Heritability Of Quantitative Traits Research Articles

A polymorphism in the MSH3 mismatch repair gene is associated with the levels of somatic instability of the expanded CTG repeat in the blood DNA of myotonic dystrophy type 1 patients.

Somatic mosaicism of the expanded CTG repeat in myotonic dystrophy type 1 is age-dependent, tissue-specific and expansion-biased, contributing toward the tissue-specificity and progressive nature of the symptoms. Previously, using regression modelling of repeat instability we showed that variation in the rate of somatic expansion in blood DNA contributes toward variation in age of onset, directly implicating somatic expansion in the disease pathway. Here, we confirm these results using a larger more genetically homogenous Costa Rican DM1 cohort (p<0.001). Interestingly, we also provide evidence that supports subtle sex-dependent differences in repeat length-dependent age at onset and somatic mutational dynamics. Previously, we demonstrated that variation in the rate of somatic expansion was a heritable quantitative trait. Given the important role that DNA mismatch repair genes play in mediating expansions in mouse models, we tested for modifier gene effects with 13 DNA mismatch gene polymorphisms (one each in MSH2, PMS2, MSH6 and MLH1; and nine in MSH3). After correcting for allele length and age effects, we identified three polymorphisms in MSH3 that were associated with variation in somatic instability: Rs26279 (p=0.003); Rs1677658 (p=0.009); and Rs10168 (p=0.031). However, only the association with Rs26279 remained significant after multiple testing correction. Although we revealed a statistically significant association between Rs26279 and somatic instability, we did not detect an association with the age at onset. Individuals with the A/A genotype for Rs26279 tended to show a greater propensity to expand the CTG repeat than other genotypes. Interestingly, this SNP results in an amino acid change in the critical ATPase domain of MSH3 and is potentially functionally dimorphic. These data suggest that MSH3 is a key player in generating somatic variation in DM1 patients and further highlight MSH3 as a potential therapeutic target.

Analysis of the validity of assumptions underlying a research on the heritability of quantitative traits.

Heritability is a statistical measure, expressing the proportion of phenotypic variance that is explained by the genetic variance. Heritability of a given trait can vary in time and may differ between populations, which is inter alia associated with interactions and correlations between genotype and environment or population-specific differences. Therefore, heritability measures are modulated by both genetic and environmental factors. Twin studies constitute one of the methods used to determine contributions of genes and environment to a given trait. However, studies of this type suffer from some methodological limitations and require certain conditions to be satisfied; both these factors were analyzed in the present study. The studied material, including 1,263 pairs of male and female twins (among them 424 pairs of monozygotic twins and 839 pairs of dizygotic twins), born between the 22nd and 41st week of gestation, was collected at the Department of Perinatology and Gynecology, Poznan University of Medical Sciences, between 2002 and 2009. We analyzed the variance of six somatic traits. The contribution of genetic factors to the phenotypic variance of the studied twin population was estimated on the basis of the two heritability measures. Failure to meet the assumption of additivity of genetic and environmental effects probably is the cause of high values of heritability coefficients documented in our study. Analyzing the phenotypic variance of a trait, one cannot ignore the role of genotype-environment interactions and covariance, as these are their effects which increase the genetic variance and related coefficients of heritability. Therefore, it can be concluded that the genotypic component of the phenotypic variance of the trait is potentiated by the effects of various environmental factors. Our study confirmed that the critical remarks regarding the methodology of heritability estimation are fully justified. Consequently, the heritability indices of somatic traits should be considered only a provisional measure of genetic polymorphism, expressing an estimated relative contribution of genotypic variance to the phenotypic variance of a given trait.

Role of standard resting ECG in the assessment of sudden cardiac death risk

Today the ECG is still, over 100 years after its invention (Willem Einthoven 1903), the most commonly used diagnostic procedure in clinical cardiology. In recent years, we have accumulated knowledge that has significantly expanded the diagnostic possibilities of ECG, through the recognition of patterns associated with a number of primary electrical diseases of the myocardium, the so-called inherited arrhythmogenic diseases. These clinical entities are caused by gene mutations that determine a substrate leading to the onset of life-threatening rhythm disturbances. The study of ECG abnormalities in these diseases showed characteristic phenotypic traits, which in combination with information derived from molecular genetics, have allowed using the ECG as a prognostic tool as well as a diagnostic test. The assessment of genotype-phenotype correlations in inherited arrhythmogenic diseases has allowed to advance the idea of the ECG as an inheritable trait. Such heritable quantitative traits are potentially related to the risk of sudden death in the general population, which is known to have a familial predisposition. This article summarizes the pathophysiology and phenotypic manifestation of the main arrhythmogenic diseases. Also shown are current possibilities and limitations of the use of a simple and low-cost technology, not only as a tool for diagnosis but also as a tool to identify prognostic markers. We will show how, rather surprisingly, the ECG often allows extracting the most important information for appropriate risk classification and clinical management.

Waxy barley breeding

Genetic peculiarities of waxy barley breeding were investigated at the Plant Production Institute nd. a V. Ya. Yuryev of NAAS for the period of 2005-2013.Purpose. Study of genetic peculiarities and efficiency of creation of forms with a high amylopectin content in starch.Material and Methods. In 2007-2009 breeding and genetic features five waxu forms and eight samples of spring barley with typical amylopectin content in starch were studied. Biochemical analyses of grain, structural analysis of plant productivity, genetic analysis by components of the genetic variance, combining ability and heritability of quantitative traits in F1 in diallel cross system were conducted. In 2005-2013 the efficiency of waxy barley breeding via hybridization followed by selection and variety testing was studied.Results and Discussion. Biochemical and morpho-biological peculiarities by productivity elements of 13 spring barley samples and varieties with different fractional starch composition as well as the variability, correlation, genetic variance, general and specific combining ability, heritability in broad and narrow sense, predominance of additive and non-additive effects of genes of quantitative morphological features and amylopectin content in starch were established. The efficiency of creating valuable lines of spring barley with a high amylopectin content in starch was demonstrated.Conclusions. The work is of theoretical and practical importance, since breeding and genetic peculiarities by the level of plant productivity structural elements, genetic variance components and heritability of quantitative morphological features as well as amylopectin content in starch in spring barley forms with different fractional composition were established. New waxy lines of spring barley with a set of valuable economic features, which will be used as a source material in barley breeding for high amylopectin content in starch were created.

Heritability of Quantitative Traits with an Important Role for Improving Gladiolus hybridus Assortment

The purpose of the experiments is to estimate the variability and the heritability for some hybridcombinations of Gladiolus by calculating the coefficient of variation and the heritability in broad sense(H2) and in narrow sense (h2) for 5 ornamental characters. Knowing that a low value of the coefficientrepresents the guaranty that the morphological trait will be transmitted to descendents, the resultsare useful for the selection of elites. The present investigation was developed during 2012 - 2013 atUASVM Cluj-Napoca. The results show medium variability for most of the analyzed characters, whilehigh heritability in broad sense was recorded to all the cyclic combination used in the experiments.Furthermore, the value of the H2 was completed by the values of h2 ranging between 0.360-0.677..

Genetic Analysis of Tomato Fruit Ripening at Polypeptide Profiles Level through Quantitative and Multivariate Approaches

Multivariate analysis became essential in functional and structural Genomics because of the large quantity of biological data provided by these new research areas. Diallel mating design was widely applied to analyze the heritability of quantitative traits but it was recently used for approaching to the inheritance patterns of other levels of gene expression such as transcript profiles. Investigating the inheritance pattern of total polypeptide profiles with a diallel design remains as a vacancy subject. The objective of the present research was to infer the inheritance of total polypeptides profiles from tomato pericarp tissue at four different ripening stages in a diallel mating design including five recombinant inbred lines (RILs) and their ten second cycle hybrids (SCH). To achieve this objective, a multivariate analysis was applied to identify eventual inheritance patterns through a data mining approach and then univariate analyses were used to verify these patterns. Mainly dominance and also overdominance, though in a minor percentage, contributed to the gene actions involved in their genetic basis. Multivariate analysis was efficient in identifying inheritance patterns of total polypeptide profiles through a data mining approach, and univariate analyses largely verified the identified gene actions.

Biases in quantitative genetic analyses using open-pollinated progeny tests from natural tree populations

In plant quantitative genetic studies conducted ex situ, the large number of seeds produced per individual has promoted the use of open-pollinated progeny tests. In subsequent analyses, seeds collected on the same mother-plant are assumed to be half-sibs. The consequences of the departure from half-sib assumption in progeny tests have been investigated since the 1960s using simulation approaches and, more recently, using molecular-based experimental approaches. This review aims to synthesize the results and conclusions of these simulation and empirical studies. We focus on tree species, where controlled crosses are difficult to carry out experimentally and departures from half-sib assumptions occur frequently in natural populations. First, the average level of relatedness expected within maternal progeny for many tree populations is higher than that of half-sibs. This is the consequence of non-random mating resulting from the small number of effective pollen donors per female, unequal male reproductive success and/or selfing. As result, estimates of genetic variance and heritability for quantitative traits may be upward biased. Alternatively, inbreeding depression, dominance effects and the heterogeneity of the male gamete pool among females are often neglected, which may lead to underestimation of the heritability of traits. A correction based on the mean genetic relatedness between offspring and the relatedness between parents is often used to compensate those biases. However, such correction cannot accurately adjust the estimates in situations where variable levels of genetic relatedness among families, dominance effects or inbreeding depression exist within the progeny. An alternative and promising approach is the use of the “animal model” approach, which optimizes the use of molecular data and paternal information to estimate heritability more accurately.

Assumptions and properties of limiting pathway models for analysis of epistasis in complex traits.

For most complex traits, results from genome-wide association studies show that the proportion of the phenotypic variance attributable to the additive effects of individual SNPs, that is, the heritability explained by the SNPs, is substantially less than the estimate of heritability obtained by standard methods using correlations between relatives. This difference has been called the “missing heritability”. One explanation is that heritability estimates from family (including twin) studies are biased upwards. Zuk et al. revisited overestimation of narrow sense heritability from twin studies as a result of confounding with non-additive genetic variance. They propose a limiting pathway (LP) model that generates significant epistatic variation and its simple parametrization provides a convenient way to explore implications of epistasis. They conclude that over-estimation of narrow sense heritability from family data (‘phantom heritability’) may explain an important proportion of missing heritability. We show that for highly heritable quantitative traits large phantom heritability estimates from twin studies are possible only if a large contribution of common environment is assumed. The LP model is underpinned by strong assumptions that are unlikely to hold, including that all contributing pathways have the same mean and variance and are uncorrelated. Here, we relax the assumptions that underlie the LP model to be more biologically plausible. Together with theoretical, empirical, and pragmatic arguments we conclude that in outbred populations the contribution of additive genetic variance is likely to be much more important than the contribution of non-additive variance.

Evidence of Inbreeding Depression on Human Height

Stature is a classical and highly heritable complex trait, with 80%–90% of variation explained by genetic factors. In recent years, genome-wide association studies (GWAS) have successfully identified many common additive variants influencing human height; however, little attention has been given to the potential role of recessive genetic effects. Here, we investigated genome-wide recessive effects by an analysis of inbreeding depression on adult height in over 35,000 people from 21 different population samples. We found a highly significant inverse association between height and genome-wide homozygosity, equivalent to a height reduction of up to 3 cm in the offspring of first cousins compared with the offspring of unrelated individuals, an effect which remained after controlling for the effects of socio-economic status, an important confounder (χ2 = 83.89, df = 1; p = 5.2×10−20). There was, however, a high degree of heterogeneity among populations: whereas the direction of the effect was consistent across most population samples, the effect size differed significantly among populations. It is likely that this reflects true biological heterogeneity: whether or not an effect can be observed will depend on both the variance in homozygosity in the population and the chance inheritance of individual recessive genotypes. These results predict that multiple, rare, recessive variants influence human height. Although this exploratory work focuses on height alone, the methodology developed is generally applicable to heritable quantitative traits (QT), paving the way for an investigation into inbreeding effects, and therefore genetic architecture, on a range of QT of biomedical importance.

Somatic instability of the expanded CTG triplet repeat in myotonic dystrophy type 1 is a heritable quantitative trait and modifier of disease severity

Deciphering the contribution of genetic instability in somatic cells is critical to our understanding of many human disorders. Myotonic dystrophy type 1 (DM1) is one such disorder that is caused by the expansion of a CTG repeat that shows extremely high levels of somatic instability. This somatic instability has compromised attempts to measure intergenerational repeat dynamics and infer genotype-phenotype relationships. Using single-molecule PCR, we have characterized more than 17 000 de novo somatic mutations from a large cohort of DM1 patients. These data reveal that the estimated progenitor allele length is the major modifier of age of onset. We find no evidence for a threshold above which repeat length does not contribute toward age at onset, suggesting pathogenesis is not constrained to a simple molecular switch such as nuclear retention of the DMPK transcript or haploinsufficiency for DMPK and/or SIX5. Importantly, we also show that age at onset is further modified by the level of somatic instability; patients in whom the repeat expands more rapidly, develop the symptoms earlier. These data establish a primary role for somatic instability in DM1 severity, further highlighting it as a therapeutic target. In addition, we show that the level of instability is highly heritable, implying a role for individual-specific trans-acting genetic modifiers. Identifying these trans-acting genetic modifiers will facilitate the formulation of novel therapies that curtail the accumulation of somatic expansions and may provide clues to the role these factors play in the development of cancer, aging and inherited disease in the general population.

Genetic aspects of skeletal muscle strength and mass with relevance to sarcopenia.

Skeletal muscle is a highly heritable quantitative trait, with heritability estimates ranging 30-85% for muscle strength and 50-80% for lean mass. That strong genetic contribution indicates the possibility of using genetic information to individualize treatments for sarcopenia or even aid in prevention strategies through the use of genetic screening prior to the functional limitations. Though these possibilities provide the rationale for genetic studies of skeletal muscle traits, few genes have been identified that appear to contribute to variation in either skeletal muscle strength or mass phenotypes, and sarcopenia per se is remarkably understudied as a trait in this regard. This review examines the heritability of skeletal muscle traits, findings of linkage and genome-wide association analyses and impact of specific genes and gene-sequence variants on these traits as relevant to sarcopenia. Despite considerable work in the area, the genetic underpinnings of skeletal muscle traits remain largely unknown and the genetic aspects of sarcopenia are even less clear. Large-scale longitudinal clinical studies relying on advanced genome-wide association and other techniques are needed to provide further insights into the genes and gene variants that contribute to skeletal muscle strength and mass, and ultimately to susceptibility to sarcopenia.

QTL replication and targeted association highlight the nerve growth factor gene for nonverbal communication deficits in autism spectrum disorders

Autism Spectrum Disorder (ASD) has a heterogeneous etiology that is genetically complex. It is defined by deficits in communication and social skills and the presence of restricted and repetitive behaviors. Genetic analyses of heritable quantitative traits that correlate with ASD may reduce heterogeneity. With this in mind, deficits in nonverbal communication (NVC) were quantified based on items from the Autism Diagnostic Interview Revised. Our previous analysis of 228 families from the Autism Genetics Research Exchange (AGRE) repository reported 5 potential quantitative trait loci (QTL). Here we report an NVC QTL replication study in an independent sample of 213 AGRE families. One QTL was replicated (P<0.0004). It was investigated using a targeted-association analysis of 476 haplotype blocks with 708 AGRE families using the Family Based Association Test (FBAT). Blocks in two QTL genes were associated with NVC with a P-value of 0.001. Three associated haplotype blocks were intronic to the Nerve Growth Factor (NGF) gene (P=0.001, 0.001, 0.002), and one was intronic to KCND3 (P=0.001). Individual haplotypes within the associated blocks drove the associations (0.003, 0.0004 and 0.0002) for NGF and 0.0001 for KCND3. Using the same methods, these genes were tested for association with NVC in an independent sample of 1517 families from an Autism Genome Project (AGP). NVC was associated with a haplotype in an adjacent NGF block (P=0.0005) and one 46 kb away from the associated block in KCND3 (0.008). These analyses illustrate the value of QTL and targeted association studies for genetically complex disorders such as ASD. NGF is a promising risk gene for NVC deficits.

Functional Evaluation of HbF-Associated Region of BCL11A Locus

Abstract 2148The severity of the major β-globin disorders, sickle cell disease and β-thalassemia, is modified by the residual level of fetal hemoglobin (HbF, α2γ2). Reactivation of HbF by derepression of γ-globin gene expression constitutes a major therapeutic goal, though an incomplete understanding of globin gene regulation has limited such efforts. The postnatal level of HbF is a highly heritable quantitative trait. Genome-wide association (GWA) studies have identified several HbF-associated loci, including the BCL11A gene. BCL11A has been demonstrated to be a bona fide repressor of γ-globin expression in mouse and man. However, the mechanisms by which common genetic variation modulate BCL11A expression remain poorly understood. Numerous GWA studies, conducted in both healthy individuals and those with hemoglobinopathies, and including populations of European, Asian, and African ancestries, have consistently found that HbF-associated variants cluster within a 14-kb region of the second intron of BCL11A. At least twenty HbF-associated SNPs have been identified within this region, with various of these genetic markers considered as “tag SNPs” most strongly associated with HbF levels depending on the particular GWA study. Based on patterns of linkage disequilibrium among SNPs, several common haplotypes have been identified. The tag SNP-dense intronic region, more than 55 kb downstream of the BCL11A transcription start site, demonstrates evolutionary sequence conservation. Here we show that this region of BCL11A is decorated by epigenetic features in human erythroid precursors indicative of distal regulatory potential. Specifically, this intronic region is marked by the presence of the histone modifications H3K4me1 and H3K27ac and the absence of H3K4me3, indicating an enhancer signature. The erythroid transcription factors GATA1 and SCL/TAL1 co-occupy discrete sequences within this region, with the binding peaks of these master erythroid regulators overlapping those of the histone marks. Furthermore, this tag SNP-dense intronic region of BCL11A displays CpG hypomethylation and exhibits DNase I hypersensitive sites restricted to the erythroid lineage but not other lineages that express BCL11A. Moreover, in in vivo transient transgenic assays, this region displays erythroid-restricted enhancer activity. A minimal 1.8-kb sequence possessing erythroid enhancer function has been mapped. This region includes GATA1 and SCL/TAL1 binding sites. We hypothesize that common polymorphisms are in linkage disequilibrium with functional variants that modulate erythroid enhancer activity. These studies further delineate pathways critical for hemoglobin switching and serve as an example of how common genetic variation may influence traits by affecting non-coding regulatory elements. Disclosures:No relevant conflicts of interest to declare.

Why endophenotype development requires families

Endophenotypes are heritable quantitative traits that are associated with disease liability, can be measured in both affected and unaffected individuals, and provide much greater power to localize and identify risk genes for mental illness than does affection status alone. Traditionally, endophenotypic markers for psychiatric illnesses include in vivo neuroanatomic and functional magnetic resonance imaging measurements and indices of neurocognitive abilities. However, neurocognitive and neuroimaging measures are by no means the only classes of endophenotypes that could be useful for identifying genes for mental illness. Given the advantages of endophenotype-based strategies for elucidating the genetic underpinnings of psychiatric disorders, it would seem prudent to develop a wide range of putative endophenotypes. In order for a measure to be considered a valid endophenotype, it must meet a number of criteria. Specifically, the trait must (1) have moderate to high heritability, (2) be associated with the illness, (3) be independent of clinical state, and (4) impairment must co-segregate with the illness within a family, with non-affected family members showing impairment relative to the general population. While each of these criteria is critical, the heritability and co-segregation requirements are really what differentiate an endophenotype from a simple biomarker. At this time, one requires an experimental design that includes families to demonstrate both heritability and co-segregation. The assertion that novel endophenotypes can not be fully established without family data does not preclude work in unrelated individuals, rather that unrelated samples will only be able to nominate potential candidate endophenotypes that subsequently need to be confirmed in family-based experiments.

Life or death? A physiogenomic approach to understand individual variation in responses to hemorrhagic shock.

Severe hemorrhage due to trauma is a major cause of death throughout the world. It has often been observed that some victims are able to withstand hemorrhage better than others. For decades investigators have attempted to identify physiological mechanisms that distinguish survivors from nonsurvivors for the purpose of providing more informed therapies. As an alternative approach to address this issue, we have initiated a research program to identify genes and genetic mechanisms that contribute to this phenotype of survival time after controlled hemorrhage. From physiogenomic studies using inbred rat strains, we have demonstrated that this phenotype is a heritable quantitative trait, and is therefore a complex trait regulated by multiple genes. Our work continues to identify quantitative trait loci as well as potential epigenetic mechanisms that might influence survival time after severe hemorrhage. Our ultimate goal is to improve survival to traumatic hemorrhage and attendant shock via regulation of genetic mechanisms and to provide knowledge that will lead to genetically-informed personalized treatments.

Editorial [Hot Topic: Evolutionary Systems Biology (Guest Editor: Jianying Gu)

Systems biology has a long history as a theoretical framework in biology, positing that cellular systems possess emergent properties that can only be explained by the interactions among the components of an organism rather than by any individual component in itself. With the advent of the genomic era, data sets encompassing systems-wide measurements of gene complements, transcription, and protein expression are becoming available. Thoughtful integration of these data can lead to a systems-level understanding of the components and dynamics of cellular machineries and the development of practical methods for inferring and constructing network models of these interactions is well under way. As the creation of plausible network models of cellular systems becomes possible, comparison of systems in an evolutionary light promises to reveal the evolutionary forces that shape these systems. Systems are dynamic and selectable, that is, they respond to pressures brought to bear by changes in their environment. Therefore, the application of the methods of evolutionary biology within a systems biology framework can aid in identifying the concerted changes that drive the emergence of new phenotypes. A better understanding of systems evolution will greatly advance our knowledge about the complexity of gene regulation and help identify new therapeutic targets for effective treatment of various diseases. This special issue of Current Genomics is intended to provide a forum for researchers to share their experiences on all aspects of genome and systems evolution. This issue includes a review article discussing about the proteomics techniques that are capable of generating high quality data for systems biology research: Chen et al. reviewed recent advances in proteolysis, a key procedure prior to mass spectrometry and peptide mapping in proteomic studies of gene function. They showed that the proteolysis strategies can be accelerated by various electromagnetic waves, such as microwave-accelerated protein digestion, infrared-assisted proteolysis, ultraviolet-enhanced protein digestion, laser-assisted proteolysis, and future prospects. This issue also includes two review articles with a special emphasis on the systems biology of bacteria, ideal model organisms for evolutionary analyses of genome plasticity and adaptive phenotypes. Tang's review is focused on microbial metabolomics, which involves fast, high throughput characterization of the metabolite complements of a microorganism, and thus summarizes the global outcome of the interplay between the developmental processes and the environment. Selected topics illustrate the impact of metabolomics on the understanding of systems microbiology. Zhou et al. provide an overview of the recent advances in Streptomyces biology that have been driven by high throughput technologies. The omics based studies have revolutionized the understanding of system control and regulation dynamics of this group of bacterial of medicinal and industrial importance. Evolutionary systems biology approaches have also been applied to biomedical studies. Cai et al. provide a phylogenomic overview of the origin, distribution, diversity, and evolution of malarial proteases, a class of promising therapeutic targets for combating this devastating infectious disease that is responsible for over 1 million deaths yearly. Klemcke et al. introduce a novel physiogenomic approach to the study of hemorraghic shock, a major cause of death throughout the world. Their findings in heritable quantitative trait loci, as well as potential epigenetic mechanisms that might influence survival time after severe hemorrhage, may lead to the improvement in survival of traumatic hemorrhage and provide knowledge of genetically-informed personalized treatments. Overall, these reviews provide a fascinating survey of the combination of systems thinking and evolutionary analysis across the biological spectrum. As modeling approaches improve and as more data from more species become available, the study of systems evolution will clarify the links among the genotype, the phenotype and the selective pressures arising from the organism’s place in the environment. As an emerging field in the post genomic era, evolutionary systems biology promises to make profound contributions to our understanding of life.

Genetic influences on survival time after severe hemorrhage in inbred rat strains

To find a genetic basis for differential ability to survive severe hemorrhage, we previously showed eightfold differences in survival times among inbred rat strains. We assumed that rat strains had similar normalized blood volumes (NBV; ml/100 g body wt). As NBV might vary among strains and constitute one genetic variable affecting survival time to hemorrhage, in experiment 1 of the current studies we first measured total blood volumes and calculated NBV in specific inbred rat strains (Brown Norway/Medical College of Wisconsin, BN; Dark Agouti, DA; Fawn Hooded Hypertensive, FHH; Lewis, LEW; and Dahl Salt-Sensitive, SS) previously found to be divergent in survival time. NBV differed by 20% (P < 0.01; BN > SS > FHH = LEW = DA) and had a heritability (h(2)) of 0.56. Hence, differential survival times in our previously published study might reflect strain-dependent differences in NBV. Then studies were conducted wherein rats were catheterized and, ∼24 h later, 47% of their blood volume was removed; these rats were observed for a maximum of 4 h. In experiment 2, blood volumes were measured the day prior to hemorrhage. Percent survival and survival time did not differ among strains. To obviate possible confounding effects of blood volume determination, in experiment 3 the average NBV for each strain was used to determine hemorrhage volumes. Percent survival (P < 0.01) and survival times (P < 0.001) were different with DA demonstrating the best (62.5%, 190 ± 29 min) and BN the worst (0%, 52 ± 5 min) survival responses. These data indicate that both blood volume and survival time after hemorrhage in rats are heritable quantitative traits, and continue to suggest that genetic assessment of these phenotypes might lead to novel therapeutics to improve survival to hemorrhage.

Genetic Variants Associated with Optic Nerve Vertical Cup-to-Disc Ratio Are Risk Factors for Primary Open Angle Glaucoma in a US Caucasian Population

Genetically complex disorders, such as primary open angle glaucoma (POAG), may include highly heritable quantitative traits as part of the overall phenotype, and mapping genes influencing the related quantitative traits may effectively identify genetic risk factors predisposing to the complex disease. Recent studies have identified SNPs associated with optic nerve area and vertical cup-to-disc ratio (VCDR). The purpose of this study was to evaluate the association between these SNPs and POAG in a US Caucasian case-control sample. Five SNPs previously associated with optic disc area, or VCDR, were genotyped in 539 POAG cases and 336 controls. Genotype data were analyzed for single SNP associations and SNP interactions with VCDR and POAG. SNPs associated with VCDR rs1063192 (CDKN2B) and rs10483727 (SIX1/SIX6) were also associated with POAG (P = 0.0006 and P = 0.0043 for rs1063192 and rs10483727, respectively). rs1063192, associated with smaller VCDR, had a protective effect (odds ratio [OR] = 0.73; 95% confidence interval [CI], 0.58-0.90), whereas rs10483727, associated with larger VCDR, increased POAG risk (OR = 1.33; 95% CI, 1.08-1.65). POAG risk associated with increased VCDR was significantly influenced by the C allele of rs1900004 (ATOH7), associated with increased optic nerve area (P-interaction = 0.025; OR = 1.89; 95% CI, 1.22-2.94). Genetic variants influencing VCDR are associated with POAG in a US Caucasian population. Variants associated with optic nerve area are not independently associated with disease but can influence the effects of VCDR variants suggesting that increased optic disc area can significantly contribute to POAG risk when coupled with risk factors controlling VCDR.

Variabilidade e herdabilidade de caracteres qualitativos relacionados à qualidade de forragem de clones de capim-elefante na Zona da Mata de Pernambuco

Objetivou-se avaliar a variabilidade e herdabilidade de caracteres quantitativos relacionados à qualidade de forragem de 32 clones de capim-elefante (três testemunhas locais, da Zona da Mata de Pernambuco, e os demais provenientes da RENACE/CNPGL). Utilizou-se delineamento inteiramente casualizado com testemunhas adicionais e aplicou-se a análise de variância por meio do procedimento de famílias com testemunhas intercalares. A avaliação foi realizada no período seco, aos 60 dias de crescimento. Foram observadas diferenças significativas entre os clones para as características fibra em detergente ácido de lâmina foliar e matéria orgânica no colmo, com médias de 34,05 e 78,83%, respectivamente. De maneira geral, a herdabilidade dos caracteres qualitativos foi baixa, inclusive com valores nulos para proteína bruta e fibra em detergente neutro de lâmina foliar e digestibilidade in vitro da MS da lâmina e do colmo. A composição química e a digestibilidade dos clones avaliados foram similares. Há poucas possibilidades de ganho na seleção de caracteres qualitativos, tendo em vista a baixa variabilidade e herdabilidade dos caracteres estudados.

Allele-specific expression of TGFBR1 in colon cancer patients

The genetic component of colorectal cancer (CRC) predisposition has been only partially explained. We recently suggested that a subtle decrease in the expression of one allele of the TGFBR1 gene was a heritable quantitative trait predisposing to CRC. Here, we refined the measurements of allele-specific expression (ASE) of TGFBR1 in a population-based series of CRC patients and controls. Five single-nucleotide polymorphisms (SNPs) in the 3′-untranslated region of the gene were genotyped and used for ASE determination by pyrosequencing. After eliminating non-informative samples and samples with RNA of insufficient quality 109 cases and 125 controls were studied. Allelic ratios ranged between 0.74 and 1.69 without evidence of bimodality or cutoff points for ‘ASE’ versus ‘non-ASE’. Treating ASE as a continuous variable, cases had non-significantly different values than controls (P = 0.081 when comparing means by permutation test). However, cases had significantly higher ASE values when comparing medians by permutation test (P = 0.0027) and when using Wilcoxon test (P = 0.0094). We conclude that with the present-day technology, ASE differences between individuals and between cases and controls are too subtle to be used to assess CRC risk. More advanced technology is expected to resolve this issue as well as the low informativity caused by the limited heterozygosity of transcribed SNPs.