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PubMed2004

Application of molecular diagnosis for detection of peritoneal micrometastasis and evaluation of preoperative chemotherapy in advanced gastric carcinoma.

BACKGROUND: In advanced gastric cancer, peritoneal recurrence is the main cause of death after curative surgical resection. The aim of this report was to describe a novel approach for quantitative genetic diagnosis using peritoneal lavage for the identification of patients at high risk for peritoneal recurrence and for evaluation of the clinical response to intraperitoneal chemotherapy in advanced gastric cancer. METHODS: Nineteen patients with advanced gastric cancer who underwent staging laparoscopy and intraperitoneal chemotherapy before surgical resection or systemic chemotherapy between June 1999 and September 2001 were enrolled in this study. All peritoneal lavage specimens, collected at both staging laparoscopy and gastrectomy, were subjected to real-time quantitative genetic diagnosis. RESULTS: The reverse transcriptase polymerase chain reaction (RT-PCR) values decreased in 8 cases, stabilized as negative in 5, and increased in 6 during therapy. Patients whose RT-PCR values diminished and were ultimately negative survived except for one, and all but one patient whose values increased during treatment died of recurrence. CONCLUSIONS: Quantitative evaluation of genetic changes can provide accurate, useful information on the effects of preoperative intra-abdominal chemotherapy and overall prognosis for patients with advanced gastric cancer.

Adenocarcinoma↗
PubMed2005

Constant light-induced retinal damage and the RPE65-MET450 variant: assessment of the NZW/LacJ mouse.

PURPOSE: In a previous constant light-induced retinal damage (CLD) quantitative genetics study between the albino C57BL/6J-c2J (B6al) and BALB/c mouse strains, we identified a very strong and highly significant quantitative trait locus (QTL) on distal Chr 3 that we associated with a variant of the Rpe65 gene. The B6al strain carries the MET450 variant of RPE65 and is resistant to CLD while the BALB/c strain carries the LEU450 variant and is sensitive. Since then, we have discovered that the NZW/LacJ (NZW) albino mouse strain is sensitive to CLD but carries the MET450 variant of RPE65. The purpose of this study was to determine if the NZW mouse disproves the hypothesis that the MET450 variant of RPE65 protects the mouse retina against constant light-induced retinal damage. METHODS: F2 progeny were bred from an intercross between the NZW/LacJ and B6al mouse strains. After a prolonged exposure to moderate constant light, F2 mice were phenotyped for retinal outer nuclear layer thickness as the quantitative trait. A subset of 156 of the 201 F2 mice was genotyped for a set of markers spanning the genome, and any marker with a significant association with the quantitative trait was genotyped in the remaining 45 F2s. Data were analyzed for QTL by the Map Manager QTX software. RESULTS: No QTL was identified at distal Chr 3, although several QTL on Chrs 1 (two), 10, 13, 14, 16, and X were detected. One QTL on middle Chr 1 (LOD 5.22) mapped to the same location of a QTL (LOD 6.8) in a previous intense, short exposure light-induced retinal damage study conducted with an intercross between the 129S1/SvImJ and BALB/c strains. QTL on Chrs 1 (distal), 10, and 14 also appeared in other retinal damage quantitative genetics studies. Three pairs of genes exhibited significant epistatic effects. Two of the pairs involved synergistic interactions between NZW and B6al alleles, and the third between two B6al alleles. CONCLUSIONS: If another gene besides Rpe65 was responsible for the QTL in the original BALB/c x B6al study, and the NZW mouse carried a light sensitive allele of this gene, a QTL should have been present in this study. Since a QTL on Chr 3 was not found, the hypothesis that RPE65-MET450 protects the retina from constant light-induced damage is left intact. The explanation for the NZW mouse being sensitive to constant light while carrying the RPE65-MET450 variant is that other light sensitive QTL (gene alleles) negate the protective effect.

Animals↗
PubMedDate not supplied

[Genetic control of immune responsiveness to bovine serum albumin in the high and low antibody producer lines of mice (author's transl)].

Mice genetically selected for high or low antibody responsiveness to sheep erythrocytes (SRBC) were used for a genetic analysis of the antibody response to an optimal dose of heat-aggregated bovine seralbumin (BSA). About 4 independent loci intervene in the quantitative genetic regulation of the response to BSA, while in these two lines the response to the selection antigen (SRBC) was found to be regulated by about 10 loci; one of them was linked to the major histocompatibility complex of the mouse (H-2). Such an H-2 linkage was not demonstrated for the regulation of the response to BSA. Dominance effect in F1 hybrids was shown to vary according to the strength of the immunization procedure used. This result raises the question of the phenotypic cellular expression of the quantitative genetic regulation of the immune response.

Animals↗
PubMed2001

Genetic architecture of testis and seminal vesicle weights in mice.

Comparisons across 13 inbred strains of laboratory mice for reproductive organ (paired seminal vesicles and paired testes) weights indicated a very marked contrast between the C57BL/6By and NZB/BINJ mice. Subsequently these strains were selected to perform a quantitative genetic analysis and full genome scan for seminal vesicle and testis weights. An F(2) population was generated. The quantitative genetic analyses indicated that each was linked to several genes. Sixty-six short sequences for length polymorphism were used as markers in the wide genome scan strategy. For weight of paired testes, heritability was 82.3% of the total variance and five QTL contributed to 72.8% of the total variance. Three reached a highly significant threshold (>4.5) and were mapped on chromosome X (LOD score 9.11), chromosome 4 (LOD score 5.96), chromosome 10 (LOD score 5.81); two QTL were suggested: chromosome 13 (LOD score 3.10) and chromosome 18 (LOD score 2.80). Heritability for weight of seminal vesicles was 50.7%. One QTL was mapped on chromosome 4 (LOD score 9.21) and contributed to 24.2% of the total variance. The distance of this QTL to the centromere encompassed the distance of the QTL linked with testicular weight on chromosome 4, suggesting common genetic mechanisms as expected from correlations in the F(2). Both testis and seminal vesicle weights were associated with a reduction in the NZB/BINJ when this strain carried the Y(NPAR) from CBA/H whereas the Y(NPAR) from NZB/BINJ in the CBA/H strain did not modify reproductive organ weights, indicating that the Y(NPAR) interacts with the non-Y(NPAR) genes. The effects generated by this chromosomal region were significant but small in size.

Animals↗
PubMed2004

Detection and quantitation of genetically modified maize (Bt-176 transgenic maize) by applying ligation detection reaction and universal array technology.

We have applied the ligation detection reaction (LDR) combined with a universal array approach to the detection and quantitation of the polymerase chain reaction (PCR) amplified cry1A(b) gene from Bt-176 transgenic maize. We demonstrated excellent specificity and high sensitivity. Down to 0.5 fmol (nearly 60 pg) of PCR amplified transgenic material was unequivocally detected with excellent linearity within the 0.1-2.0% range with respect to wild-type maize. We suggest the feasibility of extending the LDR/universal array format to detect in parallel several transgenic sequences that are being developed for food applications.

Bacillus thuringiensis Toxins↗
PubMed2006

Testing genetic models of mate choice evolution in the wild.

Understanding the mechanisms driving the evolution of mate choice, particularly the importance of indirect genetic benefits, remains a challenge, especially in wild populations. Three recent studies have attempted to quantify the importance of indirect benefits in wild bird populations using approaches derived from quantitative genetic models of mate choice. In all three cases, no support was found for a role of indirect benefits in the evolution of mate choice. These studies suggest that a quantitative genetic approach can illuminate this long-standing problem and that alternative models for the evolution of mate preferences should be tested in wild populations.

Animals↗
PubMedDate not supplied

Sociocultural influences in genetic designs of aging: unexplored perspectives.

As the aging population continues to become more diverse, there is growing interest in understanding the similar and unique aspects of aging within and across people of different ethnic groups. The impact of culture on the sources of variation identified in quantitative genetic approaches has not been well discussed in the literature. The purpose of this paper is to review previous research pertinent to the cultural aspects of quantitative genetic approaches and methodologies, and provide conceptual and statistical approaches for advancing the science. To meet this objective, results from previously published studies as well as preliminary data analyses from the Carolina African American Twin Study of Aging will be presented. There are three themes to draw from the issues discussed in this paper: (1) avoiding genetic reductionism, (2) interpreting differential heritabilities, and (3) modeling cultural influences.

Aging↗
PubMed2005

Genetic effects on sperm design in the zebra finch.

Sperm design and function are important determinants of male reproductive success and are expected to be under strong selection. The way that spermatozoa phenotypes evolve is poorly understood, because there have been few studies of the quantitative genetics of sperm. Here we show, in the zebra finch Taeniopygia guttata, an extraordinary degree of inter-male variation in sperm design that is independent of sperm swimming velocity. A quantitative genetics study using data from over 900 zebra finches in a complex breeding experiment showed that sperm head, mid-piece and flagellum length are heritable, that negative genetic correlations exist between sperm traits, and that significant indirect (maternal) genetic effects exist. Selection on the zebra finch sperm phenotype may be low because sperm competition is infrequent in this species, and this, in combination with negative genetic correlations and maternal genetic effects, may account for the variation in sperm phenotype between males. These results have important implications for the evolution of sperm in other taxa.

Animals↗
PubMed2005

How to use molecular marker data to measure evolutionary parameters in wild populations.

Estimating the genetic basis of phenotypic traits and the selection pressures acting on them are central to our understanding of the evolution and conservation of wild populations. However, obtaining such evolutionary-related parameters is not an easy task as it requires accurate information on both relatedness among individuals and their breeding success. Polymorphic molecular markers are very useful in estimating relatedness between individuals and parentage analyses are now extensively used in most taxa. The next step in the application of molecular data to wild populations is to use them to derive estimates of evolutionary-related parameters for quantitative traits, such as quantitative genetic parameters (e.g. heritability, genetic correlations) and measures of selection (e.g. selection gradients). Despite their great appeal and potential, the optimal use of molecular tools is still debated and it remains unclear how they should best be used to obtain reliable estimates of evolutionary parameters in the wild. Here, we review the methods available for estimating quantitative genetic and selection parameters and discuss their merits and shortcomings, to provide a tool that summarizes the potential uses of molecular data to obtain such parameters in wild populations.

Biological Evolution↗
PubMed2006

A comparison of methods to estimate cross-environment genetic correlations.

Advanced techniques for quantitative genetic parameter estimation may not always be necessary to answer broad genetic questions. However, simpler methods are often biased, and the extent of this determines their usefulness. In this study we compare family mean correlations to least squares and restricted error maximum likelihood (REML) variance component approaches to estimating cross-environment genetic correlations. We analysed empirical data from studies where both types of estimates were made, and from studies in our own laboratories. We found that the agreement between estimates was better when full-sib rather than half-sib estimates of cross-environment genetic correlations were used and when mean family size increased. We also note biases in REML estimation that may be especially important when testing to see if correlations differ from 0 or 1. We conclude that correlations calculated from family means can be used to test for the presence of genetic correlations across environments, which is sufficient for some research questions. Variance component approaches should be used when parameter estimation is the objective, or if the goal is anything other than determining broad patterns.

Analysis of Variance↗
PubMed1999

Genetic characterisation of protective vaccine responses in sheep using multi-valent Dichelobacter nodosus vaccines.

Protective vaccine responses to nine distinct serogroups of Dichelobacter nodosus (serogroups A-I) can be readily measured by serogroup-specific K-agglutinating antibody titres. On the basis of a large quantitative genetic experiment (1200 progeny from 129 sire groups), it was shown that variation in antibody responses following vaccination with a multi-valent pilus antigen D. nodosus vaccine (serogroups A-I) is, in part, under genetic control and thus heritable. Based on the genetic relationships between antibody responses to all nine antigens, results suggested that both genes for a broad-based and genes for serogroup-specific response contributed to genetic variation in vaccine response. Furthermore, preliminary data in 389 progeny showed that polymorphism within the ovine major histocompatibility (MHC) based on serological classification accounted for a significant proportion of the variation in vaccine responses. In subsequent experimentation, we examined the importance of genetic polymorphism within the ovine MHC, and the possibility of genes outside the MHC for their involvement in antigen-specific and broad-based vaccine response. Within two large half sib families(131, and 143 progeny), four MHC haplotypes were investigated and found to be associated with differential antibody responses to six out of eight distinct vaccine-antigens presented to the host in a multi-valent vaccine. The model used here shows how well characterised immunogens, quantitative genetic experimentation, and molecular gene mapping tools can be used to unravel genetic differences in host responses to commercial vaccines.

Agglutination Tests↗
PubMed2005

Parallel genotypic adaptation: when evolution repeats itself.

Until recently, parallel genotypic adaptation was considered unlikely because phenotypic differences were thought to be controlled by many genes. There is increasing evidence, however, that phenotypic variation sometimes has a simple genetic basis and that parallel adaptation at the genotypic level may be more frequent than previously believed. Here, we review evidence for parallel genotypic adaptation derived from a survey of the experimental evolution, phylogenetic, and quantitative genetic literature. The most convincing evidence of parallel genotypic adaptation comes from artificial selection experiments involving microbial populations. In some experiments, up to half of the nucleotide substitutions found in independent lineages under uniform selection are the same. Phylogenetic studies provide a means for studying parallel genotypic adaptation in non-experimental systems, but conclusive evidence may be difficult to obtain because homoplasy can arise for other reasons. Nonetheless, phylogenetic approaches have provided evidence of parallel genotypic adaptation across all taxonomic levels, not just microbes. Quantitative genetic approaches also suggest parallel genotypic evolution across both closely and distantly related taxa, but it is important to note that this approach cannot distinguish between parallel changes at homologous loci versus convergent changes at closely linked non-homologous loci. The finding that parallel genotypic adaptation appears to be frequent and occurs at all taxonomic levels has important implications for phylogenetic and evolutionary studies. With respect to phylogenetic analyses, parallel genotypic changes, if common, may result in faulty estimates of phylogenetic relationships. From an evolutionary perspective, the occurrence of parallel genotypic adaptation provides increasing support for determinism in evolution and may provide a partial explanation for how species with low levels of gene flow are held together.

Adaptation, Biological↗
PubMed2004

Comparing strengths of directional selection: how strong is strong?

The fundamental equation in evolutionary quantitative genetics, the Lande equation, describes the response to directional selection as a product of the additive genetic variance and the selection gradient of trait value on relative fitness. Comparisons of both genetic variances and selection gradients across traits or populations require standardization, as both are scale dependent. The Lande equation can be standardized in two ways. Standardizing by the variance of the selected trait yields the response in units of standard deviation as the product of the heritability and the variance-standardized selection gradient. This standardization conflates selection and variation because the phenotypic variance is a function of the genetic variance. Alternatively, one can standardize the Lande equation using the trait mean, yielding the proportional response to selection as the product of the squared coefficient of additive genetic variance and the mean-standardized selection gradient. Mean-standardized selection gradients are particularly useful for summarizing the strength of selection because the mean-standardized gradient for fitness itself is one, a convenient benchmark for strong selection. We review published estimates of directional selection in natural populations using mean-standardized selection gradients. Only 38 published studies provided all the necessary information for calculation of mean-standardized gradients. The median absolute value of multivariate mean-standardized gradients shows that selection is on average 54% as strong as selection on fitness. Correcting for the upward bias introduced by taking absolute values lowers the median to 31%, still very strong selection. Such large estimates clearly cannot be representative of selection on all traits. Some possible sources of overestimation of the strength of selection include confounding environmental and genotypic effects on fitness, the use of fitness components as proxies for fitness, and biases in publication or choice of traits to study.

Models, Genetic↗
PubMed2005

An exact form of the breeder's equation for the evolution of a quantitative trait under natural selection.

Starting with the Price equation, I show that the total evolutionary change in mean phenotype that occurs in the presence of fitness variation can be partitioned exactly into five components representing logically distinct processes. One component is the linear response to selection, as represented by the breeder's equation of quantitative genetics, but with heritability defined as the linear regression coefficient of mean offspring phenotype on parent phenotype. The other components are identified as constitutive transmission bias, two types of induced transmission bias, and a spurious response to selection caused by a covariance between parental fitness and offspring phenotype that cannot be predicted from parental phenotypes. The partitioning can be accomplished in two ways, one with heritability measured before (in the absence of) selection, and the other with heritability measured after (in the presence of) selection. Measuring heritability after selection, though unconventional, yields a representation for the linear response to selection that is most consistent with Darwinian evolution by natural selection because the response to selection is determined by the reproductive features of the selected group, not of the parent population as a whole. The analysis of an explicitly Mendelian model shows that the relative contributions of the five terms to the total evolutionary change depends on the level of organization (gene, individual, or mated pair) at which the parent population is divided into phenotypes, with each frame of reference providing unique insight. It is shown that all five components of phenotypic evolution will generally have nonzero values as a result of various combinations of the normal features of Mendelian populations, including biparental sex, allelic dominance, inbreeding, epistasis, linkage disequilibrium, and environmental covariances between traits. Additive genetic variance can be a poor predictor of the adaptive response to selection in these models. The narrow-sense heritability sigma2A/sigma2P should be viewed as an approximation to the offspring-parent linear regression rather than the other way around.

Biological Evolution↗
PubMed2001

Genetic epidemiology of fecal egg excretion during Schistosoma mansoni infection in an endemic area in Minas Gerais, Brazil.

There is considerable variation in the level of fecal egg excretion during Schistosoma mansoni infections. Within a single endemic area, the distribution of egg counts is typically overdispersed, with the majority of eggs excreted coming from a minority of residents. The purpose of this study was to quantify the influence of genetic factors on patterns of fecal egg excretion in a rural study sample in Brazil. Individual fecal egg excretions, expressed in eggs per gram of feces, were determined by the Kato-Katz method on stool samples collected on three different days. Detailed genealogic information was gathered at the time of sampling, which allowed assignment of 461 individuals to 14 pedigrees containing between 3 and 422 individuals. Using a maximum likelihood variance decomposition approach, we performed quantitative genetic analyses to determine if genetic factors could partially account for the observed pattern of fecal egg excretion. The quantitative genetic analysis indicated that between 21-37% of the variation in S. mansoni egg counts was attributable to additive genetic factors and that shared environment, as assessed by common household, accounted for a further 12-21% of the observed variation. A maximum likelihood heritability (h2) estimate of 0.44 +/- 0.14 (mean +/- SE) was found for the 9,604 second- and higher-degree pairwise relationships in the study sample, which is consistent with the upper limit (37%) of the genetic factor determined in the variance decomposition analysis. These analyses point to the significant influence of additive host genes on the pattern of S. mansoni fecal egg excretion in this endemic area.

Adolescent↗
PubMed1986

Composition and genetic variability of heparin-sepharose CL-6B protein fractions obtained from the solubilized proteins of mouse organs.

The solubilized proteins of liver and brain from mice of two inbred strains (C57BL/6J and DBA/2J) and their hybrids were subfractionated by heparin Sepharose (H-S) CL-6B affinity chromatography. The H-S binding and nonbinding proteins were separated by two-dimensional electrophoresis. The protein patterns obtained were analyzed with regard to their protein composition and their genetic variability (qualitative and quantitative variants). Eighty to ninety percent of the H-S binding proteins were unique to this class of proteins. This class was rich in organ-specific proteins. Compared to the nonbinding proteins the portion of basic proteins was only slightly increased, suggesting that most of the H-S binding proteins interact specifically with heparin. The frequency of qualitative protein variants revealed that H-S binding proteins are more conservative than H-S nonbinding proteins. The quantitative genetic variability was higher in liver than in brain. Quantitative protein variants occurred more frequently than qualitative variants.

Animals↗