Comparison of identity by descent and identity by state for detecting genetic regions under selection in a sorghum pedigree breeding program

Seventy sorghum inbred lines which formed part of the Queensland Department of Primary Industries (QDPI) sorghum breeding program were screened with 104 previously mapped RFLP markers. The lines were related by pedigree and consisted of ancestral source lines, intermediate lines and recent releases from the program. We compared the effect of defining marker alleles using either identity by state (IBS) or identity by descent (IBD) on our capacity to trace markers through the pedigree and detect evidence of selection for particular alleles. Allelic identities defined using IBD were much more sensitive for detecting non-Mendelian segregation in this pedigree. Only one marker allele showed significant evidence of selection when IBS was used compared with ten regions with particular allelic identities when IBD was used. Regions under selection were compared with the location of QTLs for agronomic traits known to be under selection in the breeding program. Only two of the ten regions were associated with known QTLs that matched with knowledge of the agronomic characteristics of the ancestral lines. Some of the other regions were hypothesised to be associated with genes for particular traits based on the properties of the ancestral source lines.

Hereditary pancreatitis in a family of Aboriginal descent

Hereditary pancreatitis is an autosomal dominant condition characterized by recurrent episodes of acute pancreatitis, usually starting in childhood. We present a family who was ascertained when an 11-year-old girl presented with an episode of acute pancreatitis. Her father and other family members had also had recurrent bouts of acute pancreatitis. Genetic testing revealed a pathogenic mutation in the cationic trypsinogen gene in the proband, her father and her paternal grandmother. As far as we are aware, this is the first Aboriginal kindred with mutation-proven hereditary pancreatitis. Hereditary pancreatitis is an important differential diagnosis to consider in a patient with recurrent episodes of acute pancreatitis with no obvious precipitating cause. This family is of Aboriginal descent and the implications of the family's background are also discussed when considering the aetiology of the condition. We emphasize the need to ascertain a full family history from patients with a history of repeated episodes of acute pancreatitis and also emphasize the need to avoid ethnic stereotypes when assessing patients.

Assumption-free estimation of heritability from genome-wide identity-by-descent sharing between full siblings

The study of continuously varying, quantitative traits is important in evolutionary biology, agriculture, and medicine. Variation in such traits is attributable to many, possibly interacting, genes whose expression may be sensitive to the environment, which makes their dissection into underlying causative factors difficult. An important population parameter for quantitative traits is heritability, the proportion of total variance that is due to genetic factors. Response to artificial and natural selection and the degree of resemblance between relatives are all a function of this parameter. Following the classic paper by R. A. Fisher in 1918, the estimation of additive and dominance genetic variance and heritability in populations is based upon the expected proportion of genes shared between different types of relatives, and explicit, often controversial and untestable models of genetic and non-genetic causes of family resemblance. With genome-wide coverage of genetic markers it is now possible to estimate such parameters solely within families using the actual degree of identity-by-descent sharing between relatives. Using genome scans on 4,401 quasi-independent sib pairs of which 3,375 pairs had phenotypes, we estimated the heritability of height from empirical genome-wide identity-by-descent sharing, which varied from 0.374 to 0.617 (mean 0.498, standard deviation 0.036). The variance in identity-by-descent sharing per chromosome and per genome was consistent with theory. The maximum likelihood estimate of the heritability for height was 0.80 with no evidence for non-genetic causes of sib resemblance, consistent with results from independent twin and family studies but using an entirely separate source of information. Our application shows that it is feasible to estimate genetic variance solely from within- family segregation and provides an independent validation of previously untestable assumptions. Given sufficient data, our new paradigm will allow the estimation of genetic variation for disease susceptibility and quantitative traits that is free from confounding with non-genetic factors and will allow partitioning of genetic variation into additive and non-additive components.

A gradient descent algorithm for minimizing amino acid coupling reactions when synthesizing cyclic-peptide libraries

Combinatorial chemistry has become an invaluable tool in medicinal chemistry for the identification of new drug leads. For example, libraries of predetermined sequences and head-to-tail cyclized peptides are routinely synthesized in our laboratory using the IRORI approach. Such libraries are used as molecular toolkits that enable the development of pharmacophores that define activity and specificity at receptor targets. These libraries can be quite large and difficult to handle, due to physical and chemical constraints imposed by their size. Therefore, smaller sub-libraries are often targeted for synthesis. The number of coupling reactions required can be greatly reduced if the peptides having common amino acids are grouped into the same sub-library (batching). This paper describes a schedule optimizer to minimize the number of coupling reactions by rotating and aligning sequences while simultaneously batching. The gradient descent method thereby reduces the number of coupling reactions required for synthesizing cyclic peptide libraries. We show that the algorithm results in a 75% reduction in the number of coupling reactions for a typical cyclic peptide library.

Genetic covariation of pelvic organ and elbow mobility in twins and their sisters

A range of environmental risk factors, with childbirth the most notable, have been associated with the development of pelvic organ prolapse and urinary incontinence. However, indications of genetic influence (positive family histories, ethnic differences) have prompted research into the heritability of measures of pelvic organ descent and joint mobility, which have also been associated with prolapse and incontinence. Genes appear to influence about half of the variation in these measures and, furthermore, the pelvic organ measures are associated with elbow hyperextension at a phenotypic level (r approximate to .2). We examined these measures in young, nulligravid women to determine if their association is due to a common genetic source. Data were collected from 178 Caucasian female co-twins and non-twin sisters, 50 of whom returned to be retested, which allowed reliability to be estimated and unreliable variance to be isolated in the multivariate analyses. Structural equation modeling was used to estimate genetic associations between latent elbow and bladder mobility factors for which heritabilities were estimated to be 0.80 and 0.64 respectively. The association between these factors appeared to be mediated by common genes (genetic r = .48, non-shared environmental r = -.06), with genes influencing latent elbow mobility accounting for 14% of the variation in latent bladder mobility. We speculate that genes influencing connective tissue structure may underlie this association.

Using identity-by-de scent information in affected sib pairs to increase the efficiency of genetic association studies

T he aim of this study was to determine whether identity-by-descent (IBD) information for affected sib pairs (ASPs) can be used to select a sample of cases for a genetic case-control study which will provide more power for detecting association with loci in a known linkage region. By modeling the expected frequency of the disease allele in ASPs showing IBD sharing of 0, 1, or 2 alleles, and considering additive, recessive, and dominant disease models, we show that cases selected from IBD 2 families are best for this purpose, followed by those selected from IBD 1 families; least useful are cases selected from IBD 0 families.

Simulating the effects of dominance and epistasis on selection response in the CIMMYT wheat breeding program using QuCim

Plant breeders use many different breeding methods to develop superior cultivars. However, it is difficult, cumbersome, and expensive to evaluate the performance of a breeding method or to compare the efficiencies of different breeding methods within an ongoing breeding program. To facilitate comparisons, we developed a QU-GENE module called QuCim that can simulate a large number of breeding strategies for self-pollinated species. The wheat breeding strategy Selected Bulk used by CIMMYT's wheat breeding program was defined in QuCim as an example of how this is done. This selection method was simulated in QuCim to investigate the effects of deviations from the additive genetic model, in the form of dominance and epistasis, on selection outcomes. The simulation results indicate that the partial dominance model does not greatly influence genetic advance compared with the pure additive model. Genetic advance in genetic systems with overdominance and epistasis are slower than when gene effects are purely additive or partially dominant. The additive gene effect is an appropriate indicator of the change in gene frequency following selection when epistasis is absent. In the absence of epistasis, the additive variance decreases rapidly with selection. However, after several cycles of selection it remains relatively fixed when epistasis is present. The variance from partial dominance is relatively small and therefore hard to detect by the covariance among half sibs and the covariance among full sibs. The dominance variance from the overdominance model can be identified successfully, but it does not change significantly, which confirms that overdominance cannot be utilized by an inbred breeding program. QuCim is an effective tool to compare selection strategies and to validate some theories in quantitative genetics.

Petrology and geochemistry of early cretaceous bimodal continental flood volcanism of the NW Etendeka, Namibia. Part 2: Characteristics and petrogenesis of the high-Ti latite and high-Ti and low-Ti voluminous quartz latite eruptives

As a result of their relative concentration towards the respective Atlantic margins, the silicic eruptives of the Parana (Brazil)-Etendeka large igneous province are disproportionately abundant in the Etendeka of Namibia. The NW Etendeka silicic units, dated at similar to132 Ma, occupy the upper stratigraphic levels of the volcanic sequences, restricted to the coastal zone, and comprise three latites and five quartz latites (QL). The large-volume Fria QL is the only low-Ti type. Its trace element and isotopic signatures indicate massive crustal input. The remaining NW Etendeka silicic units are enigmatic high-Ti types, geochemically different from low-Ti types. They exhibit chemical affinities with the temporally overlapping Khumib high-Ti basalt (see Ewart et al. Part 1) and high crystallization temperatures (greater than or equal to980 to 1120degreesC) inferred from augite and pigeonite phenocrysts, both consistent with their evolution from a mafic source. Geochemically, the high-Ti units define three groups, thought genetically related. We test whether these represent independent liquid lines of descent from a common high-Ti mafic parent. Although the recognition of latites reduces the apparent silica gap, difficulty is encountered in fractional crystallization models by the large volumes of two QL units. Numerical modelling does, however, support large-scale open-system fractional crystallization, assimilation of silicic to basaltic materials, and magma mixing, but cannot entirely exclude partial melting processes within the temporally active extensional environment. The fractional crystallization and mixing signatures add to the complexity of these enigmatic and controversial silicic magmas. The existence, however, of temporally and spatially overlapping high-Ti basalts is, in our view, not coincidental and the high-Ti character of the silicic magmas ultimately reflects a mantle signature.

Prevalence of rectocele in young nulliparous women

Background: It is generally assumed that fascial defects in the rectovaginal septum are the result of childbirth. However, rectoceles do occur in women who have never delivered vaginally. Aims: To determine the incidence of rectocele in a cohort of asymptomatic, young nulliparous women. Methods: Observational cohort study on 178 nulliparous caucasian women (aged 18-24) recruited for a twin study of pelvic floor dysfunction. All women were interviewed and examined by translabial ultrasound, supine and after voiding. In 52 women, 3D imaging was obtained and 171 datasets were complete and available for analysis. Ultrasound findings were reviewed for rectovaginal septal integrity by an assessor blinded against interview and demographic data for rectovaginal septal integrity. Results: A discontinuity of the anterior rectal wall with extrusion of rectal mucosa or contents (depth of ! 10 mm) was observed in 21/171 (12%). The depth of this herniation ranged from 10 to 25 mm and was filled with stool (n = 10) or rectal mucosa (n = 11). Defects were associated with a higher BMI (P = 0.049), with the complaint of constipation (P = 0.049) and non-significantly with straining at stool (P = 0.09). Descent of the ampulla to beyond the level of the symphysis pubis without fascial defect, that is, significant perineal relaxation, was observed in 23/171 (13%). Conclusions: Twelve percent of 171 young nulligravid caucasian women showed a defect of the rectovaginal septum. Associations were observed with higher body mass index and a history of constipation. It is hypothesised that in some women defects of the rectovaginal septum and perineal hypermobility may be congenital in nature.

Genetic time-series analysis identifies a major QTL for in vivo alcohol metabolism not predicted by in vitro studies of structural protein polymorphism at the ADH1B or ADH1C loci

After ingestion of a standardized dose of ethanol, alcohol concentrations were assessed, over 3.5 hours from blood (six readings) and breath (10 readings) in a sample of 412 MZ and DZ twins who took part in an Alcohol Challenge Twin Study (ACTS). Nearly all participants were subsequently genotyped on two polymorphic SNPs in the ADH1B and ADH1C loci known to affect in vitro ADH activity. In the DZ pairs, 14 microsatellite markers covering a 20.5 cM region on chromosome 4 that includes the ADH gene family were assessed, Variation in the timed series of autocorrelated blood and breath alcohol readings was studied using a bivariate simplex design. The contribution of a quantitative trait locus (QTL) or QTL's linked to the ADH region was estimated via a mixture of likelihoods weighted by identity-by-descent probabilities. The effects of allelic substitution at the ADH1B and ADH1C loci were estimated in the means part of the model simultaneously with the effects sex and age. There was a major contribution to variance in alcohol metabolism due to a QTL which accounted for about 64% of the additive genetic covariation common to both blood and breath alcohol readings at the first time point. No effects of the ADH1B*47His or ADH1C*349Ile alleles on in vivo metabolism were observed, although these have been shown to have major effects in vitro. This implies that there is a major determinant of variation for in vivo alcohol metabolism in the ADH region that is not accounted for by these polymorphisms. Earlier analyses of these data suggested that alcohol metabolism is related to drinking behavior and imply that this QTL may be protective against alcohol dependence.

Population-based continuous optimization, probabilistic modelling and mean shift

Evolutionary algorithms perform optimization using a population of sample solution points. An interesting development has been to view population-based optimization as the process of evolving an explicit, probabilistic model of the search space. This paper investigates a formal basis for continuous, population-based optimization in terms of a stochastic gradient descent on the Kullback-Leibler divergence between the model probability density and the objective function, represented as an unknown density of assumed form. This leads to an update rule that is related and compared with previous theoretical work, a continuous version of the population-based incremental learning algorithm, and the generalized mean shift clustering framework. Experimental results are presented that demonstrate the dynamics of the new algorithm on a set of simple test problems.

Coupled thermal, structural and vibrational analysis of a hypersonic engine for flight test

This paper describes a relatively simple and quick method for implementing aerodynamic heating models into a finite element code for non-linear transient thermal-structural and thermal-structural-vibrational analyses of a Mach 10 generic HyShot scramjet engine. The thermal-structural-vibrational response of the engine was studied for the descent trajectory from 60 to 26 km. Aerodynamic heating fluxes, as a function of spatial position and time for varying trajectory points, were implemented in the transient heat analysis. Additionally, the combined effect of varying dynamic pressure and thermal loads with altitude was considered. This aero-thermal-structural analysis capability was used to assess the temperature distribution, engine geometry distortion and yielding of the structural material due to aerodynamic heating during the descent trajectory, and for optimising the wall thickness, nose radius of leading edge, etc. of the engine intake. A structural vibration analysis was also performed following the aero-thermal-structural analysis to determine the changes in natural frequencies of the structural vibration modes that occur at the various temperatures associated with the descent trajectory. This analysis provides a unique and relatively simple design strategy for predicting and mitigating the thermal-structural-vibrational response of hypersonic engines. (C) 2006 Elsevier SAS. All rights reserved.

Solution structure and characterization of the LGR8 receptor binding surface of insulin-like peptide 3

Insulin-like peptide 3 (INSL3), a member of the relaxin peptide family, is produced in testicular Leydig cells and ovarian thecal cells. Gene knock-out experiments have identified a key biological role in initiating testes descent during fetal development. Additionally, INSL3 has an important function in mediating male and female germ cell function. These actions are elicited via its recently identified receptor, LGR8, a member of the leucine-rich repeat-containing G-protein- coupled receptor family. To identify the structural features that are responsible for the interaction of INSL3 with its receptor, its solution structure was determined by NMR spectroscopy together with in vitro assays of a series of B-chain alanine-substituted analogs. Synthetic human INSL3 was found to adopt a characteristic relaxin/ insulin-like fold in solution but is a highly dynamic molecule. The four termini of this two-chain peptide are disordered, and additional conformational exchange is evident in the molecular core. Alanine-substituted analogs were used to identify the key residues of INSL3 that are responsible for the interaction with the ectodomain of LGR8. These include Arg(B16) and Val(B19), with His(B12) and Arg(B20) playing a secondary role, as evident from the synergistic effect on the activity in double and triple mutants involving these residues. Together, these amino acids combine with the previously identified critical residue, Trp(B27), to form the receptor binding surface. The current results provide clear direction for the design of novel specific agonists and antagonists of this receptor.

HLA and Genomewide Allele Sharing in Dizygotic Twins

Gametic selection during fertilization or the effects of specific genotypes on the viability of embryos may cause a skewed transmission of chromosomes to surviving offspring. A recent analysis of transmission distortion in humans reported significant excess sharing among full siblings. Dizygotic (DZ) twin pairs are a special case of the simultaneous survival of two genotypes, and there have been reports of DZ pairs with excess allele sharing around the HLA locus, a candidate locus for embryo survival. We performed an allele-sharing study of 1,592 DZ twin pairs from two independent Australian cohorts, of which 1,561 pairs were informative for linkage on chromosome 6. We also analyzed allele sharing in 336 DZ twin pairs from The Netherlands. We found no evidence of excess allele sharing, either at the HLA locus or in the rest of the genome. In contrast, we found evidence of a small but significant (P = .003 for the Australian sample) genomewide deficit in the proportion of two alleles shared identical by descent among DZ twin pairs. We reconciled conflicting evidence in the literature for excess genomewide allele sharing by performing a simulation study that shows how undetected genotyping errors can lead to an apparent deficit or excess of allele sharing among sibling pairs, dependent on whether parental genotypes are known. Our results imply that gene-mapping studies based on affected sibling pairs that include DZ pairs will not suffer from false-positive results due to loci involved in embryo survival.

Identification of the semaphorin receptor PLXNA2 as a candidate for susceptibility to schizophrenia

The discovery of genetic factors that contribute to schizophrenia susceptibility is a key challenge in understanding the etiology of this disease. Here, we report the identification of a novel schizophrenia candidate gene on chromosome 1q32, plexin A2 (PLXNA2), in a genome-wide association study using 320 patients with schizophrenia of European descent and 325 matched controls. Over 25 000 single-nucleotide polymorphisms (SNPs) located within approximately 14 000 genes were tested. Out of 62 markers found to be associated with disease status, the most consistent finding was observed for a candidate locus on chromosome 1q32. The marker SNP rs752016 showed suggestive association with schizophrenia (odds ratio (OR) = 1.49, P = 0.006). This result was confirmed in an independent case control sample of European Americans (combined OR = 1.38, P = 0.035) and similar genetic effects were observed in smaller subsets of Latin Americans (OR = 1.26) and Asian Americans (OR = 1.37). Supporting evidence was also obtained from two family-based collections, one of which reached statistical significance (OR = 2.2, P = 0.02). High-density SNP mapping showed that the region of association spans approximately 60 kb of the PLXNA2 gene. Eight out of 14 SNPs genotyped showed statistically significant differences between cases and controls. These results are in accordance with previous genetic findings that identified chromosome 1q32 as a candidate region for schizophrenia. PLXNA2 is a member of the transmembrane semaphorin receptor family that is involved in axonal guidance during development and may modulate neuronal plasticity and regeneration. The PLXNA2 ligand semaphorin 3A has been shown to be upregulated in the cerebellum of individuals with schizophrenia. These observations, together with the genetic results, make PLXNA2 a likely candidate for the 1q32 schizophrenia susceptibility locus.