Mendelian Analysis Research Articles

GWAS summary-based pathway analysis correcting for the genetic confounding impact of environmental exposures

Genome-wide association study (GWAS)-based pathway association analysis is a powerful approach for the genetic studies of human complex diseases. However, the genetic confounding effects of environment exposure-related genes can decrease the accuracy of GWAS-based pathway association analysis of target diseases. In this study, we developed a pathway association analysis approach, named Mendelian randomization-based pathway enrichment analysis (MRPEA), which was capable of correcting the genetic confounding effects of environmental exposures, using the GWAS summary data of environmental exposures. After analyzing the real GWAS summary data of cardiovascular disease and cigarette smoking, we observed significantly improved performance of MRPEA compared with traditional pathway association analysis (TPAA) without adjusting for environmental exposures. Further, simulation studies found that MRPEA generally outperformed TPAA under various scenarios. We hope that MRPEA could help to fill the gap of TPAA and identify novel causal pathways for complex diseases.

The primitively social behavior of Euglossa cordata (Hymenoptera, Apidae, Euglossini): a view from the perspective of kin selection theory and models of reproductive skew

The present study investigated the level of reproductive skew during the reactivation processes of 11 nests of Euglossa cordata. Behavioral observations associated with kinship analysis between offspring and females involved in these processes were carried out. Different types of associations between females occurred in these reactivations: between mothers and daughters, sisters, cousins, and unrelated females. Behavioral observations and Mendelian segregation analysis at 12 microsatellite loci attributed all the offspring to the dominant female of each nest. The results revealed a full reproductive skew at the different processes of reactivation, irrespective of the type of association between females. Thus, our data indicate that reproductive skew was not associated with genetic relatedness in E. cordata.

Analysis of Mendelian inheritance and genetic linkage in microsatellite loci of Eucalyptus urophylla S.T. Blake.

Eucalyptus urophylla is an important species in the Brazilian forest sector due to its rapid growth rates and resistance to disease. The aim of this study was to verify Mendelian inheritance, genetic linkage, and genotypic disequilibrium for 15 microsatellite loci, with the goal of producing a robust set of genetic markers. Mendelian inheritance and genetic linkage analyses were carried out using genotypes from maternal trees, and their open-pollinated seeds and genotypic disequilibrium were assessed using adult trees. By comparing heterozygous maternal genotypes and their seeds, we found no significant deviations from the expected 1:1 Mendelian segregation and the expected 1:1:1:1 segregation hypothesis for pairwise loci. For adult trees, we did not find strong evidence of genotypic imbalance for pairwise loci. Our results indicated that the analyzed set of microsatellite loci could be used to carry out analyses of genetic diversity, mating system, and parentage in E. urophylla.

Pedigree-Defined Haplotypes and Their Applications to Genetic Studies.

A haplotype is a string of nucleotides or alleles at nearby loci on one chromosome, usually inherited as a unit. Within the major histocompatibility complex (MHC) region on human chromosome 6p, independent population studies of multiple families have identified conserved extended haplotypes (CEHs) that segregate as long stretches (≥1 megabase) of essentially identical DNA sequence at relatively high (≥0.5 %) population frequency ("genetic fixity"). CEHs were first identified through segregation analysis in the early 1980s. In European Caucasian populations, the most frequent 30 CEHs account for at least one-third of all MHC haplotypes. These CEHs provide all of the known individual MHC susceptibility and protective genetic markers within those populations for several complex genetic diseases. Haplotypes are rigorously determined directly by sequencing single chromosomes or by Mendelian segregation analysis using families with informative genotypes. Four parental haplotypes are assigned unambiguously using genotypes from the two parents and from two of their haploidentical (to each other) children. However, the most common current technique to phase haplotypes is probabilistic statistical imputation, using unrelated subjects. Such probabilistic techniques have failed to detect CEHs and are thus of questionable value in identifying long-range haplotype structure and, consequently, genetic structure-function relationships. Finally, with haplotypes rigorously defined, association studies can determine frequencies of alleles among unrelated patient haplotypes vs. those among only unaffected family members (i.e., control alleles/haplotypes). Such studies reduce, as much as possible, the confounding effects of population stratification common to all genetic studies.

Genetic control of flowering time in rice: integration of Mendelian genetics and genomics.

Integration of previous Mendelian genetic analyses and recent molecular genomics approaches, such as linkage mapping and QTL cloning, dramatically strengthened our current understanding of genetic control of rice flowering time. Flowering time is one of the most important agronomic traits for seed production in rice (Oryza sativa L.). It is controlled mainly by genes associated with photoperiod sensitivity, particularly in short-day plants such as rice. Since the early twentieth century, rice breeders and researchers have been interested in elucidating the genetic basis of flowering time because its modification is important for regional adaptation and yield optimization. Although flowering time is a complex trait controlled by many quantitative trait loci (QTLs), classical genetic studies have shown that many associated genes are inherited in accordance with Mendelian laws. Decoding the rice genome sequence opened a new era in understanding the genetic control of flowering time on the basis of genome-wide mapping and gene cloning. Heading date 1 (Hd1) was the first flowering time QTL to be isolated using natural variation in rice. Recent accumulation of information on rice genome has facilitated the cloning of other QTLs, including those with minor effects on flowering time. This information has allowed us to rediscover some of the flowering genes that were identified by classical Mendelian genetics. The genes characterized so far, including Hd1, have been assigned to specific photoperiod pathways. In this review, we provide an overview of the studies that led to an in-depth understanding of the genetic control of flowering time in rice, and of the current state of improving and fine-tuning this trait for rice breeding.

Monitoring Wnt Signaling in Zebrafish Using Fluorescent Biosensors.

In this chapter, we are presenting methods to monitor and quantify in vivo canonical Wnt signaling activities at single-cell resolution in zebrafish. Our technology is based on artificial enhancers, obtained by polymerization of TCF binding elements, cloned upstream to ubiquitous or tissue-specific promoters. The different promoter/enhancer combinations are used to drive fluorescent protein reporter constructs integrated in the zebrafish germline by microinjection of fertilized zebrafish eggs. Fish with a single integration site are selected by Mendelian analysis of fluorescent carriers, and heterozygous offspring are used to monitor and quantify canonical Wnt activities. Open source public domain software such as ImageJ/Fiji is used to calculate the integrated densities in the region of interest and compare the effect of experimental conditions on control and treated animals.

A NK complex-linked locus restricts the spread of herpes simplex virus type 1 in the brains of C57BL/6 mice.

The most frequent cause of sporadic viral encephalitis in western countries is Herpes simplex virus (HSV). Despite treatment, mortality rates reach 20-30% while survivors often suffer from significant morbidity. In mice, resistance to lethal Herpes simplex encephalitis (HSE) is multifactorial and influenced by mouse and virus strain as well as route of infection. The ability to restrict viral spread in the brain is one factor contributing to resistance. After infection of the oral mucosa with HSV type 1 (HSV-1), virus spreads throughout the brains of susceptible strains but is restricted in resistant C57BL/6 mice. To further investigate restriction of viral spread in the brain, mendelian analysis was combined with studies of congenic, intra-natural killer complex (intra-NKC) recombinant and antibody-depleted mice. Results from mendelian analysis support the restriction of viral spread as a dominant trait and consistent with a single gene effect. In congenic mice, the locus maps to the NKC on chromosome 6 and is provisionally termed Herpes Resistance Locus 2 (Hrl2). In intra-NKC recombinants, the locus is further mapped to the segment Cd69 through D6Wum34; a different location from previously identified loci (Hrl and Rhs1) also associated with HSV-1 infection. Studies with antibody-depleted mice indicate the effect of this locus is mediated by NK1.1(+) expressing cells. This model increases our knowledge of lethal HSE, which may lead to new treatment options.

Vitamin D status and hypertension: a review.

Vitamin D is a steroid prohormone synthesized in the skin following ultraviolet exposure and also achieved through supplemental or dietary intake. While there is strong evidence for its role in maintaining bone and muscle health, there has been recent debate regarding the role of vitamin D deficiency in hypertension based on conflicting epidemiological evidence. Thus, we conducted a scoping systematic literature review and meta-analysis of all observational studies published up to early 2014 in order to map trends in the evidence of this association. Mixed-effect meta-analysis was performed to pool risk estimates from ten prospective studies (n=58,262) (pooled risk for incident hypertension, relative risk [RR] =0.76 (0.63–0.90) for top vs bottom category of 25-hydroxyvitamin D [25OHD]) and from 19 cross-sectional studies (n=90,535) (odds ratio [OR] =0.79 (0.73–0.87)). Findings suggest that the better the assessed quality of the respective study design, the stronger the relationship between higher 25OHD levels and hypertension risk (RR =0.67 (0.51–0.88); OR =0.77 (0.72–0.89)). There was significant heterogeneity among the findings for both prospective and cross-sectional studies, but no evidence of publication bias was shown. There was no increased risk of hypertension when the participants were of older age or when they were vitamin D deficient. Younger females showed strong associations between high 25OHD levels and hypertension risk, especially in prospective studies (RR =0.36 (0.18–0.72); OR =0.62 (0.44–0.87)). Despite the accumulating evidence of a consistent link between vitamin D and blood pressure, these data are observational, so questions still remain in relation to the causality of this relationship. Further studies either combining existing raw data from available cohort studies or conducting further Mendelian analyses are needed to determine whether this represents a causal association. Large randomized controlled trials are also needed to determine whether vitamin supplementation may be beneficial in the prevention or the treatment of hypertension.

T-DNA Inheritance Stability of Resveratrol Rice Iksan526 over Multi-generations

Confirmation of T-DNA inheritance and stability requires testing of several parameters such as phenotypic performance of transgenic lines, transgene integrity structure and expression stability for at least three consecutive generations, and Mendelian inheritance analysis, which are very important to transgenic breeding and commercialization of genetically modified crops (GMOs). In the present study, we measured nine agronomic and yield-related traits of Iksan526 and confirmed stable phenotypic performance comparing to the donor variety Dongjin over three years. Transgene integrity structure, flanking sequence, functional element copy numbers, absence of backbone sequence and transgene expression were all verified in Iksan526 over three consecutive generations, indicating a stable inheritance of the transgene. In addition, phenotypic and genotypic segregation were analyzed on F2 and F3 populations derived from a cross of Dongjin/Iksan526, and results complied with Mendel’s law of segregation based on single transgene locus. This study demonstrated detailed analyses and confirmation of transgene event Iksan526 which is crucial for commercialization of GMO.

Diagnosis of an imprinted-gene syndrome by a novel bioinformatics analysis of whole-genome sequences from a family trio.

Whole-genome sequencing and whole-exome sequencing are becoming more widely applied in clinical medicine to help diagnose rare genetic diseases. Identification of the underlying causative mutations by genome-wide sequencing is greatly facilitated by concurrent analysis of multiple family members, most often the mother–father–proband trio, using bioinformatics pipelines that filter genetic variants by mode of inheritance. However, current pipelines are limited to Mendelian inheritance patterns and do not specifically address disorders caused by mutations in imprinted genes, such as forms of Angelman syndrome and Beckwith–Wiedemann syndrome. Using publicly available tools, we implemented a genetic inheritance search mode to identify imprinted-gene mutations. Application of this search mode to whole-genome sequences from a family trio led to a diagnosis for a proband for whom extensive clinical testing and Mendelian inheritance-based sequence analysis were nondiagnostic. The condition in this patient, IMAGe syndrome, is likely caused by the heterozygous mutation c.832A>G (p.Lys278Glu) in the imprinted gene CDKN1C. The genotypes and disease status of six members of the family are consistent with maternal expression of the gene, and allele-biased expression was confirmed by RNA-Seq for the heterozygotes. This analysis demonstrates that an imprinted-gene search mode is a valuable addition to genome sequence analysis pipelines for identifying disease-causative variants.

Whitebacked planthopper Sogatella furcifera (Horváth) (Homoptera: Delphacidae) resistance in rice variety Sinna Sivappu

Whitebacked planthopper (WBPH) along with brown planthopper (BPH) has emerged as a major pest of rice in several Asian countries. Development and cultivation of varieties resistant to both planthoppers is an ecologically acceptable strategy to manage these pests. Sinna Sivappu, a Sri Lankan landrace, was reported to be resistant to both planthoppers. While inheritance of BPH resistance has been reported, the genetics of WBPH resistance in this variety is not known. Using a mapping population of 255 F2:3 families from Taichung Native (TN)1/Sinna Sivappu cross and 128 polymorphic simple sequence repeat (SSR) markers, genes or quantitative trait loci (QTLs) for WBPH resistance quantified in ten phenotypic tests were identified, adopting classical Mendelian segregation, correlation and QTL analyses. The inheritance pattern suggested that a single recessive gene controlled regulation of seedling damage score. Antixenosis or nymphal preference was influenced by two complementary recessive genes, whereas tolerance in terms of days to wilt was under the influence of a single dominant gene. Several of these phenotypic tests recorded high degree of positive or negative correlation between them, suggesting dependence or redundancy of the tests. QTL analysis revealed 13 loci associated with nine traits. Five major-effect QTLs were detected for damage score (chromosome 6), nymphal survival (chromosome 12), and days to wilt (three QTLs on chromosome 4). We suggest involvement of four WBPH resistance genes in Sinna Sivappu, designated as wbph9(t), wbph10(t), wbph11(t), and Wbph12(t). One of the recessive genes could be allelic to any of the recessive genes reported in cluster C on chromosome 6 which might confer resistance to both BPH and WBPH.

Genetics and Characteristics of a Pigmentation Defective Laboratory Strain of the Lady Beetle, Coleomegilla maculata

Beetles in the family Coccinellidae, commonly known as ladybugs, lady beetles, or ladybirds, are easily identifiable and popular beneficial insects. Current research aims to support conservation efforts of beneficial insects in agroecosystems by exploring genetic processes related to nutrition. As a part of this research, colonies of Coleomegilla maculata have been maintained in culture and inbred over many generations since 2009. One result of this inbreeding has been the discovery of novel morphological phenotypes unique to laboratory strains or present in wild populations at such low levels that they have not yet been described. One such phenotype is described here. The strain described here, ye (yellow elytra and eyes) was characterized with classical Mendelian breeding and digital image analysis. This phenotype differs from wild populations by possessing yellow pigment in the elytra and pale grey to white eyes. In contrast, wild populations of C. maculata possess pink or red pigmented elytra with black spots, and black eyes. C. maculata is not known to exhibit polymorphism in the field. Inheritance is autosomal and recessive. This species was not previously known to exhibit the dramatic variation of color described here. The strain is stable in the homozygous recessive form, and retains laboratory rearing characteristics similar to the wild type laboratory strain.

Inheritance of resistance to Fusarium oxysporum f. sp. cubense race 1 in bananas

Fusarium wilt of bananas (also known as Panama disease), caused by the soil-borne fungus Fusarium oxysporum f. sp cubense (Foc), is a serious problem to banana production worldwide. Genetic resistance offers the most promising means to the control of Fusarium wilt of bananas. In this study, the inheritance of resistance in Musa to Foc race 1 was investigated in three F2 populations derived from a cross between ‘Sukali Ndizi’ and ‘TMB2X8075-7’. A total of 163 F2 progenies were evaluated for their response to Fusarium wilt in a screen house experiment. One hundred and fifteen progenies were susceptible and 48 were resistant. Mendelian segregation analysis for susceptible versus resistant progenies fits the segregation ratio of 3:1 (χ2 = 1.72, P = 0.81), suggesting that resistance to Fusarium wilt in Musa is conditioned by a single recessive gene. We propose panama disease 1 to be the name of the recessive gene conditioning resistance to Fusarium wilt in the diploid banana ‘TMB2X8075-7’.

Analysis pipeline for the detection of mutations causative of rare diseases on whole exome sequencing data

In this poster, a whole exome sequencing analysis pipeline for the discovery of mutations causative of human rare diseases is presented. Such methodology provides a complete strategy from SOLiD raw reads processing to mendelian analysis and variant selection, and its application over a set of samples from the Medical Genome Project, demonstrating the good performance of the proposed pipeline.

A NK complex-linked locus restricts the spread of Herpes simplex virus type 1 (HSV-1) in the central nervous system (CNS) of C57BL/6 mice

Event Abstract Back to Event A NK complex-linked locus restricts the spread of Herpes simplex virus type 1 (HSV-1) in the central nervous system (CNS) of C57BL/6 mice Lorne F. Kastrukoff1*, Allen Lau1, Fumio Takei2, Anthony Scalzo3 and Francis R. Carbone4 1 University of British Columbia, Medicine, Canada 2 British Columbia Cancer Research Center, Terry Fox Laboratory, Canada 3 Lions Eye Institute, Immunology, Australia 4 University of Melbourne, Microbiology and Immunoloy, Australia Natural resistance to mortality in mice infected with Herpes simplex virus type 1 (HSV-1) is mouse strain dependent and an autosomal dominant trait. In mice infected with virus via the oral mucosa, HSV-1 spreads throughout the central nervous system (CNS) of susceptible strains but is restricted to the brainstem of resistant mice. In resistant C57BL/6 (BL/6) mice, viral restriction is mediated by natural killer (NK) cells and CD8+ T-lymphocytes. We combined mendelian analysis, studies of congenic and intra-NKC recombinant mice, along with antibody depleted mice to further examine the restriction of viral spread in the brains of BL/6 mice. We report a NK complex-linked genetic locus, Hrl2, whose alleles determine the restriction of viral spread in the CNS. Mendelian analysis determined that restriction of viral spread is a dominant trait and consistent with a single gene effect. Studies with congenic mice determined that the locus maps to the NKC on chromosome 6 but is separate from previously identified loci; Hrl1 and Rhs1. Studies with intra-NKC recombinants determined that the locus maps to a segment between CD69 and D6Wum34. Studies with antibody depleted mice determined the effect of this locus is mediated by NK1.1 expressing cells. A NK complex-linked locus (Hrl2) restricts the spread of HSV-1 in the CNS of BL/6 mice however the precise mode of action of the locus remains unknown. Acknowledgements This work has been funded by the Canadian Institutes of Health Research Keywords: NK complex linked locus, Herpes simplex virus type 1, Central Nervous System, C57BL/6J mice, NK cells Conference: 15th International Congress of Immunology (ICI), Milan, Italy, 22 Aug - 27 Aug, 2013. Presentation Type: Abstract Topic: Host-pathogen interactions Citation: Kastrukoff LF, Lau A, Takei F, Scalzo A and Carbone FR (2013). A NK complex-linked locus restricts the spread of Herpes simplex virus type 1 (HSV-1) in the central nervous system (CNS) of C57BL/6 mice. Front. Immunol. Conference Abstract: 15th International Congress of Immunology (ICI). doi: 10.3389/conf.fimmu.2013.02.00050 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 08 Mar 2013; Published Online: 22 Aug 2013. * Correspondence: Dr. Lorne F Kastrukoff, University of British Columbia, Medicine, Vancouver, British Columbia, V6T 1Z3, Canada, lornefk@mail.ubc.ca Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Lorne F Kastrukoff Allen Lau Fumio Takei Anthony Scalzo Francis R Carbone Google Lorne F Kastrukoff Allen Lau Fumio Takei Anthony Scalzo Francis R Carbone Google Scholar Lorne F Kastrukoff Allen Lau Fumio Takei Anthony Scalzo Francis R Carbone PubMed Lorne F Kastrukoff Allen Lau Fumio Takei Anthony Scalzo Francis R Carbone Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Cold Urticaria, Immunodeficiency, and Autoimmunity Related to PLCG2 Deletions

MJ Ombrello, EF Remmers, G Sun. N Engl J Med. 2012;366:330–338 To perform Mendelian analysis of 3 families with cold-induced urticaria and identify and elucidate immunologic pathways and mechanisms. Three families with a dominantly inherited complex of cold-induced urticaria, antibody deficiency, and susceptibility to infection and autoimmunity. Immunophenotyping, including flow cytometry, analysis of serum immunoglobulins and autoantibodies, lymphocyte stimulation, and enzymatic assays, was used. …

Overview of Intellectual/Developmental Disabilities

Patients with intellectual/developmental disabilities (IDD) present many challenges to mental health professionals. The capacity to work with such patients requires a working knowledge of IDD as well as an awareness and understanding of the factors that affect the clinical presentation of mental health disorders across the spectrum of IDD.

Inheritance of somatic embryogenesis using leaf petioles as explants in upland cotton

Somatic embryogenesis (SE) is a critical step leading to plant regeneration in tissue culture of many plant species. The objective of the present study was to analyze the inheritance of SE in cotton (Gossypium hirsutum L.) using leaf petioles as explants. A high embryogenic callus (HEC)—producing line, W10, was selected by petiole callus culture from a commercial Chinese cotton cultivar CRI24 and crossed with a non embryogenic line, TM-1 and a low embryogenic (LEC) commercial Chinese cotton cultivar, CRI12, respectively. The parental lines, F1 and F2 were grown in field conditions for sources of leaf petioles as explants. The F1 plants were similar to the HEC parent in embryogenic callus (EC) induction, indicating that high EC ability is dominant. The classical Mendelian analysis showed that the high EC ability in the HEC line W10 is controlled by two independent dominant genes with complementary effect, designated Ec 1 and Ec 2 , while the LEC line CRI12 contains one dominant gene Ec 2 . A joint segregation analysis confirmed that SE ability in cotton is controlled by two major genes with epistatic effects along with other polygenes. A SSR marker analysis identified three quantitative trait loci (QTLs) on two linkage groups, one of which harbored a major QTL (qEc1) which is assigned to the major gene Ec 1 . This qualitative and quantitative genetic study has provided an incentive to fine map the genes responsible for SE towards the isolation of the SE genes in cotton.

Genetic background of resistance to cadmium-induced testicular toxicity in inbred Wistar-Imamichi rats

We have previously reported that inbred Wistar-Imamichi (WI) rats are highly resistant to cadmium (Cd)-induced testicular toxicity compared with inbred Fischer 344 (F344) rats. The present study was to elucidate the genetic background of resistance to Cd-induced testicular toxicity in WI rats. The genetic analysis of susceptibility to Cd-induced testicular toxicity was conducted by using Cd-resistant WI and Cd-sensitive F344 strains as the parental rats and by using the testicular hemoglobin level as the indicator. In the frequency distribution of testicular hemoglobin levels in parental, first filial (F(1)) and second filial (F(2)) rats treated with Cd at a dose of 2.0mg/kg, F(1) rats had testicular hemoglobin levels intermediate to WI and F344 rats, and F(2) rats segregated into three groups of low, intermediate, and high phenotypes at the expected ratio. Furthermore, the backcross progeny between WI and F(1) or between F344 and F(1) segregated into two groups with the expected ratio. Based on a simple Mendelian genetic analysis, these segregation patterns lead us to conclude that two codominant alleles at a gene locus are responsible for the susceptibility to Cd-induced testicular toxicity in rats. This is the first report for the genetic analysis of susceptibility to Cd-induced testicular toxicity in inbred rat strains.

Genetics of color polymorphism in the pea aphid, Acyrthosiphon pisum.

The genetic basis of color polymorphism is explored in the pea aphid, Acyrthosiphon pisum (Harris) (Homoptera: Sternorrhyncha), in which two color morphs have been described (pink or green). Laboratory crosses and a Mendelian genetic analysis reveal that color polymorphism in pea aphids is determined by a single biallelic locus, which we name colorama, with alleles P and p, pink being dominant to green. The putative genotypes are Pp or PP for pink morphs, and pp for green morphs. This locus is shown to be autosomal. Last, there was no evidence of influence of the direction of the cross on color inheritance, thus showing that cytoplasmic effects and/or maternally-inherited symbionts play no role in the inheritance of color polymorphism in pea aphids. The existence of a simple genetic determinism for color polymorphism in a system in which genetic investigation is possible may facilitate investigations on the physiological and molecular mechanisms of genetically-based color morph variation, and the establishment of a link between this locus and fitness in a range of ecological conditions.