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PubMed2006

Long contiguous stretches of homozygosity in the human genome.

Single nucleotide polymorphisms (SNPs) are the most common sequence variation in the human genome; they have been successfully used in mapping disease genes and more recently in studying population genetics and cancer genetics. In a population-based association study using high-density oligonucleotide arrays for whole-genome SNP genotyping, we discovered that in the genomes of unrelated Han Chinese, 34 out of 515 (6.6%) individuals contained long contiguous stretches of homozygosity (LCSHs), ranging in the size from 2.94 to 26.27 Mbp (10.22+/-5.95 Mbp). Four out of four (100%) Taiwan aborigines also demonstrated this genetic characteristic. The number of LCSH regions increased markedly in the offspring of consanguineous marriages. LCSH was also detected in Caucasian samples (11/42; 26.2%) and African American samples (2/42; 4.76%). A total of 26 LCSH regions were recurrently detected among Han Chinese, Taiwan aborigines, and Caucasians. DNA copy number determination by hybridization intensity analysis and real-time quantitative PCR (qPCR) excluded deletion as the cause of LCSH. Our results suggest that LCSHs are common in the human genome of the outbred population and this genetic characteristic could have a significant impact on population genetics and disease gene studies.

Black or African American↗
PubMed2005

Human response to alpha2-adrenergic agonist stimulation studied in an isolated vascular bed in vivo: Biphasic influence of dose, age, gender, and receptor genotype.

BACKGROUND AND OBJECTIVES: Activation of alpha 2 -adrenergic receptors regulates a broad spectrum of physiologic responses, including blood pressure (centrally and peripherally), sedation, analgesia, insulin release, renal function, cognition, and behavior. The purpose of this study was to explore systematically the local vascular responses in humans triggered by a highly selective alpha 2 -adrenergic agonist (azepexole [B-HT 933]) and whether such responses are dose-dependent or influenced by age, gender, or allelic variation at the drug's receptor. METHODS: We evaluated dorsal hand vein vascular responses to the infusion of a wide spectrum of doses of azepexole, assessing any venodilation, as well as the maximal extent of venoconstriction (B max ) and the dose that produced a half-maximal effect (K d ), in 50 healthy normotensive adults of both genders and 4 ethnicities. Genomic deoxyribonucleic acid from the study subjects was evaluated at polymorphisms of the alpha 2B -adrenergic receptor gene (ADRA2B). RESULTS: We found previously unreported initial venodilation to low doses (10-100 ng/min) of azepexole, followed by progressive, intense venoconstriction to higher doses (200-100,000 ng/min) of the drug. Younger individuals (aged <30 years) had less venodilation than older individuals (aged >30 years) with low doses of azepexole but had a greater extent of venoconstriction at higher doses of azepexole (ANOVA, P = .001). Men had less venodilation than women with low doses of azepexole but greater venoconstriction with higher doses (ANOVA, P = .036). Several common polymorphisms (>10% minor allele frequency) at ADRA2B (insertion/deletion polymorphism [Glu 322-325 ], G-98C, C1182A, and C1776A) did not show an association with either B max or K d for the drug response. The A36G (Thr12Thr) synonymous single nucleotide polymorphism displayed a nonsignificant trend (P = .073) toward higher K d in A/G heterozygotes compared with A/A homozygotes. CONCLUSIONS: Local infusion into the human dorsal hand vein of a highly selective alpha 2 -adrenergic agonist, azepexole, produces biphasic responses, with venodilation at a low dose and intense venoconstriction at a higher concentration. These responses to azepexole show prominent differences as a function of age and gender but appear not to depend on common allelic variations at the ADRA2B receptor.

Adrenergic alpha-Agonists↗
PubMed2002

Definition of gross tumor volume in lung cancer: inter-observer variability.

BACKGROUND AND PURPOSE: To determine the inter-observer variation in gross tumor volume (GTV) definition in lung cancer, and its clinical relevance. MATERIALS AND METHODS: Five clinicians involved in lung cancer were asked to define GTV on the planning CT scan of eight patients. Resulting GTVs were compared on the base of geometric volume, dimensions and extensions. Judgement of invasion of lymph node (LN) regions was evaluated using the ATS/LCSG classification of LN. Clinical relevance of the variation was studied through 3D-dosimetry of standard conformal plans: volume of critical organs (heart, lungs, esophagus, spinal cord) irradiated at toxic doses, 95% isodose volumes of GTVs, normal tissue complication probabilities (NTCP) and tumor control probabilities (TCP) were compared for evaluation of observer variability. RESULTS: Before evaluation of observer variability, critical review of planning CT scan led to up- (two cases) and downstaging (one case) of patients as compared to the respective diagnostic scans. The defined GTVs showed an inter-observer variation with a ratio up to more than 7 between maximum and minimum geometric content. The dimensions of the primary tumor had inter-observer ranges of 4.2 (transversal), 7.9 (cranio-caudal) and 5.4 (antero-posterior) cm. Extreme extensions of the GTVs (left, right, cranial, caudal, anterior and posterior) varied with ranges of 2.8-7.3 cm due to inter-observer variation. After common review, only 63% of involved lymph node regions were delineated by the clinicians (i.e. 37% are false negative). Twenty-two percent of drawn in lymph node regions were accepted to be false positive after review. In the conformal plans, inter-observer ranges of irradiated normal tissue volume were on average 12%, with a maximum of 66%. The probability (in the population of all conformal plans) of irradiating at least 95% of the GTV with at least 95% of the nominal treatment dose decreased from 96 to 88% when swapping the matched GTV with an unmatched one. The average (over all patients) inter-observer range in NTCP varied from 5% (spinal cord) to 20% (ipsilateral lung), whereas the maximal ranges amounted 16% (spinal cord) to 45% (heart). The average TCP amounted 51% with an average range of 2% (maximally 5%) in case of matched GTVs. These values shifted to 42% (average TCP) with an average range of 14% (maximally 31%) when defining unmatched GTVs. Four groups of causes are suggested for the large inter-observer variation: (1) problems of methodology; (2) impossible differentiation between pathologic structures and tumor; or (3) between normal structures and tumor, and (4); lack of knowledge. Only the minority of these can be resolved objectively. For most of the causal factors agreements have to be made between clinicians, intra- and inter-departmentally. Some of the factors will never be unequivocally solved. CONCLUSIONS: GTV definition in lung cancer is one of the cornerstones in quality assurance of radiotherapy. The large inter-observer variation in GTV definition jeopardizes comparison between clinicians, institutes and treatments.

Carcinoma, Non-Small-Cell Lung↗
PubMed2005

PAR-1 genotype influences platelet aggregation and procoagulant responses in patients with coronary artery disease prior to and during clopidogrel therapy.

Genetic variations of the protease-activated receptor-1 (PAR-1) have been associated with platelet receptor density and linked to thrombin receptor-activating peptide (TRAP)-induced phenotypes of platelet aggregation and P-selectin expression. We investigated whether the PAR-1 intervening sequence-14 A>T dimorphism influences platelet procoagulant activity. We also determined whether the P2Y12 antagonist clopidogrel could offset any observed functional polymorphism of the PAR-1 receptor by inhibiting P2Y12-mediated amplification of TRAP-induced responses. We studied 54 patients listed for elective percutaneous coronary intervention assessing TRAP-induced platelet aggregation and markers of procoagulant activity. Platelet responses were measured at baseline, 4 h post clopidogrel 300 mg, and 10 and 28 days following clopidogrel 75 mg daily. Each patient was genotyped for the PAR-1 intervening sequence-14 A/T dimorphism. Increased platelet aggregation and procoagulant responses were observed with PAR-1 A allele homozygotes. Clopidogrel significantly inhibited these platelet responses regardless of PAR-1 genotype, but did not offset the hyper-reactivity associated with the A/A homozygotes. We conclude that a common sequence variation within the PAR-1 gene influences TRAP-induced platelet procoagulant activity as well as aggregation. Higher platelet reactivity associated with PAR-1 IVSn-14 A allele homozygotes persists despite clopidogrel therapy. These individuals may be at higher risk of thromboembolic events and may require additional anti-platelet medication.

Alleles↗
PubMed2004

Variation in urological practice amongst spinal injuries units in the UK and Eire.

AIMS: To investigate variations in common urological practice between the Spinal Injuries Units (SIU) of UK and Eire. METHODS: In December 2002, each of the 12 SIU in the UK and Eire were sent a questionnaire addressing basic practice relating to urological outpatient follow-up, management of urinary tract infection, upper tract surveillance, and urodynamic studies. RESULTS: Regarding frequency of urological review, two units only saw patients when specifically required. One unit reviewed patients every 6 months and six centres reviewed patients annually. The remaining three units had a patient-specific follow-up protocol. Regarding urinary tract infection, only five units had a unified departmental management protocol. Four units advocated antibiotic prophylaxis for recurrent UTI. Only one unit would routinely treat asymptomatic UTI in individuals using catheters. The range of recommended duration of treatment for symptomatic UTI was 3-14 days (mean 6.3). All units performed routine upper tract screening, ranging from annually to every 3 years. Six units did not perform routine urodynamic studies; in other units the range of frequency of urodynamics was from annually to every 3 years. CONCLUSIONS: The variation in urological practice amongst SIU in the UK and Eire is considerable. This finding supports the need for an increase in the level of collaboration and research.

Follow-Up Studies↗
PubMed2003

[Dynamics of genetic variation of Sartov cultivars of common wheat Triticum aestivum L. (from the gliadin-coding locus) after a an 80-year period of scientific selection].

Based on analysis of gliadin patterns in common wheat cultivars developed at the Research Institute of Agriculture of the Southeast, profile dynamics in gliadin loci has been surveyed for the period of over eight decades. It was shown that long-term breeding of the wheat cultivars involved gradual replacement of alleles characteristic of ancient cultivars for those widely spread in the world, which are probably linked with alleles that currently confer advantage to their carriers. The process of reduction of inter-population genetic diversity in wheat (with special reference to the allele frequency dynamics at gliadin loci) is discussed. This process is responsible for genetic erosion of the species.

Genetic Variation↗
PubMed1995

Anatomic relationships along the low-middle convexity: Part I--Normal specimens and magnetic resonance imaging.

Sagittal sections of anatomic specimens and magnetic resonance images well display the individual gyri and sulci along the low-middle convexity. Those familiar with the typical pattern and with the common normal variations will be able to use sagittal magnetic resonance imaging to correctly localize lesions by identifying: (a) the five major rami of the sylvian fissure; (b) the subdivision of the triangular inferior frontal gyrus into the M-shaped partes orbitalis, triangularis, and opercularis by the anterior horizontal and anterior ascending rami of the sylvian fissure; (c) the zig-zag shape of the middle frontal gyrus, which characteristically angles sharply and inferiorly to fuse with the anterior surface of the precentral gyrus; (d) T-shaped bifurcation of the posterior end of the inferior frontal sulcus to form the inferior precentral sulcus; (e) separation of the central sulcus from the sylvian fissure by union of the opercular ends of the precentral and postcentral gyri to form the subcentral gyrus inferior to the central sulcus; (f) narrower sagittal dimension of the postcentral gyrus than the precentral gyrus; (g) horseshoe shape of the supramarginal gyrus perched atop the posterior ascending ramus of the sylvian fissure; (h) similar horseshoe shape of the angular gyrus perched atop the posterior end of the superior temporal sulcus; (i) commonly intercalated accessory presupramarginal and preangular gyri; and (j) the arcuate course of the intraparietal sulcus, which separates the superior from the inferior parietal lobules. The anatomic relationships described are more nearly constant anteriorly than posteriorly. When used as described, they prove helpful in correctly localizing pathology and in planning a surgical approach to lesions that may be difficult to localize on the basis of axial or coronal plane magnetic resonance images.

Brain↗
PubMed2005

Genotypic variation of N2-fixing common bean (Phaseolus vulgaris L.) in response to iron deficiency.

In calcareous soils, the yield of grain legumes is often limited by the lower availability of iron (Fe), especially when they depend upon symbiosis with root nodule bacteria for their N nutrition. In order to explore the variability of responses of N(2)-fixing common bean to Fe deficiency the common bean white-seeded lines Striker and Coco blanc, and coloured-seeded lines SVM-29-21 and ARA14 were inoculated with Rhizobium tropici (CIAT 899) and cultivated hydroaeroponically with a N-free nutrient solution supplied or not with 45microM Fe. Differences among lines were observed: Fe-deficiency-induced-chlorosis on young leaves was earlier and more severe in some lines than others. Nodule development and N(2)-fixing capacity was less affected in line ARA14 which preferentially allocated Fe towards nodules. Results suggest that Fe use efficiency for symbiotic nitrogen fixation (FeUE SNF) could be used to screen tolerant bean lines to Fe deficiency in condition of symbiotic nitrogen fixation.

Genetic Variation↗
PubMed1995

HIV-1 heterogeneity and cytokines. Neuropathogenesis.

Mild manifestations (HIV-1 associated minor cognitive/motor disorder), severe manifestations (HIV-1 associated dementia complex and HIV-1 associated myelopathy), and sensory neuropathy are consequences of HIV-1 infection. Our goal is to elucidate the role of HIV-1 in the complications of AIDS including cytokine immunopathology and HIV-1 DNA sequence variants. We have examined the brain and sensory ganglia from 60 AIDS patients and 20 seronegative controls using PCR, DNA sequencing of the HIV-1 envelope protein (env), in situ hybridization (ISH), and immunohistochemistry (IHC). Using our combined ISH-IHC technique, we could identify different types of cells and HIV-1 simultaneously in cryostat and paraffin sections. We found HIV-1 predominantly in macrophage/microglia in brain. In dorsal root ganglia (DRG) we found rare macrophages infected with HIV-1 and neurons and interstitial cells (including macrophages) which were apoptotic. Cytokines were detected in mononuclear and endothelial cells near neurons. We achieved single copy sensitivity detecting HIV-1 in nervous tissue using nested PCR. We sequenced HIV-1, DNA from 3 intravenous drug users (IDUs): from brain, CSF, and blood. PCR amplification was followed by cloning and then sequencing the HIV-1 insert: V1-V5 regions of the envelope (env) gene. We found that the env genes had increased sequence variation compared to the literature, cDNA sequences derived from RNA were less heterogeneous than clones derived from DNA from the same specimens, clones derived from brain are more closely related (show restricted heterogeneity) compared to clones from blood and CSF from the same patients. Patient 149 clones we examined to date did not correspond to any of the designated subtypes (A-F) of HIV-1 based on the DNA sequences of the C2-V3 regions. Finally, the HIV-1 RNA produced in these tissues is derived from a minority of DNA clones. Although HIV-1 infected macrophages are not entirely responsible for pathology in the brain and less so in sensory ganglia, some of the products of infection, cytokines, are more widespread in these tissues. Furthermore, HIV-1 strains infecting the brain appear to exhibit restricted heterogeneity compared to autologous CSF and blood and these strains may be associated with cytokines and pathology. HIV-1 strains that infect nervous tissue and cytokines produced in this tissue may effect neuropathogenesis, in vivo, in spite of low levels of local HIV-1 infection. We attempt to delineate, here, common sequence variations in HIV-1 isolates in the hope of developing future therapeutic strategies.

AIDS Dementia Complex↗
PubMed2006

Rhizosphere bacteria affected by transgenic potatoes with antibacterial activities compared with the effects of soil, wild-type potatoes, vegetation stage and pathogen exposure.

A greenhouse experiment was performed to analyze a potential effect of genetically modified potatoes expressing antibacterial compounds (attacin/cecropin, T4 lysozyme) and their nearly isogenic, nontransformed parental wild types on rhizosphere bacterial communities. To compare plant transformation-related variations with commonly accepted impacts caused by altered environmental conditions, potatoes were cultivated under different environmental conditions, for example using contrasting soil types. Further, plants were challenged with the blackleg pathogen Erwinia carotovora ssp. atroseptica. Rhizosphere soil samples were obtained at the stem elongation and early flowering stages. The activities of various extracellular rhizosphere enzymes involved in the C-, P- and N-nutrient cycles were determined as the rates of fluorescence of enzymatically hydrolyzed substrates containing the highly fluorescent compounds 4-methylumbelliferone or 7-amino-4-methyl coumarin. The structural diversity of the bacterial communities was assessed by 16S rRNA-based terminal restriction fragment length polymorphism analysis, and 16S rRNA gene clone libraries were established for the flowering conventional and T4 lysozyme-expressing Desirée lines grown on the chernozem soil, each line treated with and without E. carotovora ssp. atroseptica. Both genetic transformation events induced a differentiation in the activity rates and structures of associated bacterial communities. In general, T4 lysozyme had a stronger effect than attacin/cecropin. In comparison with the other factors, the impact of the genetic modification was only transient and minor, or comparable to the dominant variations caused by soil type, plant genotype, vegetation stage and pathogen exposure.

Anti-Bacterial Agents↗
PubMed1999

Gene polymorphism of t-PA is associated with forearm vascular release rate of t-PA.

We have observed marked interindividual differences in release rates of tissue-type plasminogen activator (t-PA) among healthy subjects. The objective of the current study was to test the hypothesis that there is an association between a genetic variation at the t-PA locus and the in vivo release rate of t-PA. Fifty-one healthy males were studied at rest in the morning and 27 of these were also subjected to a mental stress test. Net release rates of total t-PA across the forearm vascular bed were calculated as the product of the venoarterial concentration gradient and forearm plasma flow. Zygosity for an Alu-repeat polymorphism in intron 8 of the t-PA gene was determined by a polymerase chain reaction. Basal t-PA release rates differed markedly by genotype (ANOVA, P<0.05); subjects homozygous for the insertion had a significantly higher release rate (mean 10.9 ng. min-1. L-1, n=19) than both heterozygotes (4.5 ng. min-1. L-1, n=26) and subjects homozygous for the deletion (0.9 ng. min-1. L-1, n=6). After 2 minutes of mental stress release rates had increased approximately 2-fold in all groups. Arterial and venous plasma levels of t-PA were unrelated to genotype. In conclusion, the current results provide the first evidence of an association between a common genetic variation at the t-PA locus and interindividual differences in net release rates of t-PA in vivo. The relationship is not reflected by circulating steady-state plasma levels and can thus not be disclosed by conventional venous plasma sampling.

Adult↗
PubMed2003

Genetic variation in lectin-like oxidized low-density lipoprotein receptor 1 (LOX1) gene and the risk of coronary artery disease.

BACKGROUND: We examined the association of 3 polymorphisms in the lectin-like oxidized LDL receptor-1 (LOX1 or OLR1) gene with coronary artery disease in the Women's Ischemia Syndrome Evaluation (WISE) study population. METHODS AND RESULTS: The WISE sample comprised 589 white and 122 black women who underwent angiography for suspected ischemia. The sample was divided into 3 groups: <20% stenosis (38.7%), 20% to 49% stenosis (24.9%), and >or=50% stenosis (35.3%). The three LOX1 polymorphisms (intron 4/G-->A, intron 5/T-->G, and 3' UTR/T-->C) were in linkage disequilibrium and thus behaved as a single polymorphism. The frequency of the 3'UTR/T allele was significantly higher in whites than blacks (49% versus 19%; P<0.0001). Among white women, the frequency of the 3'UTR/T allele carriers (TC+TT genotypes) increased gradually from 67.9% to 75.0% and 79.2% in the <20%, 20% to 49%, and >or=50% stenosis groups, respectively (chi2 trend=6.23; P=0.013). Logistic regression analyses indicated that APOE (odds ratio, 1.90; P=0.007) and LOX1 (odds ratio, 1.67; P=0.025) genotypes were independently associated with the risk of disease and that there was no interaction between the two genes. The 3'UTR/T allele carriers also had significantly higher IgG anti-oxLDL levels than individuals carrying the CC genotype (0.94+/-0.20 versus 0.86+/-0.16; P=0.032). Furthermore, our electrophoretic mobility shift assay data show that the 3'UTR polymorphic sequence affects the binding of a putative transcription factor in an allele-specific manner. CONCLUSIONS: Our data suggest that common genetic variation in the LOX1 gene may be associated with the risk of coronary artery disease in white women.

3' Untranslated Regions↗
PubMed2004

Angiotensin II type I receptor gene and myocardial infarction: tagging SNPs and haplotype based association study. The Beijing atherosclerosis study.

OBJECTIVES: The present study aimed to assess the effect of haplotype variation in angiotensin II type I receptor (AGTR1) gene on the risk of myocardial infarction (MI) in Chinese males. METHODS: We used 48 patients to identify the putative functional polymorphisms in AGTR1 gene by direct sequencing. The program tagSNPs was used to identify an optimal set of tagging single nucleotide polymorphisms (SNPs). These selected SNPs were then genotyped in 419 male patients with MI and 400 age-matched male controls. The program haplo.stats was used to investigate the relationship between the haplotypes and MI. RESULTS: Sixteen polymorphisms in AGTR1 gene were identified. Based on the linkage disequilibrium pattern among these SNPs, six polymorphisms, SNP1, SNP6-SNP7 and SNP13-SNP15, were selected as haplotype tagging SNPs and further genotyped. Single SNP analyses indicated that the SNP1, SNP6 and SNP13 were significantly associated with MI, adjusted for covariates. Haplotype-based association analyses identified the frequency of haplotype AGATAA was lower in cases than in controls (P = 0.006). In comparison, three haplotypes (AAATAA, TAGCAA and AAACAG) were found to significantly increase the risk of MI with adjusted odds ratio equal to 1.33, 1.75 and 2.64, respectively (P = 0.029, 0.026 and 0.015). CONCLUSIONS: Our study suggests that common genetic variations in the AGTR1 gene may affect the risk of MI in Chinese males, and that there might be several functional variants in AGTR1 gene and the combined effect of these variants seemed to have a larger effect on the risk of MI in Chinese males.

Adult↗
PubMed2005

Risk of spontaneous preterm birth is associated with common proinflammatory cytokine polymorphisms.

BACKGROUND: Preliminary data suggest that common genetic variation in immune response genes can contribute to the risk for spontaneous preterm birth and possibly small-for-gestational age (SGA). METHODS: We investigated the relationship of polymorphisms in 6 cytokine genes associated with inflammation-interleukin (IL)1alpha, IL1beta, IL2, IL6, tumor necrosis factor (TNF), and lymphotoxin alpha (LTA)-with spontaneous preterm and SGA birth in a nested case-control study drawn from a prospective pregnancy cohort. Women were recruited between 24 and 29 weeks' gestation at the Wake County and University of North Carolina, Chapel Hill obstetric clinics between February 1996 and June 2000. We inferred haplotypes using the EM algorithm and the Bayesian method, PHASE. We then compared haplotype frequency distributions and implemented semi-Bayesian hierarchical logistic regression analyses to obtain odds ratio (OR) estimates and 95% confidence intervals (CIs) for each polymorphism. RESULTS: Two haplotypes spanning the TNF/LTA genes were associated with increased risk for spontaneous preterm birth in white subjects (for the AGG haplotype, OR = 1.5 [95% CI=0.8-2.6]; for the GAC haplotype, 1.6 [0.9-2.9]). Additionally, carriers of the GAG haplotype were found to have decreased risk of spontaneous preterm birth (0.6; 0.3-1.0). The TNF(-488)A and LTA(IVS1-82)C variants, constituents of the AGG and GAC haplotypes respectively, were also strongly associated with increased risk of spontaneous preterm birth. CONCLUSIONS: Our results suggest that common genetic variants in proinflammatory cytokine genes could influence the risk for spontaneous preterm birth. Selected TNF/LTA haplotypes were associated with spontaneous preterm birth in both African-American and white subjects. Our data do not support an inflammatory etiology for SGA.

Black or African American↗
PubMed2005

Common polymorphism in H19 associated with birthweight and cord blood IGF-II levels in humans.

BACKGROUND: Common genetic variation at genes that are imprinted and exclusively maternally expressed could explain the apparent maternal-specific inheritance of low birthweight reported in large family pedigrees. We identified ten single nucleotide polymorphisms (SNPs) in H19, and we genotyped three of these SNPs in families from the contemporary ALSPAC UK birth cohort (1,696 children, 822 mothers and 661 fathers) in order to explore associations with size at birth and cord blood IGF-II levels. RESULTS: Both offspring's and mother's H19 2992C>T SNP genotypes showed associations with offspring birthweight (P = 0.03 to P = 0.003) and mother's genotype was also associated with cord blood IGF-II levels (P = 0.0003 to P = 0.0001). The offspring genotype association with birthweight was independent of mother's genotype (P = 0.01 to P = 0.007). However, mother's untransmitted H19 2992T allele was also associated with larger birthweight (P = 0.04) and higher cord blood IGF-II levels (P = 0.002), suggesting a direct effect of mother's genotype on placental IGF-II expression and fetal growth. The association between mother's untransmitted allele and cord blood IGF-II levels was more apparent in offspring of first pregnancies than subsequent pregnancies (P-interaction = 0.03). Study of the independent Cambridge birth cohort with available DNA in mothers (N = 646) provided additional support for mother's H19 2992 genotype associations with birthweight (P = 0.04) and with mother's glucose levels (P = 0.01) in first pregnancies. CONCLUSION: The common H19 2992T allele, in the mother or offspring or both, may confer reduced fetal growth restraint, as indicated by associations with larger offspring birth size, higher cord blood IGF-II levels, and lower compensatory early postnatal catch-up weight gain, that are more evident among mother's smaller first-born infants.

Birth Weight↗
PubMed1994

Mitochondrial DNA diversity in the pea aphid Acyrthosiphon pisum.

The pea aphid Acyrthosiphon pisum has been established in North America for at least a century and occurs on a broad range of host plants. Despite its importance as a crop pest, there is little understanding of the genetic structure of its populations or the extent of genetic divergence associated with different host plant utilization. This study examined the extent of mitochondrial DNA (mtDNA) diversity among 35 clones of pea aphids from alfalfa. Polymorphisms were detected at only 2 of 126 restriction sites, suggesting the same impoverished level of genetic diversity found in prior allozyme studies. However, length variation was common and apparently arose as a result of tandem repeats in two regions of the mtDNA molecule. Region 1 occurred in proximity to the control region of the molecule, while region 2 was close to a cluster of tRNA genes flanking the NAD-dehydrogenase subunit 3 gene on the opposite side of the mtDNA molecule. Each of the aphid clones was homoplasmic for a single length variant in region 1, which varied with respect to the number of copies of a 120-bp repeat. By contrast, one-third of the clones were heteroplasmic at region 2, where they possessed a variable number of copies of a 210-bp repeat. Reanalysis of clones after 30 generations of parthenogenetic reproduction established the stability of length variants over this interval, suggesting their value in studies of the genetic structure of aphid populations.

Animals↗
PubMed2004

Reproductive output, maternal age, and survivorship in captive common marmoset females (Callithrix jacchus).

Common marmosets (Callithrix jacchus) demonstrate significant variation in reproductive output on both a yearly and lifetime basis in comparison to other anthropoid primates. We explore the factors that may be most important in determining reproductive variation in captive common marmosets. Studies have found that maternal age, maternal condition, and dam survivorship are related to reproductive output; however, these reports are not in agreement and are far from conclusive. With the use of a large, multicolony, demographic database pooling data across five marmoset colonies, we examined litter information for 1,649 litters, and reproductive summaries for 400 dams to assess 1) how reproductive output variation (total production, total weaned production) is determined by litter size, interbirth interval (IBI), age at first birth, and dam survival age; 2) the relationship between maternal age and reproductive output variables; and 3) relationship between the reproductive output variables and survival. We used stepwise regression procedures to describe the amount of variation in lifetime reproductive output among dams, and found that mean litter size accounted for 18% of the variance in total production, survival age accounted for 10.6%, age at first birth accounted for 8.8%, and mean IBI accounted for 5%. For total (nonzero) weaned production, survival age accounted for 7.6% of variance, age at first birth accounted for 7.2%, mean IBI accounted for 2%, and mean litter size accounted for 1.6%. We identified significant effects (P<0.05) of maternal age on litter size and IBI length, but no effect of dam age on weaned litter size. Cox proportional hazards regression analyses revealed significant effects (P<0.01) of number of litters, age at first birth, and site on dam survivorship. Dams that produced more litters showed higher survivorship. Age at first birth showed a positive relationship with dam survivorship, i.e., dams that delayed first reproduction had higher survival. Our findings about reproductive variation in marmosets may have practical applications for the management of marmoset breeding colonies.

Animals↗
PubMed2005

The search for genenotype/phenotype associations and the phenome scan.

All the approaches to the search for genotype/phenotype associations have their share of problems. Comparing the genome scan and candidate gene approaches, the former makes fewer assumptions at the genetic level or about mechanism but has greater statistical difficulties while the latter partially solves the statistical problem but makes more assumptions at both genetic and mechanistic levels. Among current difficulties is a lack of information about the nature of gene variant/phenotype associations: the frequency with which different classes of gene or sequence are involved; the type of genetic variation most commonly involved; the appropriate genetic models to apply to analysis. The overarching problem is that of multiple testing, one solution to which is to integrate genetic information to create a smaller number of compound variables. At the other end of the scale, decisions about the level of complexity at which to pitch the identification of phenotypes also affect the multiple testing problem: whether to pitch them at the level of disease outcomes, or at any of the multiple levels of intermediate phenotypes or traits. The third issue is how best to deal with gene/gene or gene/environment interactions, or whether to ignore them. Only as more genotype/phenotype associations emerge, by whatever means, will the numbers of results allow these questions to be answered. We describe here a new approach to genotype/phenotype association studies, the phenome scan, in which dense phenotypic information in human cohorts is scanned for associations with individual genetic variants. We believe that this approach can generate data that will be useful in answering generic questions about genotype/phenotype associations as well as in discovering novel ones.

Environmental Exposure↗