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PubMed2006

Optimization of dairy cattle breeding programs for different environments with genotype by environment interaction.

Dairy cattle breeding organizations tend to sell semen to breeders operating in different environments and genotype x environment interaction may play a role. The objective of this study was to investigate optimization of dairy cattle breeding programs for 2 environments with genotype x environment interaction. Breeding strategies differed in 1) including 1 or 2 environments in the breeding goal, 2) running either 1 or 2 breeding programs, and 3) progeny testing bulls in 1 or 2 environments. Breeding strategies were evaluated on average genetic gain of both environments, which was predicted by using a pseudo-BLUP selection index model. When both environments were equally important and the genetic correlation was higher than 0.61, the highest average genetic gain was achieved with a single breeding program with progeny-testing all bulls in both environments. When the genetic correlation was lower than 0.61, it was optimal to have 2 environment-specific breeding programs progeny-testing an equal number of bulls in their own environment only. Breeding strategies differed by 2 to 12% in average genetic gain, when the genetic correlation ranged between 0.50 and 1.00. Ranking of breeding strategies, based on the highest average genetic gain, was relatively insensitive to heritability, number of progeny per bull, and the relative importance of both environments, but was very sensitive to selection intensity. With more intense selection, running 2 environment-specific breeding programs was optimal for genetic correlations up to 0.70-0.80, but this strategy was less appropriate for situations where 1 of the 2 environments had a relative importance less than 10 to 20%. Results of this study can be used as guidelines to optimize breeding programs when breeding dairy cattle for different parts of the world.

Animals↗
PubMed2006

Oral poliovaccine: will it help eradicate polio or cause the next epidemic?

BACKGROUND: Poliovirus rapidly evolves by nucleic acid substitutions and genetic recombination with other polioviruses and non-polio enteroviruses. Evolving oral poliovaccine can rapidly revert to neurovirulence and undergo antigenic alterations. OBJECTIVES: To evaluate the threat of vaccine-derived poliovirus (1-15% divergence from the respective Sabin strain) for a poliomyelitis-free population in a country with a long-standing routine vaccination program. METHODS: We characterized genetic and antigenic changes in OPV (Sabin) strains isolated from sewage in Israel and evaluated intestinal immunity by measuring fecal excretion after OPV challenge of vaccinated children. RESULTS: Characterization of poliovirus from sewage revealed eight type 2 and three type 3 vaccine polioviruses that had replicated and started to evolve (vaccine that replicated and diverged by 0.5 to < or = 1.0%) and nine highly diverged type 2 vaccine-derived polioviruses (1-15% divergence from the respective Sabin strain) with 8-14% divergence between the years 1998 and 2005. Six of the eleven VRPV uniquely recombined with OPV and/or NPEV. The nine VDPV were epidemically related, genotypically neurovirulent, and had 10-15 amino acid substitutions in antigenic sites altering their antigenicity, but shared a single recombination. Type 2 OPV was excreted by 23% and 17% of infants challenged with OPV 3 months after partial immunization (two doses each of OPV and enhanced inactivated poliovirus) or full immunization (three doses of each) respectively, despite high humoral antibody titers. CONCLUSIONS: Our findings, which show that OPV is excreted for a significant period by children with high humoral immunity, emphasize the long-term potential threat from VDPV in highly vaccinated populations. An adequate immunization program, combined with environmental surveillance, is necessary to prevent poliomyelitis and community transmission of poliovirus.

Adolescent↗
PubMed2004

A prospective study of HDL-C and cholesteryl ester transfer protein gene mutations and the risk of coronary heart disease in the elderly.

High density lipoprotein cholesterol (HDL-C) levels are inversely associated with the incidence of coronary heart disease (CHD) in middle-aged individuals; in the elderly, the association is less clear. Genetic factors, including variations in the cholesteryl ester transfer protein (CETP) gene, play a role in determining HDL-C levels. Controversy remains about whether CETP deficiency and the resultant rise in HDL-C are antiatherogenic, or whether CETP has the opposite effect due to its role in reverse cholesterol transport. In a seven-year follow-up of 2340 men aged 71-93 in the Honolulu Heart Program, the age-adjusted CHD incidence rates were significantly lower in men with high versus low HDL-C levels. After adjustment for age, hypertension, smoking, and total cholesterol, the relative risk of CHD for those with HDL-C levels >or=60 mg/dl, compared with those with HDL-C levels <40 mg/dl, was 0.6. Men with a CETP mutation had the lowest rates of CHD, although this was not statistically significant. These data indicate that HDL-C remains an important risk factor for CHD in the elderly. Whether a CETP mutation offers additional protection against CHD warrants further investigation.

Age Factors↗
PubMed2005

MITOMAP: a human mitochondrial genome database--2004 update.

MITOMAP (http://www.MITOMAP.org), a database for the human mitochondrial genome, has grown rapidly in data content over the past several years as interest in the role of mitochondrial DNA (mtDNA) variation in human origins, forensics, degenerative diseases, cancer and aging has increased dramatically. To accommodate this information explosion, MITOMAP has implemented a new relational database and an improved search engine, and all programs have been rewritten. System administrative changes have been made to improve security and efficiency, and to make MITOMAP compatible with a new automatic mtDNA sequence analyzer known as Mitomaster.

DNA, Mitochondrial↗
PubMed2005

T-bet polymorphisms are associated with asthma and airway hyperresponsiveness.

RATIONALE: T-bet (TBX21 or T-box 21) is a critical regulator of T-helper 1 lineage commitment and IFN-gamma production. Knockout mice lacking T-bet develop airway hyperresponsiveness (AHR) to methacholine, peribronchial eosinophilic and lymphocytic inflammation, and increased type III collagen deposition below the bronchial epithelium basement membrane, reminiscent of both acute and chronic asthma histopathology. Little is known regarding the role of genetic variation surrounding T-bet in the development of human AHR. OBJECTIVES: To assess the relationship between T-bet polymorphisms and asthma-related phenotypes using family-based association. METHODS: Single nucleotide polymorphism discovery was performed by resequencing the T-bet genomic locus in 30 individuals (including 22 patients with asthma). Sixteen variants were genotyped in 580 nuclear families ascertained through offspring with asthma from the Childhood Asthma Management Program clinical trial. Haplotype patterns were determined from this genotype data. Family-based tests of association were performed with asthma, AHR, lung function, total serum immunoglobulin E, and blood eosinophil levels. MAIN RESULTS: We identified 24 variants. Evidence of association was observed between c.-7947 and asthma in white families using both additive (p = 0.02) or dominant models (p = 0.006). c.-7947 and three other variants were also associated with AHR (log-methacholine PC(20), p = 0.02-0.04). Haplotype analysis suggested that an AHR locus is in linkage disequilibrium with variants in the 3'UTR. Evidence of association of AHR with c.-7947, but not with other 3'UTR SNPs, was replicated in an independent cohort of adult males with AHR. CONCLUSIONS: These data suggest that T-bet variation contributes to airway responsiveness in asthma.

Adolescent↗
PubMed2000

Genetic distinctness of African, Asian and South American local chickens.

The genetic variability of various local chicken populations derived from Bolivia, India, Nigeria and Tanzania was evaluated with 22 microsatellites. Between two and 11 alleles per locus were detected. All populations showed high levels of heterozygosity with the lowest value of 45% for the population named Aseel from India and the highest value of 67% for Arusha from Tanzania. A dendrogram was constructed based on CHORD distance by upgMa analysis. Within this tree the populations were assorted according to their geographical origin. Bootstrapping values within the dendrogram were between 37 and 99%. The contribution of the determination of genetic variability with genetic markers to the decision on conservation and/or further use of the populations in crossbreeding programs designed to create genetic stocks with improved adaptability and productivity in tropical countries is discussed.

Africa↗
PubMed2006

Distinguishable haplotype blocks in the HTR3A and HTR3B region in the Japanese reveal evidence of association of HTR3B with female major depression.

BACKGROUND: Genetic variations in the serotonin receptor 3A (HTR3A) and 3B (HTR3B) genes, positioned in tandem on chromosome 11q23.2, have been shown to be associated with psychiatric disorders in samples of European ancestry. But the polymorphisms highlighted in these reports map to different locations in the two genes, therefore it is unclear which gene exerts a stronger effect on susceptibility. METHODS: To determine the haplotype block structure in the genomic regions of HTR3A and HTR3B, and to examine whether genetic variations in the region show evidence of association with schizophrenia and affective disorder in the Japanese, we performed haplotype-based case-control analysis using 29 polymorphisms. RESULTS: Two haplotype blocks each were revealed for HTR3A and HTR3B in Japanese samples. In HTR3B, haplotype block 2 that included a nonsynonymous single nucleotide polymorphism (SNP), yielded evidence of association with major depression in females (global p = .0023). Analysis employing genome-wide SNPs using the STRUCTURE program did not detect population stratification in the samples. CONCLUSIONS: Our results suggest an important role for HTR3B in major depression in women and also raise the possibility that previously proposed disease-associated SNPs in the HTR3A/B region in Caucasians are in linkage disequilibrium with haplotype block 2 of HTR3B in the Japanese.

Adult↗
PubMed1998

Measurement of genetic variation within and between Japanese quail lines using DNA fingerprinting.

The objective of the present experiment was to study genetic variation within and among well-defined Japanese quail lines by DNA fingerprinting. The Japanese quail lines included a randombred control line (R1) and lines developed from R1 by divergent selection over 30 generations for 4-wk BW (HW, LW) and total plasma phosphorus (TPP) (HP, LP), a measure of yolk precursor in the blood. In addition, two sublines (HW-HP, HW-LP) of HW, developed in the ninth generation, were included in the analysis. Males of the sublines were selected for increased 4-wk BW whereas females were selected for increased (HW-HP) or decreased (HW-LP) TPP. Sixteen individual DNA samples per line were digested with HaeIII restriction enzyme and hybridized with Jeffreys' 33.6 probe. The DNA fingerprints were analyzed with computer programs designed to measure band sharing (BS). Within lines, BS ranged from 0.384 to 0.525. The BS within the R1 line was less than that of all selected lines, except for the HP and LP lines, indicating that, in general, selection had increased genetic homogeneity within the selected lines. Between lines, BS was less than within lines and the R1 line had the highest average level of BS (0.278) with the other lines. The BS between lines for the selected lines ranged from 0.230 to 0.308 with an average of 0.265. In the comparison of the R1 line with the selected lines, it appeared that selection for increased TPP or decreased BW may have influenced BS levels. The relationships of the HW line with its sublines (HW-HP and HW-LP) were not accurately predicted by the DNA fingerprinting technique used. All lines were separated, as indicated by the genetic distance between lines.

Animals↗
PubMed1984

The contribution of chromosomal translocations to antigenic variation in Trypanosoma brucei.

Genomic rearrangements influencing gene expression occur throughout nature. Several of these rearrangements disrupt normal gene expression, as exemplified by the genetic alterations caused by the mobile genetic elements of maize or Drosophila (see Shapiro 1983). Other rearrangements are part of the normal developmental programme of an organism. An understanding of the control of genomic rearrangements and their effects on gene expression should contribute to our insight into the mechanism of genetic programming and cellular development. The protozoan parasite Trypanosoma brucei exhibits a variety of genomic rearrangements that influence the expression of genes that code for versions of the variant surface glycoprotein (v.s.g.), which makes up the cell surface coat. V.s.g. genes are expressed in a mutually exclusive manner. Several v.s.g. genes are activated by duplicative transposition of the gene to a telomeric expression site where they are transcribed, while others can be activated without detectable genomic rearrangements. Recently we have been able to fractionate the chromosomes of T. brucei in agarose gels (Van der Ploeg et al. 1984 a). This led to the observations that duplicative transpositions occur inter-chromosomally and that the chromosomes of T. brucei are subject to frequent recombinations that displace hundreds of kilobase pairs. At least two and possibly more telomeric expression sites can be used for v.s.g. gene transcription. How these sites are activated and inactivated is still unsolved, but this does not depend on recombinations in the vicinity of the gene. Gross genomic rearrangements occur sometimes in correlation with antigenic switching and this suggests that such rearrangements have a function in regulating the mutually exclusive transcription of the different expression sites. V.s.g. genes consist of two exons. No physical linkage of the 35 nucleotide (n.t.) mini-exon to the v.s.g. gene main exon occurred within 15 kilobase pairs in variant 118a and possibly 150 kilobase pairs in variant 1.8b. These mapping data give additional support for the hypothesis that both exons might represent separate transcription units. Transcription initiation of v.s.g. genes would thus be from a promoter other than the mini-exon repeat unit. We propose that transcription of the v.s.g. gene in the expression site can be regulated by a position effect on the gene.

Animals↗
PubMed1997

Molecular mechanisms of Campylobacter fetus surface layer protein expression.

Cells of the Gram-negative bacteria Campylobacter fetus are covered by monomolecular arrays of surface layer proteins (SLPs) critical for both persistence in their natural hosts and for virulence. For C. fetus cells, expression of SLPs essentially eliminates C3b binding and their antigenic variation thwarts host immunological defences. Each cell possesses multiple partially homologous and highly conserved SLP gene cassettes, tightly clustered in the genome, that encode SLPs of 97-149 kDa. These attach non-covalently via a conserved N-terminus to the cell wall lipopolysaccharide. Recent studies indicate that C. fetus reassorts a single promoter, controlling SLP expression, and one, or more, complete open reading frame strictly by DNA inversion, and that rearrangement is independent of the distance between sites of inversion. In contrast to previously reported programmed DNA inversion systems, inversion in C. fetus is recA-dependent. These rearrangements permit variation in protein expression from the family of SLP genes and suggest an expanding paradigm of programmed DNA rearrangements among microorganisms.

Animals↗
PubMed2004

HapBlock: haplotype block partitioning and tag SNP selection software using a set of dynamic programming algorithms.

UNLABELLED: Recent studies have revealed that linkage disequilibrium (LD) patterns vary across the human genome with some regions of high LD interspersed with regions of low LD. Such LD patterns make it possible to select a set of single nucleotide polymorphism (SNPs; tag SNPs) for genome-wide association studies. We have developed a suite of computer programs to analyze the block-like LD patterns and to select the corresponding tag SNPs. Compared to other programs for haplotype block partitioning and tag SNP selection, our program has several notable features. First, the dynamic programming algorithms implemented are guaranteed to find the block partition with minimum number of tag SNPs for the given criteria of blocks and tag SNPs. Second, both haplotype data and genotype data from unrelated individuals and/or from general pedigrees can be analyzed. Third, several existing measures/criteria for haplotype block partitioning and tag SNP selection have been implemented in the program. Finally, the programs provide flexibility to include specific SNPs (e.g. non-synonymous SNPs) as tag SNPs. AVAILABILITY: The HapBlock program and its supplemental documents can be downloaded from the website http://www.cmb.usc.edu/~msms/HapBlock.

Algorithms↗
PubMed1997

Design of hydrophobic core of E. coli malate dehydrogenase based on the side-chain packing.

We have developed computational programs for the de novo design of hydrophobic cores of proteins. The first program optimizes side-chain conformations using an updated rotamer library for potential hydrophobic residues, based on the backbone structure of the protein of interest. The second program selects candidates to be engineered among the sequences by estimating changes in Gibbs free energy between the folded and unfolded structure of the proteins with new sequence. Using these programs, we constructed several variants of E. coli malate dehydrogenase (eMDH) which could have increased stability at 25 degrees C, compared to the wild type enzyme. To quantitate stability change between variants and the wild type, circular dichroism spectra were measured as a function of guanidine hydrochloride concentration at 25 degrees C, pH 7.0. This analysis showed that three variants constructed in this study were stabilized more than or equal to the wild type. This demonstrated that our programs may be powerful tools to design new proteins with high stability.

Amino Acid Sequence↗
PubMed2002

The epidemiology of yellow fever in Africa.

Yellow fever (YF) is still a major public heath problem, particularly in Africa, despite the availability of a very efficacious vaccine. The World Health Organization estimates that there are 200,000 cases of YF annually, including 30,000 deaths, of which over 90% occur in Africa. In the past 15 years, the number of YF cases has increased tremendously, with most of the YF activity in West Africa. This increase in YF activity is in part due to a breakdown in YF vaccination and mosquito control programs. Five genotypes of YF virus have been found in Africa, and each genotype circulates in a distinct geographical region. West Africa genotype I, found in Nigeria and surrounding areas, is associated with frequent epidemics, whereas the three genotypes in East and Central Africa are in regions where YF outbreaks are rare. Other factors, including genetic and behavioral variation among vector species, are also thought to play a role in the epidemiology of YF in Africa.

Aedes↗
PubMed2005

Casein haplotype structure in five Italian goat breeds.

The aim of this work was to investigate the genetic structure of the casein gene cluster in 5 Italian goat breeds and to evaluate the haplotype variability within and among populations. A total of 430 goats from Vallesana, Roccaverano, Jonica, Garganica, and Maltese breeds were genotyped at alphas1-casein (CSN1S1), alphas2-casein, (CSN1S2), beta-casein (CSN2), and kappa-casein (CSN3) loci using several genomic techniques and milk protein analysis. Casein haplotype frequencies were estimated for each breed. Principal component analysis was carried out to highlight the relationship among breeds. Allele and haplotype distributions indicated considerable differences among breeds. The haplotype CSN1S1*F- CSN1S2*F-CSN3*D occurred in all breeds with frequencies >0.100 and was the most common haplotype in the Southern breeds. A high frequency of CSN1S1*0-CSN1S2*C-CSN3*A haplotype was found in Vallesana population (0.162). Principal component analysis clearly separated the Northern and Southern breeds by the first component. The variability of the caprine casein loci and variety of resulting haplotypes should be exploited in the future using specific breeding programs aiming to preserve biodiversity and to select goat genetic lines for specific protein production.

Animals↗
PubMed2006

Genetic variation in p53 and ATM haplotypes and risk of glioma and meningioma.

BACKGROUND: P53 and ATM are central checkpoint genes involved in the repair of DNA damage after ionising irradiation, which has been associated with risk of brain tumours. Therefore, we tested the hypothesis that polymorphisms and haplotypes in p53 and ATM could be associated with glioma and meningioma risk. MATERIAL AND METHODS: Six hundred and eighty glioma cases (298 glioblastoma (GBM)), 503 meningioma cases, and 1555 controls recruited in the Nordic-UK Interphone study, were analysed in association with three polymorphisms in p53 (rs2287499, rs1042533, rs1625895) and five polymorphisms in ATM ( rs228599, rs3092992, rs664143, rs170548, rs3092993). Haplotypes were constructed using the HAPLOSTAT program. RESULTS: The global statistical test of glioblastoma and p53 haplotypes was p = 0.02. The haplotype analysis on glioblastoma revealed the 1-2-2 haplotype (promotor-codon72-intron 6) had a frequency of 6.1% in cases compared with 9.8% in controls (p = 0.003). The 1-2-1 haplotype was significantly more frequent in GBM cases, 10.2%, than in controls, 7.3% (p = 0.02). The haplotype analysis in ATM revealed an increased frequency of the 1-1-1-2-1 haplotype in meningioma cases (33.8%) compared with controls (30.3%) (p = 0.03). The 2-1-2-1-1 haplotype had a lower frequency in meningioma cases (36.1%) than controls (40.7%) (p = 0.009). CONCLUSIONS: This study found both positive and negative associations of haplotypes in p53 for glioblastoma and ATM for meningioma. This study provides new data that could add to our understanding of brain tumour susceptibility.

Adult↗
PubMed2002

Genetic management of nonhuman primates.

Genetic management is widely recognized as a critical component of the overall management of captive nonhuman primate colonies which produce animals for biomedical research. In this paper, we review the roles of conservation-oriented genetic management, research-oriented genetic management, genetic management at the level of taxomomic class, genetic management at the level of the population, and quantitative genetic analysis in comprehensive genetic management programs for nonhuman primate colonies. We conclude that genetic management is crucial for maintaining nonhuman primate populations suitable for genetic research on normal and disease-related phenotypes. In addition, for research programs that do not have specific genetic objectives, genetic management is essential to facilitate the selection of samples of well-matched unrelated animals for experimental purposes.

Animals↗
PubMed2005

Genetic determinants on rat chromosome 6 modulate variation in the hypercapnic ventilatory response using consomic strains.

To understand the genetic basis of pathways involved in the control of breathing, a large scale, high-throughput study using chromosomal substitution strains of rats is underway. Eight new consomic rat stains (SS-2(BN), SS-4(BN), SS-6(BN), SS-7(BN), SS-8(BN), SS-11(BN), SS-12(BN), SS-14(BN), SS-Y(BN)), containing one homozygous BN/NHsdMcwi (BN) chromosome on a background of SS/JrHsdMcwi (SS), were created by PhysGen (http://pga.mcw.edu) Program for Genomic Applications. Male and female rats were studied using standard plethysmography under control conditions and during acute hypoxia (inspired oxygen fraction = 0.12) and hypercapnia (inspired CO(2) fraction = 0.07). The rats were also studied during treadmill exercise. Both male and female BN rats had a significantly lower ventilatory response during 7% CO(2) compared with SS rats of the same gender. SS-6(BN) female rats had a significantly reduced ventilatory response, similar to BN rats due primarily to a reduced tidal volume. Male SS-6(BN) rats had a significantly reduced tidal volume response to hypercapnia but a slightly increased frequency response during hypercapnia. Gene(s) on the Y chromosome may play a role in this increased frequency response in the male rats because the SS-Y(BN) hypercapnic ventilatory response involves a significantly increased frequency response. Several chromosomal substitutions slightly altered the ventilatory responses to hypoxia and exercise. However, genes on chromosomes 6 and Y of those studied are of primary importance in aspects of ventilatory control currently studied.

Animals↗
PubMed2003

Gibbs Recursive Sampler: finding transcription factor binding sites.

The Gibbs Motif Sampler is a software package for locating common elements in collections of biopolymer sequences. In this paper we describe a new variation of the Gibbs Motif Sampler, the Gibbs Recursive Sampler, which has been developed specifically for locating multiple transcription factor binding sites for multiple transcription factors simultaneously in unaligned DNA sequences that may be heterogeneous in DNA composition. Here we describe the basic operation of the web-based version of this sampler. The sampler may be acces-sed at http://bayesweb.wadsworth.org/gibbs/gibbs.html and at http://www.bioinfo.rpi.edu/applications/bayesian/gibbs/gibbs.html. An online user guide is available at http://bayesweb.wadsworth.org/gibbs/bernoulli.html and at http://www.bioinfo.rpi.edu/applications/bayesian/gibbs/manual/bernoulli.html. Solaris, Solaris.x86 and Linux versions of the sampler are available as stand-alone programs for academic and not-for-profit users. Commercial licenses are also available. The Gibbs Recursive Sampler is distributed in accordance with the ISCB level 0 guidelines and a requirement for citation of use in scientific publications.

Algorithms↗