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PubMed2004

Genetic structure of seventy cocoyam (Xanthosoma sagittifolium, Linn, Schott) accessions in Ghana based on RAPD.

Seventy cocoyam accessions collected from the eastern and Volta regions of Ghana were studied using RAPD technique. Ten primers were used to study the genetic diversity and structure of the experimental material and a total of 120 different bands were detected. Levels of polymorphic fragments detected by the ten primers ranged from 69.2% to 100%. In the accessions from the eastern region, the mean observed and effective number of alleles per individual per population and mean Nei's gene diversity were 1.99+/-0.01, 1.53+/-0.12 and 0.312+/-0.05, respectively. Mean observed and effective number of alleles per individual per population and Nei's gene diversity were 1.76+/-0.17, 1.44+/-0.16 and 0.264+/-0.08, respectively for the accessions from the Volta region. Considering the entire collections, the mean observed and effective number of alleles per individual per population and Nei's gene diversity for primers were 1.99+/-0.02, 1.54+/-0.12 and 0.319+/-0.05, respectively. In terms of Nei's F-statistics in the subdivided populations for all primers, the overall gene diversity (Ht) ranged from 0.230 to 0.396 with a mean of 0.313+0.06, within sample gene diversity (Hs) ranged from 0.214 to 0.372 with a mean of 0.286+0.06, gene differentiation (Gst) ranged between 0.005 and 0.178 with a mean of 0.086. Geneflow estimate ranged between 2.309 and 99.500 with a mean of 5.314. The accessions grouped into three main clusters. Accession BD96/183 was the most diverse and may be incorporated into cocoyam breeding programs. The 70 accessions did not cluster into their distinct geographical regions suggesting that there may have been movement of germplasm across the two regions.

DNA Primers↗
PubMed2003

Mhc class II DRB sequences of lion-tailed macaques (Macaca silenus).

The lion-tailed macaque (Macaca silenus) is an endangered species. Research into the genetics of this species is important as a basis for coordinated breeding programs of captive populations. Therefore, we sought to analyze the Mhc class II DRB genes of this species because of it is highly polymorphic in genetically heterogeneous populations of most species. Ten individuals from seven families were evaluated. Nine DRB second exon sequences belonging to eight allelic lineages were identified. These lineages are also present in the best-studied macaque species: the rhesus (Macaca mulatta). Although only these relatively few alleles could be isolated, they display variation on the lineage level. This may be a mechanism for increasing their functional diversity.

Amino Acid Sequence↗
PubMed1998

Genetic variation at the apoA-IV gene locus and response to diet in familial hypercholesterolemia.

Plasma lipid response to dietary fat and cholesterol is, in part, genetically controlled. The apolipoprotein A-IV (apoA-IV protein; APOA4, gene) has been shown to influence the response to dietary changes in normolipidemic individuals. The response to diet in subjects with familial hypercholesterolemia (FH) is also variable, and no studies are available on the influence of APOA4 mutations on dietary response in these subjects. We studied the effect of 2 common apoA-IV genetic variants (Gln360-->His and Thr347-->Ser) on the lipid response to the National Cholesterol Education Program type I (NCEP-I) diet in 67 FH heterozygotes (43 women and 24 men). Subjects were studied at baseline (after consuming for 1 month a diet with 35% fat [10% saturated] and 300 mg/d cholesterol) and after 3 months of consuming a low-fat diet. No sex-related differences were found, and results were combined for men and women. The APOA4-360 mutation was assessed in 67 subjects, 51 with genotype 1/1 and 16 with genotype 1/2. The APOA4-2 allele was associated with marginally significantly lower (P=0.049) low density lipoprotein (LDL) cholesterol levels and significantly lower (P=0.027) apoB levels independent of diet effects. After consuming an NCEP-I diet, carriers of the APOA4-2 allele showed a significantly lower reduction in apoB concentration (6.2%) than 1/1 subjects (14.1%; P=0.036); however, no significant differences in response were noted for LDL cholesterol. The APOA4-347 mutation was assessed in 63 individuals, 44 with the A/A allele and 19 with the A/T and T/T alleles. No significant differences were observed in baseline or post-NCEP-I diet values for these 2 groups in total, LDL, and high density lipoprotein cholesterol and plasma apoB levels. After dietary intervention, A/A individuals showed significant reductions in plasma triglyceride and very low density lipoprotein cholesterol levels; no changes were found in carriers of the T allele. Haplotype analysis suggested that in these FH subjects, the APOA4-360-2 allele was associated with lower plasma lipid levels during the NCEP-I diet period, whereas no significant effects were observed for the APOA4-347-T allele.

Adult↗
PubMed2024

Genetic diversity, disease resistance, and environmental adaptation of Arachis duranensis L.: New insights from landscape genomics.

The genetic diversity that exists in natural populations of Arachis duranensis, the wild diploid donor of the A subgenome of cultivated tetraploid peanut, has the potential to improve crop adaptability, resilience to major pests and diseases, and drought tolerance. Despite its potential value for peanut improvement, limited research has been focused on the association between allelic variation, environmental factors, and response to early (ELS) and late leaf spot (LLS) diseases. The present study implemented a landscape genomics approach to gain a better understanding of the genetic variability of A. duranensis represented in the ex-situ peanut germplasm collection maintained at the U.S. Department of Agriculture, which spans the entire geographic range of the species in its center of origin in South America. A set of 2810 single nucleotide polymorphism (SNP) markers allowed a high-resolution genome-wide characterization of natural populations. The analysis of population structure showed a complex pattern of genetic diversity with five putative groups. The incorporation of bioclimatic variables for genotype-environment associations, using the latent factor mixed model (LFMM2) method, provided insights into the genomic signatures of environmental adaptation, and led to the identification of SNP loci whose allele frequencies were correlated with elevation, temperature, and precipitation-related variables (q < 0.05). The LFMM2 analysis for ELS and LLS detected candidate SNPs and genomic regions on chromosomes A02, A03, A04, A06, and A08. These findings highlight the importance of the application of landscape genomics in ex situ collections of peanut and other crop wild relatives to effectively identify favorable alleles and germplasm for incorporation into breeding programs. We report new sources of A. duranensis germplasm harboring adaptive allelic variation, which have the potential to be utilized in introgression breeding for a single or multiple environmental factors, as well as for resistance to leaf spot diseases.

Arachis↗
PubMed1990

Computer-assisted methods for assessing strain relatedness in Candida albicans by fingerprinting with the moderately repetitive sequence Ca3.

When used to probe EcoRI-digested Candida albicans DNA, the moderately repetitive sequence Ca3 generated a Southern blot hybridization pattern which included 15 to 25 bands, depending upon the strain. The pattern was stable through 400 generations in each of three independent strains but variable between most of 46 unrelated tester strains, making it a very effective probe for discrimination between strains. Computer-assisted methods (Dendron) were developed for storage of Ca3 patterns in data files, calculation of similarity (SAB) values between strains based upon band positions and intensities, and generation of histograms and dendrograms based on SAB values for all strains or any subset of strains in large epidemiological studies. In testing the effectiveness of the system, it was found that (i) multiple isolates from different body locations of the same healthy individual could represent either the same strain or different strains, (ii) isolates from oral lesions of a husband and wife represented the same strain, (iii) strains isolated from the mouths of 10 healthy individuals on the same day and in the same geographical location were as dissimilar on average as the 46 unrelated tester strains, and (iv) strains isolated from seven immunocompromised patients hospitalized over a 2.5-month period in the same hospital were highly similar, indicating nosocomial origin. The apparent effectiveness of these fingerprinting methods and the Dendron program suggests that interlaboratory procedures for fingerprinting should be standardized and all patterns should be analyzed and stored in a common and accessible data base for broad epidemiological analysis.

Blotting, Southern↗
PubMed1995

Evidence for nosocomial transmission of Candida albicans obtained by Ca3 fingerprinting.

The moderately repetitive sequence Ca3 was used to fingerprint Candida albicans isolates from 32 patients hospitalized for more than 3 days, 17 recent admissions or outpatients, and 8 recently readmitted patients and 10 commensal isolates from the community in Wellington, New Zealand, plus isolates from 21 hospitalized patients, 26 outpatients or recent admissions, 4 recently readmitted patients, and 10 healthy individuals in the community in Auckland, New Zealand. In Wellington, isolates from patients hospitalized in Wellington Hospital for more than 3 days were genetically significantly less diverse than were isolates from outpatients or recent admissions or isolates from healthy individuals in the community. In addition, two clusters of genetically similar strains were isolated from hospitalized patients significantly more often than from other individuals. These observations provide evidence (albeit indirectly) for nosocomial transmission of hospital-specific C. albicans strains. In contrast, no indication of hospital-specific transmission of C. albicans was found in Auckland Hospital. Since these results were obtained under conditions in which no candidiasis outbreak occurred in either hospital, they also suggest that Ca3 fingerprinting may be a useful tool in preventive nosocomial infection control programs, allowing assessment of the extent of C. albicans transmission occurring in a hospital.

Adolescent↗
PubMed2026

Structural variant discovery and diagnostic impact in rare diseases from short-read and long-read sequencing.

Rare diseases collectively affect 1 in 10 individuals, yet current genetic testing fails to identify a causal variant for most cases. At present, cytogenetic methods and/or sequencing approaches such as exome (ES) or short-read genome sequencing (srGS) represent the state-of-the-art for comprehensive clinical discovery of sequence and structural variants (SVs), including copy number variants, balanced SVs, complex SVs, and tandem repeats (TRs). Recently, long-read genome sequencing (lrGS), coupled with multiomics data, has presented great promise to resolve variation in genomic regions recalcitrant to characterization by srGS such as highly repetitive simple repeat sequences and segmental duplications. However, there are few guidelines to enable clinical interpretation of genetic variation in these highly repetitive genomic regions, and the enthusiasm of the field in adopting lrGS has made it difficult to assess the true added diagnostic yield of this technology due to widely variable and inconsistently applied analytic pipelines and variable degrees of pre-screening by ES or srGS. Here, we investigated the contribution of SVs to rare diseases using srGS as a front-line strategy when paired with highly sensitive SV discovery and evaluate the added diagnostic yield of incorporating lrGS for a subset of cases. Our srGS analysis encompassed 1,462 families (3,450 individuals) recruited through the Broad Institute Center for Mendelian Genetics and the Genomics Research to Elucidate the Genetics of Rare Diseases (GREGoR) programs. Diagnostic SVs were identified in 5.4% of cases (79/1,462), of which 80% were uniquely detectable by srGS compared to standard cytogenetic techniques. For 96 families (including 10 families with a heterozygous variant observed in a known recessive gene of clinical relevance), we performed lrGS with methylation profiling, as well as long-read transcriptomic analyses in a subset of 20 trios. Analyses with lrGS yielded over 25,000 SVs per genome, 63% of which were not captured by srGS, along with an additional ~200 rare SNV/indels per genome not previously captured and 12 differentially methylated regions per genome. Among these, we identified only one diagnostic variant not interpreted by srGS, an apparently mosaic de novo SNV in CASK that was absent in the srGS callset due to allelic imbalance. No new diagnoses were supported by long-read transcriptomics or episignatures. In this well characterized rare disease cohort, the added diagnostic yield was thus 1.04% (1/96 families). Following a systematic literature review of prior lrGS studies, we find that most reported diagnoses were detectable by srGS and that our added diagnostic yield is consistent with those prior studies. These studies emphasize the significant impact of comprehensive SV discovery in rare disease cases and further demonstrate the power for increased discovery of novel genomic variation and episignatures from lrGS. Nonetheless, they also serve to temper expectations of dramatic diagnostic advances in rare disease patients until there is more extensive annotation of the functional and clinical impact of all coding and noncoding variation uniquely accessible to lrGS with extensive reference databases spanning highly repetitive genomic sequencing that could be enabled by this transformative technology.

Journal Article↗
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↗
PubMed1998

Regulation of the human menstrual cycle.

Our understanding of the regulation of the menstrual cycle has recently improved with the development of various tools of investigation. The cycle is now thought to be determined mainly by the ovary itself, which sends various signals to the pituitary and the hypothalamus. The aim of the cycle is to produce a single mature oocyte each month from puberty to menopause. However, the most common evolution of a follicle is atresia, a consequence of the genetically controlled, ovarian apotosis (or "programmed cell death"). Follicular growth and maturation are mostly independent of gonadotropins, from the stage of primordial follicles to antral follicles. A complete intraovarian paracrine system is implied in this gonadotropin-independent follicular growth, and in the modulation of the actions of the gonadotropins in the ovary. FSH allows the rescue of a minority of follicles from atresia and is indispensable to only the final maturation of the preovulatory follicle. The cyclical variations of the gonadotropins are under the control of ovarian steroids (estradiol and progesterone) and peptides (inhibin). The cycle length is determined by follicular growth and by the fixed life span of the corpus luteum. The mechanism of action of gonadotropins is much better understood since the gonadotropins and their receptor cDNA have been cloned. The recent description of naturally occurring mutations has lead to a better understanding of the role of each gonadotropin, demonstrating the crucial role of FSH in the terminal maturation of the follicles. The ovarian cycle can also be monitored at the level of target tissues of steroids such as the endometrium. The cellular mechanisms of endometrial maturation, under the control of estradiol and progesterone, are better understood. The endometrial maturation is synchronized to follicular development and allows implantation of the conceptus. The genes implied in the implantation of the embryo are being identified (e.g., integrins). Last but not least, the mechanisms of endometrial shedding are being elucidated, especially the role of metalloproteases and angiogenic factors. These concepts will allow the development of new treatments for infertility, the design of new contraceptive techniques, and a better tolerance of treatments using sex steroids, particularly progestin-only pill.

Endometrium↗
PubMed2006

CART variance stabilization and regularization for high-throughput genomic data.

MOTIVATION: mRNA expression data obtained from high-throughput DNA microarrays exhibit strong departures from homogeneity of variances. Often a complex relationship between mean expression value and variance is seen. Variance stabilization of such data is crucial for many types of statistical analyses, while regularization of variances (pooling of information) can greatly improve overall accuracy of test statistics. RESULTS: A Classification and Regression Tree (CART) procedure is introduced for variance stabilization as well as regularization. The CART procedure adaptively clusters genes by variances. Using both local and cluster wide information leads to improved estimation of population variances which improves test statistics. Whereas making use of cluster wide information allows for variance stabilization of data. AVAILABILITY: Sufficient details for our CART procedure are given so that the interested reader can program the method for themselves. The algorithm is also accessible within the Java software package BAMarray(TM), which is freely available to non-commercial users at www.bamarray.com. CONTACT: hemant.ishwaran@gmail.com.

Artificial Intelligence↗
PubMed2006

[SSR polymorphism on the waxy gene locus and their relationship to amylose content in wheat].

Variation of one simple sequence repeat (SSR)(AT (AT)n AT) in the 3 end of the waxy gene was analyzed in samples of 32 cultivars, including different wheat cultivars in Shandong region and representing a wide distribution range of amylose content (AC) in cultivated wheat. In this study, we found two fragments were present in all cultivars, one of 204bp, the expected size, and one of 225-346bp. 204bp fragment located on the chromosome 7DS, while 225-346bp fragment located on the chromosome 7AS. That is, Wx-Ala gene and Wx-Dla gene present in all wheat lines, but the larger fragment showed length polymorphism. The result showed that the amylose level is highly positive correlated with the length of the polymorphic SSR. Amplified fragment is long in high AC cultivars and electrophoresis migration rate is small, while the fragment is short in low AC cultivars and electrophoresis migration rate is large. AC is highly diverse among different lines with the various SSR genotypes. Although the SSR variation did not seem to have obvious function in the synthesis of the starch synthase encoded by the waxy gene, the correlation between the SSR and AC level could be used as molecular marker for quality improvement in wheat programs.

Amylose↗
PubMed2006

HER-2 fluorescence in situ hybridization: results from the survey program of the College of American Pathologists.

CONTEXT: Fluorescence in situ hybridization (FISH) is a common method used to determine HER-2 status in breast cancer. Limited information is available concerning reproducibility of FISH in determining HER-2 gene amplification. OBJECTIVE: To present proficiency testing results of FISH for HER-2 conducted by the Cytogenetics Resource Committee of the College of American Pathologists/American College of Medical Genetics. DESIGN: During the past 5 years, unstained sections from 9 invasive breast carcinomas were used for HER-2 FISH proficiency testing, allowing for comparison of FISH results among a large number of laboratories. Additional data were collected using an educational (ungraded) challenge and supplemental questions in the surveys. RESULTS: The number of laboratories participating in HER-2 FISH proficiency testing has increased steadily during the past 5 years (from 35 in 2000 to 139 in 2004). Reproducibility of test results among laboratories was excellent for breast tumors with low copy number (no HER-2 amplification) and for breast tumors with high copy number (HER-2 amplification). However, there was considerable variation in interpretation of results for a tumor with low-level HER-2 amplification that was tested on 2 separate occasions. Responses to supplemental questions indicated that there was a need for consensus on the use of a separate equivocal/borderline interpretative category and the need for standardization of cutoff values used to define interpretative categories. CONCLUSIONS: The College of American Pathologists proficiency survey programs provide useful information concerning the reproducibility of clinical testing for HER-2 by FISH and reflect clinical interpretation of HER-2 FISH analyses from laboratories across the country.

Adenocarcinoma↗
PubMed2004

piggyBac transformation of the New World screwworm, Cochliomyia hominivorax, produces multiple distinct mutant strains.

Sterile insect technique (SIT) programs are designed to eradicate pest species by releasing mass-reared, sterile insects into an infested area. The first major implementation of SIT was the New World Screwworm Eradication Program, which successfully eliminated the New World screwworm (NWS), Cochliomyia hominivorax (Coquerel) (Diptera: Calliphoridae), from the Continental US, Mexico and much of Central America. Ionizing radiation is currently used for sterilization, but transgenic insect techniques could replace this method, providing a safer, more cost-effective alternative. Genetic transformation methods have been demonstrated in NWS, and verified by Southern blot hybridization, PCR and sequencing of element insertion junctions. A lethal insertional mutation and enhancer detection-like phenotypic expression variations are presented and discussed. In addition to supporting the eradication efforts, transformation methods offer potential means to identify genes and examine gene function in NWS.

Animals↗
PubMed2003

Evidence for bivariate linkage of obesity and HDL-C levels in the Framingham Heart Study.

BACKGROUND: Epidemiological studies have indicated that obesity and low high-density lipoprotein (HDL) levels are strong cardiovascular risk factors, and that these traits are inversely correlated. Despite the belief that these traits are correlated in part due to pleiotropy, knowledge on specific genes commonly affecting obesity and dyslipidemia is very limited. To address this issue, we first conducted univariate multipoint linkage analysis for body mass index (BMI) and HDL-C to identify loci influencing variation in these phenotypes using Framingham Heart Study data relating to 1702 subjects distributed across 330 pedigrees. Subsequently, we performed bivariate multipoint linkage analysis to detect common loci influencing covariation between these two traits. RESULTS: We scanned the genome and identified a major locus near marker D6S1009 influencing variation in BMI (LOD = 3.9) using the program SOLAR. We also identified a major locus for HDL-C near marker D2S1334 on chromosome 2 (LOD = 3.5) and another region near marker D6S1009 on chromosome 6 with suggestive evidence for linkage (LOD = 2.7). Since these two phenotypes have been independently mapped to the same region on chromosome 6q, we used the bivariate multipoint linkage approach using SOLAR. The bivariate linkage analysis of BMI and HDL-C implicated the genetic region near marker D6S1009 as harboring a major gene commonly influencing these phenotypes (bivariate LOD = 6.2; LODeq = 5.5) and appears to improve power to map the correlated traits to a region, precisely. CONCLUSIONS: We found substantial evidence for a quantitative trait locus with pleiotropic effects, which appears to influence both BMI and HDL-C phenotypes in the Framingham data.

Adult↗
PubMed1985

Animal health and management and their impact on economic efficiency.

Relationships between animal health and economic efficiency were examined using data from genetic investigations and management studies. Genetic investigations have indicated that cows bred for high production do require more health care, but that increased costs for health care negate only a small fraction of the greater returns from cows that are genetically superior for yield traits. These same studies have identified age of cow and stage of lactation as important sources of variation in health care costs. Health care costs increase with age and are highest at parturition and immediately thereafter, and decrease to much lower levels as lactation progresses. Animal health issues considered from a management perspective were macro-environment (climate, housing, facilities), nutrition-reproduction complex, replacement management, mastitis and udder health, and herd health preventive medicine programs. Most advances in management of animal health were beneficial, but some are economical only for large herds. Improvement of udder health through continued and expanded research on milking procedures and equipment design is an area of unusual promise. Additional research appears needed to cope with stress and fatigue to legs and feet in modern facilities. Preventive medicine programs become more cost effective as herds become larger and should be used by a larger percentage of dairy producers. The economic efficiency of many management practices is uncertain due to a paucity of data. Animal scientists should plan to incorporate economic comparisons into much more of their research.

Animal Husbandry↗
PubMed1982

Early arterial lesions in infancy and childhood and ways of prevention.

Arterial lesions appear in the human vascular system early in life. In some predisposed arterial segments calcifications of the internal elastic sheets have regularly been demonstrated macroscopically in infancy and early childhood. Atherosclerotic lesions also begin in childhood, and the seeds of their later clinical manifestations are probably sown in infancy. Hyperlipemia, hypertension, and cigarette smoking represent the major risk factors of atherosclerosis and its premature development. Accordingly, the main task of pediatricians is early identification of the risk groups and their appropriate treatment, particularly of children with hyperlipoproteinemia type II and those with family history indicating a premature atherosclerotic event, hypertension, and diabetes mellitus. In most populations, however, elevated serum cholesterol levels are probably not caused by genetically determined metabolic disorders but mainly promoted by environmental factors, such as nutrition. Therefore, establishment of beneficial nutritional habits early in life may prevent the development or at least limit the extent of fatty streaks and their further transformation into fibrous plaques or more advanced atherosclerotic lesions. The education of the community, especially of parents, to the hazards of the cardiovascular risk factors must become an essential part of preventive programs directed to sound cardiovascular health. The wide individual variation of the extent of early lesions, e.g., of fatty streaking in childhood even in most homogeneous population subgroups, points to the existence of still undiscovered risk factors. Cooperative efforts between pediatric pathologists and pediatricians appear, therefore, a necessity for further progress in the evaluation of these factors and for establishing successful preventive programs.

Adult↗
PubMed1984

Beta-thalassemia disease prevention: genetic medicine applied.

We report here an evaluation of a program for thalassemia-disease prevention, comprising education, population screening for heterozygotes, and reproductive counseling; the evaluation includes cost analysis. A preprogram survey in 1978 of 3,247 citizens in the high-risk communities (85% were high-school students) showed that 88% favored a program but that only 31% considered fetal diagnosis as an acceptable option. Screening in high school or before marriage was preferred by 56%. In a 25-month period (December 1979-December 1982), we screened 6,748 persons, including 5,117 senior high-school students, using MCV/HbA2 indices. The participation rate was 80% in the high-school group. The frequency for beta-thalassemia heterozygosity was 4.7% with 10-fold variation among ethnic groups at risk; the overall frequency for all variants found was 5.4%. We surveyed 60 carriers and 120 noncarriers after screening high-school students (response rate 77%): most carriers told parents (95%) and friends (67%) the test result; and 38% of the carriers' parents (vs. 18% of the noncarriers' parents) were also screened. Carriers would ascertain their spouses' genotype (91%) and approved uniformly (95%) the high-school screening experience and its goal. We performed 11 fetal diagnoses in a 25-month interval (greater than 75% participation in target population) either by fetoscopy and globin-chain analysis or by amniocentesis and genomic DNA analysis; two of three affected fetuses were aborted at parental request, there was one spontaneous abortion (after fetoscopy), and seven live births. The at-risk couples claimed pregnancy would not be contemplated without the fetal-diagnosis option. We analyzed economic costs of the program: cost per case prevented is approximately equal to $ 6,700, slightly less than cost-per-patient-treatment-year or about 4% of undiscounted treatment cost incurred in the first 25 years of life for an affected individual. These findings indicate: collective acceptance of the program, appropriate attitudes among carriers, general acceptance and efficacy of fetal diagnosis, and global cost-effectiveness.

Adolescent↗
PubMed1998

Nucleotide substitution models and estimation of phylogeny.

The nucleotide substitution matrix inferred from avian data sets using cytochrome b differs considerably from the models commonly used in phylogenetic analyses. To analyze the possible effects of this particular pattern of change in phylogeny estimation we performed a computer simulation in which we started with a real sequence and used the inferred model of change to produce a tree of 10 species. Maximum parsimony (MP), maximum likelihood (ML), and various distance methods were then used to recover the topology and the branch lengths. We used two kinds of data with varying levels of variation. In addition, we tested with the removal of third positions and different weighting schemes. At low levels of variation, MP was outstanding in recovering the topology (90% correct), while unweighted pair-group method, arithmetic average (UPGMA), regardless of distances used, was poor (40%). At the higher level, most methods had a chance of around 40%-58% of finding the true tree. However, in most cases, the trees found were only slightly wrong, with only one or a few branches misplaced. On the other hand, the use of a "wrong" model had serious effects on the estimation of branch lengths (distances). Although precision was high, accuracy was poor with most methods, giving branch lengths that were biased downward. When seeded with the true distance matrix, Fitch and NJ always found the true tree, while UPGMA frequently failed to do so. The effect of removing third positions was dramatic at low levels of variation, because only one MP program was able to find a true tree at all, albeit rarely, while none of the others ever did so. At higher levels, the situation was better, but still much worse than with the whole data set.

Animals↗