blood lead level. We then measured the activity of the enzyme amino levulinate dehydratase in 306 of these children, and found that ALA-d activity was lower in children with higher protoporphyrin elevation, independent of the effects of lead. This observation, coupled with reports in the literature of families with ALA-d deficiencies and elevated red cell protoporphyrin values, makes likely a genetic basis for some of the variation in susceptibility to lead. The mechanism by which the two effects are associated remains unknown.

Adolescent↗

PubMed2004

Effects of education, vaccination and treatment on HIV transmission in homosexuals with genetic heterogeneity.

Genetic studies report the existence of a mutant allele Delta32 of CCR5 chemokine receptor gene at high allele frequencies (approximately 10%) in Caucasian populations. The presence of this allele is believed to provide partial or full resistance to HIV. In this study, we look at the impact of education, temporarily effective vaccines and therapies on the dynamics of HIV in homosexually active populations. In our model, it is assumed that some individuals possess one or two mutant alleles (like Delta32 of CCR5) that prevent the successful invasion or replication of HIV. Our model therefore differentiates by genetic and epidemiological status and naturally ignores the reproduction process. Furthermore, HIV infected individuals are classified as rapid, normal or slow progressors. In this complex setting, the basic reproductive number R0 is derived in various situations. The separate or combined effects of therapies, education, vaccines, and genetic resistance are analyzed. Our results support the conclusions of Hsu Schmitz that some integrated intervention strategies are far superior to those based on a single approach. However, treatment programs may have effects which counteract each other, as may genetic resistance.

AIDS Vaccines↗

PubMed1988

Statistical analysis of DNA sequences.

Developments in the statistical analysis of DNA sequence data since 1984 are reviewed. Mathematical methods employing dynamic programming or incorporating Markov chain theory have been developed to search sequences for regions of similarity and to align sequences. When the biological forces of mutation and genetic drift are included in models, distances between aligned sequences allow the construction of evolutionary trees. Theory based on models may lead to estimates of variation of parameter estimates and so give a means of assessing the statistical significance of observed patterns and relationships. The complexity of DNA sequences, however, suggests that most statistical inferences will rest on random permutations of sequences.

Base Sequence↗

PubMed2005

Genome-wide linkage analysis for loci affecting pulse pressure: the Family Blood Pressure Program.

Pulse pressure, the difference between systolic and diastolic blood pressure, is an independent risk factor for cardiovascular disease. Increased pulse pressure reflects reduced compliance of arteries and is a marker of atherosclerosis. To locate genes that affect pulse pressure, a genome-wide linkage scan for quantitative trait loci influencing pulse pressure was performed using variance components methods as implemented in sequential oligogenic linkage analysis routines. The analysis sample included 10 798 participants in 3320 families who were recruited as part of the Family Blood Pressure Program and were phenotyped with an oscillometric blood pressure measurement device using a consistent protocol across centers. Pulse pressure was adjusted for the effects of sex, age, age2, age-by-sex interaction, age2-by-sex interaction, body mass index, and field center to remove sources of variation other than the genetic effects related to pulse pressure. Significant linkage was observed on chromosome 18 (logarithm of odds [LOD]=3.2) in a combined racial sample, chromosome 20 (LOD=4.4), and 17 (LOD=3.6) in Hispanics, chromosome 21 (LOD=4.3) in whites, chromosome 19 (LOD=3.1) in a combined sample of blacks and whites, and chromosome 7 (logarithm of odds [LOD]=3.1) in blacks from the GenNet Network. Our genome scan shows significant evidence for linkage for pulse pressure in multiple areas of the genome, supporting previous published linkage studies. The identification of these loci for pulse pressure and the apparent congruence with other blood pressure phenotypes provide increased support that these regions contain genes influencing blood pressure phenotypes.

Adult↗

PubMed2006

Status of newborn screening programs in the United States.

BACKGROUND: Newborn screening programs have expanded over the years; currently, many programs screen for dozens of congenital conditions that, if not detected and treated early, could result in catastrophic health consequences, including death. Some programs, however, still require universal newborn screening for only a few conditions. Although all 51 US programs (all states and the District of Columbia) have statutory screening requirements and similarities exist in many parts of the different screening systems, the enabling statutes, rules, regulations, protocols, and financing strategies vary dramatically. Consequently, there is a significant lack of equity in newborn screening services across the country. METHODS: We investigated program variations existing in and around January 2005 and provide baseline information with which future program comparisons can be made. We used program surveys, electronic searches of legislation, and individual input (validation) from program decision-makers to create a reservoir of program information. RESULTS: Included is a compilation of pertinent newborn screening statutes, information from genetic privacy statutes that potentially affects newborn screening programs, and a review of state laws that affect specimen and information retention. In addition, program policies related to the use of residual newborn screening blood spots are reviewed, along with the developmental processes affecting program informational brochures, including the information contained and the strategies for brochure dissemination. CONCLUSIONS: Building on a progressive and successful history, newborn screening continues as an example of an essential population genetic screening program. As the intricacies of screening systems have increased in complexity, so have the policy issues that shape program successes and failures. The summary information in this article provides a basis for national and individual program evaluation. Indeed, some of the information reported here has already been useful for program refinements reported elsewhere in this supplement.

Confidentiality↗

PubMed2000

An improved genetic linkage map of rat chromosome 20.

BACKGROUND AND PURPOSE: Rat chromosome 20 is one of special interest because it contains some diabetogenic genes, such as a major histocompatibilitiy complex (MHC)-linked genetic components and quantitative trait loci. We studied rat chromosome 20, using the backcross progeny between BB/Wor and PVG.R23 rats, and confirmed the genetic linkage map by use of another backcross panel. METHODS: Backcross panels were done between BB/Wor and PVG.R23 rats, and BN and KZC rats. Length variations of simple sequence length polymorphism markers were analyzed by use of polymerase chain reaction (PCR) analysis. Alleles of RT1-Bb and RT1-Db were analyzed by use of the PCR-restriction fragment length polymorphism method. Genetic maps of rat chromosome 20 were constructed, using the Map Manager computer program. RESULTS: Fifty-two loci were mapped on rat chromosome 20. Genetic length was 57.9 cM, with average spanning of 1.11 cM between markers. The positions of RT1-N1, Tnf, and RT1-Bb into the MHC region were separated and confirmed by results of two backcross panels in our linkage studies. CONCLUSIONS: The genetic linkage map of rat chromosome 20 was improved, and was a useful tool for genetic analysis of a diabetogenic gene(s) and for producing MHC congenic strains.

Animals↗

PubMed2004

Strain-dependent differences in responses to exercise training in inbred and hybrid mice.

The aim of this study was to characterize the response to exercise training in several mouse strains and estimate the genetic contribution to phenotypic variation in the responses to exercise training. Male mice from three inbred strains [C57Bl/6J (BL6), FVB/NJ (FVB), and Balb/cJ (Balb/c)] and three hybrid F(1) strains [CB6F1/J (CB6 = female Balb/c x male BL6), B6F F(1) (female BL6 x male FVB), and FB6 F(1) (female FVB x male BL6)] completed an exercise performance test before and after a 4-wk treadmill running program. Distance was used as the primary estimate of endurance exercise performance. FVB mice showed the greatest response to training, with five- to sevenfold greater increases in distance run compared with BL6 and Balb/c strains. Specifically, BL6, FVB, and Balb/c strains increased distance by 33, 172, and 23%, respectively. A similar pattern of changes across strains was observed for run time (17, 87, and 11%) and work (99, 287, and 57%). As a group, F(1) hybrid mice derived from BL6 and FVB strains showed an intermediate response to training (61%). However, further analysis indicated that training responses in FB6 F(1) mice (80%) were approximately 2.5-fold greater than responses in B6F F(1) mice (33%, P = 0.08). A similar pattern of changes between FB6 and B6F F(1) mice was observed for run time (44.5 and 17%) and work (141 and 59%). These data demonstrate that there are large strain-dependent differences in training responses among inbred mouse strains, suggesting that genetic background contributes significantly to adaptation to exercise. Furthermore, the contrasting responses in B6F and FB6 F(1) strains show that a maternal component strongly influences strain-dependent differences in training responses.

Animals↗

PubMed2004

A Bayesian approach to reconstructing genetic regulatory networks with hidden factors.

MOTIVATION: We have used state-space models (SSMs) to reverse engineer transcriptional networks from highly replicated gene expression profiling time series data obtained from a well-established model of T cell activation. SSMs are a class of dynamic Bayesian networks in which the observed measurements depend on some hidden state variables that evolve according to Markovian dynamics. These hidden variables can capture effects that cannot be directly measured in a gene expression profiling experiment, for example: genes that have not been included in the microarray, levels of regulatory proteins, the effects of mRNA and protein degradation, etc. RESULTS: We have approached the problem of inferring the model structure of these state-space models using both classical and Bayesian methods. In our previous work, a bootstrap procedure was used to derive classical confidence intervals for parameters representing 'gene-gene' interactions over time. In this article, variational approximations are used to perform the analogous model selection task in the Bayesian context. Certain interactions are present in both the classical and the Bayesian analyses of these regulatory networks. The resulting models place JunB and JunD at the centre of the mechanisms that control apoptosis and proliferation. These mechanisms are key for clonal expansion and for controlling the long term behavior (e.g. programmed cell death) of these cells. AVAILABILITY: Supplementary data is available at http://public.kgi.edu/wild/index.htm and Matlab source code for variational Bayesian learning of SSMs is available at http://www.cse.ebuffalo.edu/faculty/mbeal/software.html.

Bayes Theorem↗

PubMedDate not supplied

An unexpected wide population variation of the G1733A polymorphism of the androgen receptor gene: data on the Mediterranean region.

The androgen receptor (AR) has been proposed as a candidate gene for several cancers (breast, prostate, uterine endometrium, colon, and esophagus). Ethnicity is considered an associated risk factor for some of these cancers. Several case-control genetic studies have been focused in samples of the main ethnic groups, but little is known about the distribution of risk polymorphisms in current populations with accurate ethnic and/or geographic origins. The A allele of the G1733A polymorphism of the AR gene has been associated with increased risk of prostate cancer. We provide data from this marker in 12 samples from 7 Mediterranean countries such as Spain, Italy (Sardinia), Greece, Turkey, Morocco, Algeria, and Egypt. A sample from Ivory Coast has also been analyzed. The A allele distribution shows a frequency in the Ivory Coast population (65.17%) that contrasts with the low values found in Northern Mediterraneans (mean average value of 13.98%). North African populations present two-times higher frequencies (average value of 27.19%) than Europeans. The wide population variation range found for the A allele strengthens the potential interest of further screening as a baseline to the design of future preventive and population health programs.

Alleles↗

PubMed2003

Identification and distribution of HIV type 1 genetic diversity and protease inhibitor resistance-associated mutations in Shanghai, P. R. China.

OBJECTIVE: To investigate the genetic diversity of the HIV-1 circulating in Shanghai and to analyze the mutations in the protease (PR) gene associated with resistance to protease inhibitors (PIs). DESIGN: The genetic diversity of HIV-1 and PI resistance-associated mutations was studied in 40 Shanghai HIV-1-seropositive treatment-naive residents. The patients studied were exposed to the infection mainly through contaminated blood products (hemophiliacs) (n = 17) and sexual contacts (n = 19). Samples from 2 injecting drug users (IDUs) and 2 children born to HIV-1 infected mothers were also analyzed. METHODS: HIV-1 partial gag, pol, and env genes in infected plasma samples were amplified by reverse transcriptase polymerase chain reaction, sequenced, and phylogenetically analyzed. Analysis of PI resistance-associated amino acid substitution in PR was performed. RESULTS: HIV-1 genes in 38 of the 40 plasma samples were successfully amplified and analyzed. Polymerase chain reaction amplification was successful for 16/17 hemophilia patients and 18/19 sexually infected individuals. While all the 16 hemophilia patients infected through contaminated blood products were infected with subtype B', the 18 patients infected through sexual contact were infected with several subtypes including subtype A (n = 2), B (n = 4), B' (n = 1), C (n = 2), CRF08_BC (n = 1), CRF01_AE (n = 7), and intersubtype recombinant CRF01_AE/B (n = 1). The 2 IDUs were infected with CRF08_BC and the 2 children born to HIV-1 infected mothers were infected with subtype B' and CRF01_AE. PI resistance-associated amino acid substitutions were found at 1 codon in primary and 7 codons in secondary regions of the PR gene. Amino acid substitutions were more frequently found in the B/B' sequences (69%) than in the non-B sequences (31%). Substitutions characteristic with the subtype B/B' sequences mainly among hemophiliacs included L63P (87%), A71V/T (27%), and V77I (93%) while those that characterized the non-B sequences mainly found among heterosexuals included M36I (69%) and K20R (19%). CONCLUSION: This study reveals the presence of multiple HIV-1 subtypes and recombinants infecting Shanghai residents. The broad HIV-1 diversity is being introduced into this city through heterosexual contacts. This study also reveals that viruses infecting these treatment-naive patients have acquired both primary or secondary mutations in their PR genes. These studies should provide the basis for further epidemiologic surveys of HIV-1 subtypes and set strategies for treatment intervention and vaccine programs.

Adolescent↗

PubMed1979

Distribution and effects of the 1/29 Robertsonian translocation in cattle.

The distribution and effects of the 1/29 translocation in cattle, defined with chromosome banding techniques, are described. Findings in different parts of the world are reported, and the origin of the translocation in some cases is explained. Geographical distribution as known at present reflects the areas in which chromosome investigations have been carried out rather than the true distribution. It is not known whether the occurrence of the 1/29 translocation in different geographical areas and breeds is due to recurrent mutation or distribution of an ancient mutation, but many observations point to the latter. Although direct observations of an increased embryonic mortality are lacking, reduced fertility of males and females heterozygous for 1/29 is established. No correlations of the 1/29 translocation with other characteristics have been found, and variability in incidence between different populations is probably due to genetic drift. The importance in animal breeding of introducing eradication programs is emphasized, and it is stressed that cattle populations using artificial insemination should undergo routine cytogenetic investigations.

Animals↗

PubMed2004

Memetic algorithms for the unconstrained binary quadratic programming problem.

This paper presents a memetic algorithm, a highly effective evolutionary algorithm incorporating local search for solving the unconstrained binary quadratic programming problem (BQP). To justify the approach, a fitness landscape analysis is conducted experimentally for several instances of the BQP. The results of the analysis show that recombination-based variation operators are well suited for the evolutionary algorithms with local search. Therefore, the proposed approach includes--besides a highly effective randomized k-opt local search--a new variation operator that has been tailored specially for the application in the hybrid evolutionary framework. The operator is called innovative variation and is fundamentally different from traditional crossover operators, since new genetic material is included in the offspring which is not contained in one of the parents. The evolutionary heuristic is tested on 35 publicly available BQP instances, and it is shown experimentally that the algorithm is capable of finding best-known solutions to large BQPs in a short time and with a high frequency. In comparison to other approaches for the BQP, the approach appears to be much more effective, particularly for large instances of 1000 or 2500 binary variables.

Algorithms↗

PubMed1986

Producing more pigs per sow per year--genetic contributions.

This review paper summarizes available knowledge on the genetic manipulation of litter size in pigs. Selection among breeds permits the exploitation of existing variation and this has already proceeded much further in Europe than in the United States. Crossbreeding strategies are available to enable the commercial herd to maximize sow productivity while ensuring carcasses acceptable to each particular market demand. These involve either the regular purchase of both replacement gilts and boars, or a high standard of management of the herd breeding program. Selection within purebred lines to increase further prolificacy seems possible, in spite of some contrary results from initial experiments. Success will only be achieved in well-designed and carefully executed programs with adequate population size that are continued for many generations. It is likely that breeders can continue to improve the potential of their stock at the commercial level, and this will be achieved by a degree of specialization between sire and dam lines.

Animal Husbandry↗

PubMed2004

Cloning and identification of two novel splice variants of human PD-L2.

PD-L2, a newly identified member of B7 family, plays a role in down-regulating T cell responses. The common PD-L2 mRNA (type I) is the splicing product containing all 6 exons. We report here the identification of two human PD-L2 splice variants in activated leukocytes. One splice variant (type II) is generated through splicing out exon 3 encoding Ig constant-like domain; it retains all other regions without a frame shift. The other variant (type III) is created by splicing out exon 3 to an alternative acceptor site 5 bp downstream of the canonical acceptor site, leading to a frame shift. Consequently, the translated protein should be a soluble form. Furthermore, type I isoform is expressed on the plasma surface whereas type II isoform showed a pattern of intracellular membrane distribution in the transiently transfected K562 cells. In addition, the expression patterns of PD-L2 splice variants are variable in different individuals and distinct cellular status. These results suggest that PD-L2 expression may be controlled by posttranscriptional regulation through alternative splicing, and modulation of PD-L2 isoform expression may influence the outcome of immune response.

Alternative Splicing↗

PubMed2006

Linkage and mapping of resistance genes to Xanthomonas axonopodis pv. passiflorae in yellow passion fruit.

The cultivated passion fruit (Passiflora edulis f. flavicarpa) is a cross-pollinated species native to South America. In the current study, a segregating F1 population derived from a single cross between the clones IAPAR-06 and IAPAR-123 was used to construct AFLP-based linkage maps and to map resistance genes to bacterial spot caused by Xanthomonas axonopodis pv. passiflorae. Linkage analysis was performed by the 2-way pseudo-testcross mapping method using markers that segregated in a 1:1 ratio. The IAPAR-06 linkage map was constructed using 115 markers, 112 of which were allocated to 9 linkage groups (LG) covering 790.2 cM. The map of IAPAR-123 was constructed using 140 markers, 138 of which were allocated to 9 LG covering 488.9 cM. In both maps, clusters of markers were detected, indicating that the AFLP markers were not distributed at random. Bacterial resistance was assessed by measuring the diseased leaf area after wound-inoculating the leaves of F1 plants. Quantitative resistance loci (QRLs) mapping was carried out by composite interval mapping and 1 QRL was detected, which explained 15.8% of the total phenotypic variation. The possibility of considering these data for marker-assisted selection in passion fruit breeding programs is discussed.

Genetic Linkage↗

PubMed2006

Computational prediction of the effects of non-synonymous single nucleotide polymorphisms in human DNA repair genes.

Non-synonymous single nucleotide polymorphisms (nsSNPs) represent common genetic variation that alters encoded amino acids in proteins. All nsSNPs may potentially affect the structure or function of expressed proteins and could therefore have an impact on complex diseases. In an effort to evaluate the phenotypic effect of all known nsSNPs in human DNA repair genes, we have characterized each polymorphism in terms of different functional properties. The properties are computed based on amino acid characteristics (e.g. residue volume change); position-specific phylogenetic information from multiple sequence alignments and from prediction programs such as SIFT (Sorting Intolerant From Tolerant) and PolyPhen (Polymorphism Phenotyping). We provide a comprehensive, updated list of all validated nsSNPs from dbSNP (public database of human single nucleotide polymorphisms at National Center for Biotechnology Information, USA) located in human DNA repair genes. The list includes repair enzymes, genes associated with response to DNA damage as well as genes implicated with genetic instability or sensitivity to DNA damaging agents. Out of a total of 152 genes involved in DNA repair, 95 had validated nsSNPs in them. The fraction of nsSNPs that had high probability of being functionally significant was predicted to be 29.6% and 30.9%, by SIFT and PolyPhen respectively. The resulting list of annotated nsSNPs is available online (http://dna.uio.no/repairSNP), and is an ongoing project that will continue assessing the function of coding SNPs in human DNA repair genes.

Computational Biology↗

PubMed2004

Evidence for multiple alleles at the DGAT1 locus better explains a quantitative trait locus with major effect on milk fat content in cattle.

A quantitative trait locus (QTL) for milk fat percentage has been mapped consistently to the centromeric region of bovine chromosome 14 (BTA14). Two independent studies have identified the nonconservative mutation K232A in the acylCoA-diacylglycerol-acyltransferase 1 (DGAT1) gene as likely to be causal for the observed variation. Here we provide evidence for additional genetic variability at the same QTL that is associated with milk fat percentage variation within the German Holstein population. Namely, we show that alleles of the DGAT1 promoter derived from the variable number of tandem repeat (VNTR) polymorphism are associated with milk fat content in animals homozygous for the allele 232A at DGAT1. Our results present another example for more than two trait-associated alleles being involved in a major gene effect on a quantitative trait. The segregation of multiple alleles affecting milk production traits at the QTL on BTA14 has to be considered whenever marker-assisted selection programs are implemented in dairy cattle. Due to the presence of a potential transcription factor binding site in the 18mer element of the VNTR, the variation in the number of tandem repeats of the 18mer element might be causal for the variability in the transcription level of the DGAT1 gene.

Acyltransferases↗

PubMed2001

[CSNP discovery by two-dimensional gene scanning (TDGS)].

Challenges in the post-genomic era are to use genetic information in correlating individual gene variations (SNPs; single nucleotide polymorphisms, the most common form of genetic variation) with medically important parameters, such as disease susceptibility, individual responses to drugs and prognostic variables. What is missing is a high-throughput technology to identify all possible SNPs in essentially all human genes in population-based studies with high accuracy and speed in a cost-effective manner. Most tests advocated for their high throughput at low cost are actually SNP screening tests. That is, they screen samples for the presence of one or multiple previously identified SNPs. Such screening methods are only useful when all relevant SNPs in the genes of interest are known, which is presently not the case. Moreover, the usefulness of any one SNP varies enormously from population to population. Indeed, for the Korean population, where no information on possible sequence variation is available, a mutational scanning method, capable to detect all possible gene variations will be most useful. Two-Dimensional Gene Scanning (TDGS) is a high-throughput platform that enables to detect all possible SNPs in an entire gene in one gel under one set of conditions, with high sensitivity and specificity. TDGS is based on automated two-dimensional (2-D) DNA electrophoresis according to size and base pair sequence to detect DNA fragments containing all possible variations. Because the 2-D format permits the analysis of as many as 40 fragments of 250 bp on average in parallel, TDGS allows extensive multiplex PCR (megaplex PCR), i.e. up to 26 fragments in one single reaction, resulting in a significant cost reduction. TDGS tests are designed using a computer program to optimally position PCR primers around the relevant target sequences (exons). A simple automated 2-D instrument allows scanning all exons of a large gene in 8 different samples well within 3 hours. Using three different fluorophores this provides a throughput.

BRCA1 Protein↗