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1
Chilakamarri, Sunita R. "Genetic differentiation in Alewife populations using microsatellite loci". Link to electronic thesis, 2005. http://www.wpi.edu/Pubs/ETD/Available/etd-053105-164623/.
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2
Nicholls, Felicity K. M. "Genetic analysis of the gene Additional sex combs and interacting loci". Thesis, University of British Columbia, 1990. http://hdl.handle.net/2429/29644.
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In order to recover new mutant alleles of the Polycomb group gene Additional sex combs (Asx), mutagenized chromosomes were screened over the putative Asx allele XT129. Thirteen new mutant strains that fail to complement XT129 were recovered. Unexpectedly, the thirteen strains sorted into four complementation groups. Recombination mapping suggests that each complementation group represents a separate locus. The largest group fails to complement a deletion of Asx and maps in the vicinity of 2-72, the published location of Asx. All new mutant strains enhance the phenotype of Polycomb mutant flies and are not allelic to any previously discovered second chromosome Polycomb group genes. Therefore, the new mutants may be considered putative new members of the Polycomb group. This study suggests that Asx belongs to a sub-group of genes displaying intergenic non-complementation.Science, Faculty of
Zoology, Department of
Graduate
3
Good, David Andrew, i n/a. "Genetic Loci for Paget's Disease of Bone". Griffith University. School of Biomolecular and Biomedical Science, 2003. http://www4.gu.edu.au:8080/adt-root/public/adt-QGU20040319.125358.
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Paget's disease of the bone is a skeletal disorder of unknown cause. This disease is characterised by excessive and abnormal bone remodelling brought about by increased bone resorption followed by disorganised bone formation. Increased bone turnover results in a disorganised mosaic of woven and lamellar bone at affected skeletal sites. This produces bone that is expanded in size, less compact, more vascular, and more susceptible to deformity or fracture than normal bone. Symptoms of Paget's disease may include bone pain, bone deformity, excessive warmth over bone from hypervascularity, secondary arthritis, and a variety of neurologic complications caused in most instances by compression of the neural tissues adjacent to pagetic bone. Genetic factors play a role in the pathogenesis of Paget's disease but the molecular basis remains largely unknown. The identification of the molecular basis of Paget's disease is fundamental for an understanding of the cause of the disease, for identifying subjects at risk at a preclinical stage, and for the development of more effective preventive and therapeutic strategies for the management of the condition. With this in mind, the aim of this project is to identify genetic loci, in a large pedigree, that may harbour genes responsible for Paget's disease of bone. A large Australian family with evidence of Paget's disease was recruited for these studies (Chapter 3). This pedigree has characterised over 250 individuals, with 49 informative individuals affected with Paget's disease of bone, 31 of whom are available for genotypic analysis. The pattern of disease in these individuals is polystotic, with sites of involvement including the spine, pelvis, skull and femur. Although the affected individuals have a severe early-onset form of the disease, the clinical features of the pedigree suggest that the affected family members have Paget's disease and not familial expansile osteolysis (a disease with some similarities to Paget's disease), as our patients have extensive skull and axial skeletal involvement. The disease is inherited as an autosomal dominant trait in the pedigree with high penetrance by the sixth decade. Due to the large size of this family and multiple affected members, this pedigree is a unique resource for the detection of the susceptibility gene in Paget's disease. The first susceptibility loci for Paget's disease of bone have been mapped by other investigators to chromosome 6p21 (PDB1) and 18q21.1-q22 (PDB2) in different pedigrees. Linkage analysis of the Australian pedigree in these studies was performed with markers at PDB1: these data showed significant exclusion of linkage, with LOD scores < - 2 in this region (Chapter 4). Linkage analysis of microsatellite markers from the PDB2 region excluded linkage with this region also, with a 30 cM exclusion region (LOD score < -2.0) centred on D18S42 (Chapter 4). This locus on chromosome 18q21.1-q22 contains a serine protease (serpin) cluster with similarities to chromosome 6p21. Linkage analysis of this region also failed to provide evidence of linkage to this locus (Chapter 4). These data are consistent with genetic heterogeneity of Paget's disease of bone. A gene essential for osteoclast formation encoding receptor activator of nuclear factor-kB (RANK), TNFRSF11A, has been previously mapped to the PDB2 region. Mutations in the TNFRSF11A gene have been identified segregating in pedigrees with Familial Expansile Osteolysis and early onset familial Paget's disease, however, linkage studies and mutation screening have excluded the involvement of RANK in the majority of Paget's disease patients. For the Australian pedigree, mutation screening at the TNFRSF11A locus revealed no mutations segregating with affected individuals with Paget's disease (Chapter 4). Based on these findings, our hypothesis is that a novel susceptibility gene relevant to the pathogenesis of Paget's disease of bone lies elsewhere in the genome in the affected members of this pedigree; this gene should be identifiable using a microsatellite genome-wide scan followed by positional cloning. A genome-wide scan of the Australian pedigree was carried out, followed by fine mapping and multipoint analysis in regions of interest (Chapter 5). The peak 2-point LOD scores from the genome-wide scan were LOD = 2.75 at D7S507 and LOD = 1.76 at D18S70. Two additional regions were also considered for fine mapping: chromosome 19p11-q13.1 with a LOD of 1.58 and chromosome 5q35-qter with a LOD of 1.57. Multipoint and haplotype analysis of markers flanking D7S507 did not support linkage to this region (Chapter 5). Similarly, fine mapping of chromosome 19p11-q13.1 failed to support linkage to this region (Chapter 5). Linkage analysis with additional markers in the region on chromosome 5q35-qter revealed a peak multipoint LOD score of 6.77 (Chapter 5). A distinct haplotype was shown to segregate with all members of the family, except the offspring of III-5 and III-6. Haplotype analysis of markers flanking D18S70 demonstrated a haplotype segregating with Paget's disease in a large sub-pedigree (descendants of III-3 and III-4) (Chapter 5). This sub-pedigree had a significantly lower age at diagnosis than the rest of the pedigree (51.2 + 8.5 vs. 64.2 + 9.7 years, p = 0.0012). Linkage analysis of this sub-pedigree demonstrated a peak two-point LOD score of 4.23 at marker D18S1390 (q = 0.00), and a peak multipoint LOD score of 4.71, at marker D18S70. An implication of these data is that 18q23 harbours a novel modifier gene for reducing the age of onset of Paget's disease of bone. A number of candidate Paget's genes have previously been identified on chromosome 18q23, including the nuclear factor of activated T cells (NFATc1), membrane-associated guanylated kinase (MAGUK) and a zinc finger protein. Candidate gene sequencing of these genes in these studies has failed to identify mutations segregating with affected family members in the sub-pedigree linked to chromosome 18q23 (Chapter 6). More recently, a mutation in the gene encoding the ubiquitin-binding protein sequestosome 1 (SQSTM/p62) has been shown to segregate with affected members of Paget's disease families of French-Canadian origin. In this study, a single base pair deletion (1215delC) was identified as segregating with the majority of affected members in the pedigree (Chapter 6). This deletion introduces a stop codon at amino acid position 392 which potentially results in early termination of the protein and loss of the ubiquitin binding domain. The three affected members of the family that do not share the affected haplotype do not carry a mutation in the coding region of SQSTM/p62. Screening of affected members from 10 further Paget's disease families identified the previously reported P392L mutation in 2 (20%) families. No SQSTM1/p62 coding mutations have been found in the remaining 8 families or in 113 aged matched controls. In conclusion, this project has identified genetic loci and mutations that segregate with individuals affected with Paget's disease. Further investigation of the functional significance of the genetic changes at these loci is expected to lead to a better understanding of the molecular basis of this disease.
4
Good, David Andrew. "Genetic Loci for Paget's Disease of Bone". Thesis, Griffith University, 2003. http://hdl.handle.net/10072/365759.
Pełny tekst źródłaStreszczenie:
Paget's disease of the bone is a skeletal disorder of unknown cause. This disease is characterised by excessive and abnormal bone remodelling brought about by increased bone resorption followed by disorganised bone formation. Increased bone turnover results in a disorganised mosaic of woven and lamellar bone at affected skeletal sites. This produces bone that is expanded in size, less compact, more vascular, and more susceptible to deformity or fracture than normal bone. Symptoms of Paget's disease may include bone pain, bone deformity, excessive warmth over bone from hypervascularity, secondary arthritis, and a variety of neurologic complications caused in most instances by compression of the neural tissues adjacent to pagetic bone. Genetic factors play a role in the pathogenesis of Paget's disease but the molecular basis remains largely unknown. The identification of the molecular basis of Paget's disease is fundamental for an understanding of the cause of the disease, for identifying subjects at risk at a preclinical stage, and for the development of more effective preventive and therapeutic strategies for the management of the condition. With this in mind, the aim of this project is to identify genetic loci, in a large pedigree, that may harbour genes responsible for Paget's disease of bone. A large Australian family with evidence of Paget's disease was recruited for these studies (Chapter 3). This pedigree has characterised over 250 individuals, with 49 informative individuals affected with Paget's disease of bone, 31 of whom are available for genotypic analysis. The pattern of disease in these individuals is polystotic, with sites of involvement including the spine, pelvis, skull and femur. Although the affected individuals have a severe early-onset form of the disease, the clinical features of the pedigree suggest that the affected family members have Paget's disease and not familial expansile osteolysis (a disease with some similarities to Paget's disease), as our patients have extensive skull and axial skeletal involvement. The disease is inherited as an autosomal dominant trait in the pedigree with high penetrance by the sixth decade. Due to the large size of this family and multiple affected members, this pedigree is a unique resource for the detection of the susceptibility gene in Paget's disease. The first susceptibility loci for Paget's disease of bone have been mapped by other investigators to chromosome 6p21 (PDB1) and 18q21.1-q22 (PDB2) in different pedigrees. Linkage analysis of the Australian pedigree in these studies was performed with markers at PDB1: these data showed significant exclusion of linkage, with LOD scores < - 2 in this region (Chapter 4). Linkage analysis of microsatellite markers from the PDB2 region excluded linkage with this region also, with a 30 cM exclusion region (LOD score < -2.0) centred on D18S42 (Chapter 4). This locus on chromosome 18q21.1-q22 contains a serine protease (serpin) cluster with similarities to chromosome 6p21. Linkage analysis of this region also failed to provide evidence of linkage to this locus (Chapter 4). These data are consistent with genetic heterogeneity of Paget's disease of bone. A gene essential for osteoclast formation encoding receptor activator of nuclear factor-kB (RANK), TNFRSF11A, has been previously mapped to the PDB2 region. Mutations in the TNFRSF11A gene have been identified segregating in pedigrees with Familial Expansile Osteolysis and early onset familial Paget's disease, however, linkage studies and mutation screening have excluded the involvement of RANK in the majority of Paget's disease patients. For the Australian pedigree, mutation screening at the TNFRSF11A locus revealed no mutations segregating with affected individuals with Paget's disease (Chapter 4). Based on these findings, our hypothesis is that a novel susceptibility gene relevant to the pathogenesis of Paget's disease of bone lies elsewhere in the genome in the affected members of this pedigree; this gene should be identifiable using a microsatellite genome-wide scan followed by positional cloning. A genome-wide scan of the Australian pedigree was carried out, followed by fine mapping and multipoint analysis in regions of interest (Chapter 5). The peak 2-point LOD scores from the genome-wide scan were LOD = 2.75 at D7S507 and LOD = 1.76 at D18S70. Two additional regions were also considered for fine mapping: chromosome 19p11-q13.1 with a LOD of 1.58 and chromosome 5q35-qter with a LOD of 1.57. Multipoint and haplotype analysis of markers flanking D7S507 did not support linkage to this region (Chapter 5). Similarly, fine mapping of chromosome 19p11-q13.1 failed to support linkage to this region (Chapter 5). Linkage analysis with additional markers in the region on chromosome 5q35-qter revealed a peak multipoint LOD score of 6.77 (Chapter 5). A distinct haplotype was shown to segregate with all members of the family, except the offspring of III-5 and III-6. Haplotype analysis of markers flanking D18S70 demonstrated a haplotype segregating with Paget's disease in a large sub-pedigree (descendants of III-3 and III-4) (Chapter 5). This sub-pedigree had a significantly lower age at diagnosis than the rest of the pedigree (51.2 + 8.5 vs. 64.2 + 9.7 years, p = 0.0012). Linkage analysis of this sub-pedigree demonstrated a peak two-point LOD score of 4.23 at marker D18S1390 (q = 0.00), and a peak multipoint LOD score of 4.71, at marker D18S70. An implication of these data is that 18q23 harbours a novel modifier gene for reducing the age of onset of Paget's disease of bone. A number of candidate Paget's genes have previously been identified on chromosome 18q23, including the nuclear factor of activated T cells (NFATc1), membrane-associated guanylated kinase (MAGUK) and a zinc finger protein. Candidate gene sequencing of these genes in these studies has failed to identify mutations segregating with affected family members in the sub-pedigree linked to chromosome 18q23 (Chapter 6). More recently, a mutation in the gene encoding the ubiquitin-binding protein sequestosome 1 (SQSTM/p62) has been shown to segregate with affected members of Paget's disease families of French-Canadian origin. In this study, a single base pair deletion (1215delC) was identified as segregating with the majority of affected members in the pedigree (Chapter 6). This deletion introduces a stop codon at amino acid position 392 which potentially results in early termination of the protein and loss of the ubiquitin binding domain. The three affected members of the family that do not share the affected haplotype do not carry a mutation in the coding region of SQSTM/p62. Screening of affected members from 10 further Paget's disease families identified the previously reported P392L mutation in 2 (20%) families. No SQSTM1/p62 coding mutations have been found in the remaining 8 families or in 113 aged matched controls. In conclusion, this project has identified genetic loci and mutations that segregate with individuals affected with Paget's disease. Further investigation of the functional significance of the genetic changes at these loci is expected to lead to a better understanding of the molecular basis of this disease.Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Biomolecular and Biomedical Sciences
Full Text
5
Roberts, Simon Benedict. "Investigating new genetic susceptibility loci in osteoarthritis". Thesis, University of Edinburgh, 2018. http://hdl.handle.net/1842/28982.
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Primary osteoarthritis (OA) is a late-onset, degenerative condition of synovial joints, and is the major cause of pain and disability in older persons. OA represents a significant disease burden and focus of research, especially as no disease-modifying therapies exist to manage the condition. The genetic influence to OA is complex and polygenic. The arcOGEN study, the most powerful genome-wide association study yet to investigate OA in humans, identified the 9q33.1 locus to be significantly associated with hip OA in females. TRIM32 lies within the 9q33.1 susceptibility locus and may have strong biological relevance to OA; it encodes a protein with E3 ubiquitin ligase activity. Sanger sequencing of TRIM32 in the youngest 500 female patients with hip OA from the arcOGEN study was performed to identify rare variants in TRIM32 that are associated with OA of the hip in females. Polymorphisms were identified in the proximal promoter, and 3’untranslated regions (3’UTR) of TRIM32 that are disproportionately represented in female patients with hip OA, compared to the control population. In vitro studies identified expression of TRIM32 in human femoral head cartilage; reduced expression of TRIM32 was also demonstrated in femoral head primary articular chondrocytes from patients with hip OA compared to control patients. Trim32 knockout resulted in increased aggrecanolysis in murine femoral head explants. Murine chondrocytes deficient in Trim32 also exhibited increased expression of markers of a mature chondrocyte phenotype in response to anabolic cytokine stimulation, and increased expression of markers of a hypertrophic chondrocyte phenotype upon catabolic cytokine stimulation. In vivo studies of joint degeneration in Trim32 knockout mice demonstrated increased cartilage degradation and tibial epiphyseal bone changes after surgically induced knee joint instability, compared to wild-type mice. Increased cartilage degradation and medial knee subchondral bone changes were also identified upon ageing of Trim32 knockout mice. These results further implicate TRIM32 in the genetic predisposition to OA, and indicate a role for TRIM32 in the joint degeneration evident in OA. These results support the further study of TRIM32 in the pathophysiology of OA and development of novel therapeutic strategies to manage OA.
6
Ahmed, Helal Uddin. "Mapping stress tolerance genetic loci in Arabidopsis thaliana". Thesis, University of Newcastle Upon Tyne, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.246628.
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Oakenfull, Elizabeth Ann. "A molecular genetic study of equid #alpha#-globin loci". Thesis, University of Oxford, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.317915.
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Mavridou, Annoula. "Genetic loci of Rhizobium leguminosarum affecting nod gene expression". Thesis, University of East Anglia, 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.316102.
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King, Alistair Lawrence. "Studies to identify genetic susceptibility loci in coeliac disease". Thesis, King's College London (University of London), 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.406682.
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Rask-Andersen, Mathias. "Obesity Genetics : Functional Aspects of Four Genetic Loci Associated with Obesity and Body Mass". Doctoral thesis, Uppsala universitet, Funktionell farmakologi, 2013. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-204449.
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Obesity is a complex disorder which has reached epidemic proportions in many parts of the world. Twin studies have demonstrated a high heritability for obesity. The subsequent appli-cation of genome wide association studies (GWAS) in the last decade have identified at least 32 genetic loci associated with body mass and obesity. Despite these great advances, these loci are almost exclusively completely naïve in a functional context. Genetic variations within the gene encoding the fat mass and obesity associated gene (FTO) are the strongest and most consistently observed genetic variants associated with obesity and body mass throughout various studied populations from all parts of the world. The identification of association of FTO with obesity has spurred immense interest in the function of the FTO protein and the functional consequences of its variants. However, the implications of genetic variants at other genetic loci on protein molecular function and body mass development remain undetermined. This thesis aims to examine more closely four of the genetic loci associated with obesity; in proximity of, or associated with: FTO, TMEM18, MAP2K5 and STK33, in two cohorts of children of European descent: a case-control of clinically obese children and normal weight controls from the Stockholm area; and a cross sectional cohort of Greek children. These smaller cohorts allow for studies of more specific effects of genetic variants as individuals in these cohorts can be more carefully studied. TMEM18 gene expression was also studied in the rat-brain where a positive correlation was observed between the body weight of the animal and TMEM18 expression. We also employed next generation sequencing to more carefully study obesity-associated genetic loci related to FTO and TMEM18. We utilized a novel strategy in this project to study genetic variation in the entire FTO- and TMEM18 genes, as well as in the GWAS-identified BMI-associated loci located downstream from TMEM18. This analysis was performed on a case-control cohort of Swedish children (n = ~1000). Through this analysis, we were able to observe genetic variants within intron 1 of the FTO gene to be the main genetic variants asso-ciated with obesity at this locus. We also observed, for the first time, obesity-associated genetic variants within the gene encoding TMEM18. To analyze the potential functional context of FTO we used an in silico approach, utilizing public information databases on mRNA co-expression and protein-protein interaction. Based on our findings, we speculate on a wider functional role of FTO in extracellular ligand-induced neuronal plasticity, possibly via interaction or modulation of the BDNF/NTRK2 signaling pathway.
11
Campino, Susana. "Genetic analysis of murine malaria". Doctoral thesis, Umeå universitet, Medicinsk biovetenskap, 2003. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-124.
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Malaria, an infectious disease caused by Plasmodium parasites, is one of the major world-scale health problems. Despite the efforts aimed at finding an effective way to control the disease, the success has been thwarted by the emergence of parasite drug resistance and mosquito resistance to insecticides. This thesis focuses on the genetic analysis of resistance to murine malaria induced by the lethal Plasmodium berghei ANKA using a wild-derived-inbred strain (WDIS). The aim of this thesis was to exploit the genetic diversity represented among WDIS for identifying loci contributing to resistance/susceptibility to murine malaria. The work included a genome-wide polymorphism survey using microsatellite markers performed on 10 WDIS. Comparisons of these strains to laboratory inbred strains confirmed a higher rate of polymorphism among the WDIS. We conclude that these WDIS represent repositories of unique naturally occurring genetic variability that may prove to be invaluable for the study of complex phenotypes. Next, we used the WDIS to search for novel phenotypes related to malaria pathogenesis. Whereas most laboratory strains were susceptible to experimental cerebral malaria (ECM) after infection with P. berghei ANKA, several WDIS were found to be resistant. To study the genetic inheritance of resistant/susceptibility to P. berghei ANKA infection we analysed backcross and F2 cohorts derived from crossing the WLA wild-derived strain with a laboratory mouse strain (C57BL/6). A novel phenotype represented by the cure of infection, clearance of parasitaemia and establishment of immunological memory was observed in the F2 progeny. The backcross progeny was used to genetically map one locus on chromosome 1 (Berr1) and one locus on chromosome 11 (Berr2) that mediate control of resistance to ECM induced by P. berghei ANKA. Genetic mapping using the F2 progeny showed that a locus on chromosome 1 (Berr1) and a locus on chromosome 9 (Berr3) were contributing to control survival time after infection with lethal Plasmodium. Finally, we identified, a locus on chromosome 4 (Berr4) that appears to control time of death due to hyperparasitaemia. This thesis underlines the value of using WDIS to reveal genetic factors involved in the aetiology of disease phenotypes. The characterisation of the genetic factors represented by the malaria resistance loci identified here are expected to provide a better understanding of the malaria pathology.
12
Goode, Ellen Lee. "Epidemiology of hereditary prostate cancer : genetic analysis of susceptibility loci incorporating clinical characteristics /". Thesis, Connect to this title online; UW restricted, 2000. http://hdl.handle.net/1773/10856.
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Maller, Julian Benjamin. "Fine scale mapping of genetic loci associated with human disease". Thesis, University of Oxford, 2013. https://ora.ox.ac.uk/objects/uuid:2e1dcc74-cccb-4253-961c-431e965bf204.
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Genome-wide association studies (GWAS) use custom SNP arrays that provide ef- fective genetic coverage, but do not detail the association of confirmed susceptibil- ity regions with as dense a marker map as possible. In this thesis I will describe a fine mapping study across 14 associated regions, in 8,000 samples from three dis- eases (Type 2 diabetes mellitus (T2D), coronary artery disease (CAD) and Graves Disease (GD)) and a control group, including over 5,500 successfully genotyped SNPs. We defined using Bayes theorem sets of SNPs (credible sets) that were 95% likely (posterior probability) to contain the causal disease variants. In three of the 14 regions TCF7L2 and CDKN2A/B in T2D and CTLA4 in GD, we found that much of the posterior probability after the fine mapping rested on a single SNP. In seven of the 14 regions (CDKN2A/B in CAD, CTLA4 in GD, and CDKAL1, FTO, HHEX, TCF7L2) and CDKN2A/B in T2D), including the three just mentioned, the credible sets are relatively small. For these regions, the fine mapping experi- ment has provided useful information, at least in excluding large numbers of SNPs from being causal. Almost none of the SNPs in our credible regions had obvious functions, illustrating our lack of knowledge of genome sequence in modulating gene expression and susceptibility to common disease. Based on this experiment, I outline and discuss the possibilities and challenges in identifying causal variants for complex traits through fine mapping of GWA signals. Further, I evaluate the possibility of using genotype imputation in the context of fine mapping, both as a method for fine mapping and as a way to increase efficiency in fine mapping studies.
14
Bett, Kirstin E. "Genome analysis and genetic mapping of restorer loci in Raphanus". Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2001. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp05/NQ63844.pdf.
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Wilhelm, Edward. "Genetic analysis of the Group IV Rht LOCI in wheat". Thesis, University of East Anglia, 2011. https://ueaeprints.uea.ac.uk/49761/.
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The introduction of the group IV semi-dwarf Rht alleles, Rht-B1b (formerly Rht1) and Rht-D1b (formerly Rht2) into bread wheat varieties from the donor line „Norin 10‟ that began in the 1960s was a major contributor to the „green revolution‟. Rht-B1b and Rht-D1b were characterised and cloned over a decade ago (Gale and Youssefian 1985; Peng et al. 1999), however the Rht-A1 locus has not been isolated and little is known regarding the genetic diversity of the group IV Rht loci or the genetic composition of the contiguous sequence surrounding Rht that was presumably introgressed into wheat varieties along with the dwarfing alleles. To investigate the contiguous region around Rht, a hexaploid wheat („Chinese Spring‟ (CS)) BAC library was screened using a PCR-based technique (Febrer et al. 2009). This identified several Rht-containing BAC clones, three of which (representing the A, B, and D genomes) were sequenced and found to contain one to two genes upstream of Rht in conserved order. Gene synteny was also highly conserved in rice, Brachypodium distachyon, sorghum, and maize. The previously unidentified Rht-A1 homoeologue was physically mapped to the long arm of chromosome 4A using aneuploid lines and mapped relative to genetic markers. To estimate genetic diversity, the entire coding regions of Rht-A1, Rht-B1, and Rht-D1 and the flanking regions (approximately 1800 bp 5‟ and 450 bp 3‟) were sequenced in 40 diverse wheat accessions. Little polymorphism and few haplotypes were identified on the A and D genomes, but on the B genome a relative abundance of haplotypes and polymorphism were present, including insertions (relative to CS) of 160 bp and 197 bp within 600 nucleotides of the ORF. The Rht-B1 insertions did not have a pronounced effect on RNA transcript level when assessed in seedlings. In an analysis of 368 lines from the INRA bread wheat core collection (BWCC) (Balfourier et al., 2007), lines with the Rht-B1 insertions were associated with reduced heights and reduced GA sensitivity relative to lines without an insertion, but only the height reductions associated with the 197 bp insertion were significant (p < 0.05). GA sensitivity tests of the INRA BWCC did not reveal any novel GA insensitive mutants. An investigation of the origin of the „Norin 10‟ alleles revealed potential discrepancies between the published pedigree and of „Norin 10‟ and the genotypes of seed stocks. Sequence, annotation, and comparative genomics of the Rht-containing BAC clones, the mapping of Rht-A1, and the discovery and investigation of novel genetic diversity provides greater insight into the Rht region and also provides tools for further analysis of this region and for the potential improvement of bread wheat. *Article from 'Genome' submitted as an appendix (further bibliographic details contained within thesis contents) not uploaded. Please contact author for further information. Article available on submitted CD deposited with UEA Library.
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Harenza, Jo Lynne. "Genetic Dissection of Quantitative Trait Loci for Substances of Abuse". VCU Scholars Compass, 2013. http://scholarscompass.vcu.edu/etd/3190.
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It has been reported that an individual’s initial level of response to a drug might be predictive of his or her future risk of becoming dependent, thus basal gene expression profiles underlying those drug responses may be informative for both predicting addiction susceptibility and determining targets for intervention. This dissertation research aims to elucidate genetic risk factors underlying acute alcohol and nicotine dependence phenotypes using mouse genetic models of addiction. Phenotyping, brain region-specific mRNA expression profiling, and genetic mapping of a recombinant inbred panel of over 25 mouse strains were performed in order to identify quantitative trait loci (QTL) harboring candidate genes that may modulate these phenotypes. Previous BXD (B6 x D2) behavioral studies performed in our laboratory identified an ethanol-induced anxiolysis-like QTL (Etanq1) in the light dark box (LDB). We hypothesized that genetic variation within Nin (a gene within the Etanq1 support interval involved in microtubule-anchoring) may modulate anxiolytic-like responses to acute ethanol in the LDB as well as other preclinical models of anxiety, the elevated plus maze (EPM), and marble burying (MB) task. Molecular studies have allowed us to confirm cis regulation of Nin transcript levels in the NAc. To elucidate potential mechanisms mediating Etanq1, the pharmacological tools, diazepam and HZ166 (a benzodiazepine derivative) were utilized to interrogate whether GABAA receptor activation modulates ethanol’s anxiety-like behaviors in the LDB. We show that the LDB phenotype, percent time spent (PTS) in the light following a brief restraint stress, is not being modulated through direct activation of GABAA α2/α3 receptor subunits. To genetically dissect Etanq1 as well as parse the ethanol anxiolytic-like phenotype, we have assayed 8 inbred strains, selected based on genotypes at Nin, in various preclinical models of anxiety. Principal components analysis of these behavioral data suggests that the gene(s) modulating the ethanol anxiolytic-like component in the LDB do not overlap with similar phenotypes in the elevated plus maze (EPM), nor the MB phenotype. Furthermore, site-specific delivery of an sh-Nin lentivirus into the NAc of D2 mice revealed that Nin may modulate one LDB endophenotype, latency to enter the light side of the LDB, which loaded as a part of the “anxiolysis” principal component. These data strongly imply that basal neuronal Nin expression in the NAc is important for acute ethanol anxiolytic-like behavior, perhaps through a novel mechanism involving synaptic remodeling. In separate behavioral QTL mapping studies, we hypothesized that genetic variation regulating expression of Chrna7 modulates the reward-like phenotype, conditioned place preference (CPP), for nicotine. We provide evidence for genetic regulation of Chrna7 across the BXD panel of mice and through pharmacological and genetic behavioral studies, confirm Chrna7 as a quantitative trait gene modulating CPP for nicotine in mice. Microarrays, followed by network analyses, allowed us to identify a genetically co-regulated network within the nucleus accumbens (NAc), differentially expressed in mice null for Chrna7, which was similarly correlated in the BXD panel of mice. Our network and molecular analyses suggest a putative role for Chrna7 in regulating insulin signaling in the NAc, which together, may contribute to the enhanced sensitivity to nicotine observed in strains of mice that lack or have low mRNA levels of Chrna7 in the NAc. Overall, this research has elucidated and confirmed new genetic risk factors underlying alcohol and nicotine dependence phenotypes and has enabled a better understanding of the neurogenomic bases of alcohol and nicotine addiction. Future studies that further investigate the signaling pathways and/or gene interactions involving Nin and Chrna7 may lead the field to new candidates for pharmacotherapies that may be tailored for use in individuals with susceptible genotypes. Supported by NIAAA grants P20AA017828 and R01AA020634 to MFM, NIDA T32DA007027 to WLD, and NIDA R01DA032246 to MFM and MID.
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Qianren, Jin. "Search for susceptibility loci and candidate genes for breast cancer /". Stockholm, 2004. http://diss.kib.ki.se/2004/91-7140-030-3/.
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Nagy, Réka. "Genetic analysis using family-based populations". Thesis, University of Edinburgh, 2018. http://hdl.handle.net/1842/28978.
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Most human traits are influenced by a combination of genetic and environmental effects. Heritability expresses the proportion of trait variance that can be explained by genetic factors, and the 1980s heralded the beginning of studies that aimed to pinpoint genetic loci that contribute to trait variation, also known as quantitative trait loci (QTLs). Subsequently, the availability of cheap, high-resolution genotyping chips ushered in the era of genome-wide association studies (GWAS). These genetic studies have discovered many associations between single-nucleotide polymorphisms (SNPs) and complex traits, but these associations do not explain the genetic component of these traits entirely. This is known as the ‘missing heritability’ problem. Within this thesis, 40 medically-relevant human complex traits are studied in order to identify new QTLs. These traits include eye biometric traits, blood biochemical traits and anthropometric traits measured in approximately 28,000 individuals belonging to family-based samples from the general Scottish population (the Generation Scotland study) or from population isolates from Croatian (Korčula, Vis) or Scottish (Shetland, Orkney) islands. These individuals had been genotyped using commercially-available arrays, and unobserved genotypes were imputed using the Haplotype Reference Consortium (HRC) dataset. In parallel to standard GWAS, these traits are analysed using two other statistical genetics approaches: variance component linkage analysis and regional heritability (RH) mapping. Each study is analysed separately, in order to detect study-specific genetic effects that may not generalise across populations. At the same time, because most traits are available in several studies, this also enables meta-analysis, which boosts the power of discovery and can reveal cross-study genetic effects. These methods are a priori complementary to each other, exploiting different aspects of human genetic variation, such as the segregation of variants within families (identity by descent, IBD), or the presence of the same variant throughout the general population (identity by state, IBS). The strengths and weaknesses of these methods are systematically assessed by applying them to real and simulated datasets.
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McEwen, Kirsten Rose. "Epigenetic regulation of imprinted loci in the mouse". Thesis, University of Cambridge, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.609297.
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Nyström, Per-Erik. "Quantitative trait loci in pig production /". Uppsala : Swedish Univ. of Agricultural Sciences (Sveriges lantbruksuniv.), 1999. http://epsilon.slu.se/avh/1999/91-576-5712-2.pdf.
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Wise, Lesley Hilary. "Meta-analysis of genetic studies for complex diseases". Thesis, King's College London (University of London), 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.325514.
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Zouk, Hana. "Functional characterization of novel genetic loci associated with type 1 diabetes". Thesis, McGill University, 2013. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=116897.
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Type 1 diabetes (T1D) is an autoimmune disease that results from the destruction of the insulin producing beta cells by the immune system. A disease of complex etiology, it involves both genetic and environmental factors. Over 40 genetic loci have been shown to increase T1D risk, where allelic variation at several polymorphisms underlies their genetic association. Two of the most important ones map to chromosome 2q24.3, containing functional polymorphisms at the IFIH1 gene, whose role is to bind double stranded (ds) viral RNA and to subsequently induce a type I interferon response, and to chromosome 16p13, encompassing the single CLEC16A gene whose function is unknown. To elucidate the mechanism of these associations, we undertook separate studies to functionally evaluate the role of a T1D-associated IFIH1 polymorphism and to characterize the possible role of CLEC16A in immunity. We began by investigating the role of the T1D-associated coding polymorphism in the IFIH1 gene, Thr946Ala, contained in a linkage disequilibrium (LD) block that encompasses three other genes. Due to the extent of the LD in the region and the possibility of genetic heterogeneity, the Thr946Ala IFIH1 polymorphism could be a marker for a regulatory variant that affects the expression of IFIH1 or the other genes in the IFIH1 block: GCA, KCNH7, and FAP. Upon testing this hypothesis, we observed no significant transcriptional effects at the IFIH1 locus in tissues most relevant to T1D. We also report that protein alleles of the Thr946Ala single nucleotide polymorphism (SNP) had no significant effect on secreted IFN-α levels induced by poly I:C, a dsRNA mimic. Taken together, both studies suggest that the mechanisms of the observed association of the Thr946Ala SNP remains to be determined but does not involve modulation of mRNA or a poly I:C-driven IFN-α response. For the latter, a greater sample size would be needed to confirm this, due to the large observed variability in the IFN response.Our last study focused on the characterization of the CLEC16A protein, whose preferential expression in two antigen presenting cell types points to its potential role in immunity. We thus hypothesized that CLEC16A could be involved in T-cell co-stimulation and activation and assessed this in an antigen-independent model. We found that CLEC16A does not participate in the T-cell co-stimulation pathway, as shown by the lack of effect of the CLEC16A knockdown on T-cell activation and proliferation. We also show subcellular localization of CLEC16A to the rough endoplasmic reticulum (ER). Our results highlight the difficulty in transitioning from T1D genetic associations to functional studies, which are essential in bridging genetic predisposition with biological mechanisms underlying the immune dysregulation associated with T1D. All hypotheses will need to be examined and ruled out one by one until the true mechanism is discovered.Le diabète de type 1 (DT1) est une maladie auto-immune où les cellules bêta, productrices de l'insuline, sont détruites par le système immunitaire. Cette maladie dont l'étiologie est complexe, implique à la fois des facteurs génétiques et environnementaux. Plus de 40 loci génétiques, où il y a une association avec la variation allélique de plusieurs polymorphismes, ont été montré comme augmentant le risque de DT1. Deux de ces régions les plus importantes sont localisés dans la région chromosomique 2q24.3, qui contient des polymorphismes fonctionnels au niveau du gène IFIH1 dont le rôle est de lier l'ARN double brin (DS) viral pour à la suite induire une réponse interféron de type I (IFN), et dans la région chromosomique 16p13, englobant un seul gène nommé CLEC16A dont la fonction est inconnue. Pour élucider le mécanisme de ces associations, nous avons entrepris des études distinctes pour évaluer le rôle fonctionnel d'un polymorphisme de IFIH1 associé au DT1 et de caractériser le rôle possible de CLEC16A dans l'immunité. Nous avons commencé par étudier le rôle d'un polymorphisme codant, Thr946Ala, du gène IFIH1 associé au DT1 et situé dans un bloc de déséquilibre de liaison (DL) qui comprend trois autres gènes. En raison de l'ampleur du DL dans la région ainsi que la possibilité d'une hétérogénéité génétique, le polymorphisme Thr946Ala IFIH1 pourrait être un marqueur pour un variant qui affecte l'expression du gène IFIH1 ou des autres gènes dans le bloc : GCA, KCNH7 et FAP. Lorsque nous avons testé cette hypothèse, nous n'avons observé aucun effet significatif sur la transcription au niveau du locus IFIH1 dans les tissus les plus pertinents pour le DT1. Nous indiquons également que les allèles protéiniques du polymorphisme d'un seul nucléotide (SNP) Thr946Ala n'ont pas d'effets significatifs sur les niveaux l'IFN-α sécrété suite à une stimulation par le poly I:C, un composé imitant l'ARN double brin. Pris ensemble, ces deux études suggèrent que les mécanismes de l'association observée pour le SNP Thr946Ala restent à déterminer, mais n'impliquent pas la modulation de l'ARNm ou la réponse d'IFN-α via le poly I:C. Pour ce dernier, un échantillonnage plus grand serait nécessaire afin de confirmer cette hypothèse en raison de la grande variabilité observée dans la réponse IFN. Notre dernière étude portait sur la caractérisation de la protéine CLEC16A dont l'expression préférentielle par deux types de cellules présentatrice d'antigènes, suggère un rôle potentiel dans l'immunité. Nous avons donc émis l'hypothèse que CLEC16A pourrait être impliqué dans la co-stimulation et l'activation des lymphocytes T et avons évalué celle-ci dans un modèle indépendant d'un antigène. Nous avons constaté que CLEC16A ne participe pas dans la voie de la co-stimulation, comme en témoigne par l'absence d'effets sur l'activation et la prolifération des lymphocytes T lors de la déplétion de CLEC16A. Nous montrons également que la localisation subcellulaire de CLEC16A est dans le réticulum endoplasmique rugueux (RE). Nos résultats mettent en évidence la difficulté qu'est de faire la transition à partir d'associations génétiques avec le DT1 vers des études fonctionnelles, qui sont essentielles pour pouvoir faire le pont entre la prédisposition génétique et les mécanismes biologiques qui sous-tendent le dysfonctionnement immunitaire associé au DT1. Toutes les hypothèses devront être examinées et écartées une par une jusqu'à ce que le mécanisme réel soit découvert.
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Zhang-Barber, Li. "Characterisation of genetic loci of Salmonella typhimurium involved in growth inhibition". Thesis, Imperial College London, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.338933.
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Quaranta, Maria. "A molecular genetic analysis of Crohn's disease susceptibility loci in psoriasis". Thesis, King's College London (University of London), 2012. https://kclpure.kcl.ac.uk/portal/en/theses/a-molecular-genetic-analysis-of-crohns-disease-susceptibility-loci-in-psoriasis(bd43230e-4836-4a73-84e7-0da4212eb834).html.
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Psoriasis is an immune-mediated skin disorder that is inherited as a complex trait. Genome-wide linkage and association studies have identified a major disease susceptibility locus (PSORS1) and several genetic determinants of smaller effect. At least two of these (the IL12B and IL23R genes) have independently been associated with Crohn’’s disease (CD). Thus, the aim of this project was to investigate the genetic overlap between psoriasis and CD, with a view to identifying shared pathogenic pathways. In the first phase of the study, 26 CD variants were genotyped in 1,256 psoriatic patients and 2,938 unaffected individuals. Significant associations (FDR < 0.01) were observed for three markers, mapping to chromosomes 6p22, 21q21 and 21q22. The analysis of an independently ascertained dataset (1,348 cases vs. 1,368 controls) validated the chromosome 6p22 association, with the critical SNP (rs6908425) yielding a combined P value of 4 x 10-6. This marker lies within the CDKAL1 gene, which also harbours type 2 diabetes (T2D) associated alleles. Since the mechanisms mediating the pathogenic effect of CDKAL1 are poorly understood, an investigation into gene function was undertaken in the second part of the study. Real-time PCR analyses of multiple cDNA panels showed that CDKAL1 is abundantly expressed in immune cells, especially in CD4+ and CD19+ lymphocytes. Stable CDKAL1 knock-down cell lines generated by sh-RNA lentiviral transduction were also analysed. This showed that CDKAL1 silencing results in reduced cell proliferation and altered cell cycle progression. Transcription profiling of the knock- down cells identified a number of differentially expressed genes, mostly involved in housekeeping functions and inflammatory responses. Taken together, these findings indicate that CDKAL1 is a pleiotropic gene conferring susceptibility to psoriasis, CD and T2D. The results of functional studies suggest that this pathogenic role may be mediated by an effect on inflammatory responses and cell cycle progression.
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Westbury, Sarah Kate. "Mechanisms in heamopietic differentiation : insights from novel loci in genetic thrombocytopenia". Thesis, University of Bristol, 2017. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.752731.
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Albagha, Omar M. E. "Investigation and characterisation of loci influencing the genetic susceptibility to osteoporosis". Thesis, University of Aberdeen, 2001. http://digitool.abdn.ac.uk/R?func=search-advanced-go&find_code1=WSN&request1=AAIU534859.
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The main aim of this thesis was to identify novel genes or to further define the role of existing candidate genes in the regulation of BMD. In chapter 3, the role of the oestrogen receptor (ER)- and - genes in BMD regulation was investigated because of the importance of oestrogen deficiency in the pathogenesis of postmenopausal osteoporosis. The results showed that ER- haplotypes defined by two intronic polymorphisms (Pvull and XbaI) were significantly associated with BMD in postmenopausal women from the U.K. No significant association was found between a novel ER- polymorphism and BMD. In chapter 4, linkage analysis was performed on a candidate locus on chromosome 11q12-13 that has previously been found to be linked to a high BMD trait. Although the linkage study was insufficiently powered to detect linkage, analysis of a positional candidate gene (the Fra-1 gene) located in the 11q12-13 region showed a strong association with BMD. Fos related antigen-1 (Fra-1) is important in osteoclast differentiation. In chapter 5, a novel polymorphism was identified in the Fra-1 gene and found to be highly associated with BMD in a study of perimenopausal women from the U.K. In chapter 6, association mapping using DNA pooling was performed on the chromosome 1p36 locus which has previously been found to be linked to hip BMD using sib-pair linkage analysis. Analysis of 17 microsatellite markers from the 1p36 region in a group of individuals with high and low BMD showed five positive markers associated with hip BMD. Analysis of two candidate genes in the 1p36 region (the TNFR2 and NPPB genes) showed significant association between polymorphisms in the TNFR2 gene and BMD.
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Carlborg, Örjan. "New methods for mapping quantitative trait loci /". Uppsala : Dept. of Animal Breeding and Genetics, Swedish Univ. of Agricultural Sciences ([Institutionen för husdjurens genetik], Sveriges lantbruksuniv.), 2002. http://projkat.slu.se/SafariDokument/210.htm.
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Reed, Peter Wayne. "Genetic analysis of Type 1 (insulin-dependent) diabetes mellitus". Thesis, University of Oxford, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.325788.
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Evenstone, Lauren. "Employing Limited Next Generation Sequence Data for the Development of Genetic Loci of Phylogenetic and Population Genetic Utility". FIU Digital Commons, 2015. http://digitalcommons.fiu.edu/etd/2191.
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Massively parallel high throughput sequencers are transforming the scientific research by reducing the cost and time necessary to sequence entire genomes. The goal of this project is to produce preliminary genome assemblies of calliphorid flies using Life Technologies’ Ion Torrent sequencing and Illumina’s MiSeq sequencing. I located, assembled, and annotated a novel mitochondrial genome for one such fly, the little studied Chrysomya pacifica that is central to one hypothesis about blow fly evolution. With sequencing data from Chrysomya megacephala, its forensically relevant sister species, much insight can be gained by alignments, sequence and protein analysis, and many more tools within the CLC Genomics Workbench software program. I present these analyses here of these recently diverged species.
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Zhu, Guohua. "Ascertainment in two-phase sampling designs for segregation and linkage analysis /". Connect to text online, 2005. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=case1112844349.
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Thesis (Ph. D.)--Case Western Reserve University, 2005.[School of Medicine] Department of Epidemiology and Biostatistics. Includes bibliographical references. Available online via OhioLINK's ETD Center.
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Newbury, Dianne F. "A genome wide screen for loci involved in specific language impairment". Thesis, University of Oxford, 2002. http://ora.ox.ac.uk/objects/uuid:2b30517a-cecd-49f3-8a5d-556cef6d6723.
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Approximately 4% of English-speaking children are affected by Specific Language Impairment (SLI); a disorder in the development of language skills despite adequate opportunity and normal intelligence. Several studies have indicated the importance of genetic factors in SLI; a positive family history confers an increased risk of development, and monozygotic concordance consistently exceeds that of dizygotic twins. However, like many behavioural traits, SLI is assumed to be genetically complex with several loci contributing to the overall risk. This thesis aims to clarify the genetic mechanisms underlying Specific Language Impairment by the exploitation of recent advances in technological, genetic and statistical techniques. This goal is achieved, for the main part, through the completion of the first-ever, systematic genome-wide screen for loci involved in the disorder. A collection of 98 families was drawn from both epidemiological and clinical populations, all with probands who display severe deficits in language skills. Genome-wide linkage analyses were completed for three language-related measures and identified two regions which may harbour susceptibility gene variants for SLI, one on chromosome 16 and a second on chromosome 19. Both of these loci yielded maximum LOD scores of 3.55 and exceeded the threshold for suggestive linkage under all types of analysis performed. Fine mapping of the chromosome 19 locus with a high-density map of microsatellite markers provided further support for the role of this region in SLI but failed to narrow the area of linkage. The second section of the thesis therefore explores alternative genetic strategies that may facilitate the localisation of susceptibility variants from the genomic regions identified. Mutation screening and association analyses were performed for two candidate genes within a subset of 48 families affected by SLI. The first ⎼ numblike (NBL), or numb-related (NUMB-R) (MIM 604018) ⎼ was selected from the region of linkage on chromosome 19q and the second ⎼ Forkhead-bOX domain P2 (FOXP2) (MIM 605317) ⎼ has recently been shown to be mutated in a family with a severe speech and language disorder. Finally, I describe the mapping of a translocation breakpoint within a child affected by a severe language impairment and orofacial dyspraxia. This breakpoint lies on chromosome 2q and coincides with a putative region of linkage in both language impairment and autism. In the long-term it is hoped that techniques similar to those described here will allow the identification of the gene variants which underlie SLI allowing to the development of better diagnosis and treatment for those children with language impairments.
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Shen, Xia. "Novel Statistical Methods in Quantitative Genetics : Modeling Genetic Variance for Quantitative Trait Loci Mapping and Genomic Evaluation". Doctoral thesis, Uppsala universitet, Beräknings- och systembiologi, 2012. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-170091.
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This thesis develops and evaluates statistical methods for different types of genetic analyses, including quantitative trait loci (QTL) analysis, genome-wide association study (GWAS), and genomic evaluation. The main contribution of the thesis is to provide novel insights in modeling genetic variance, especially via random effects models. In variance component QTL analysis, a full likelihood model accounting for uncertainty in the identity-by-descent (IBD) matrix was developed. It was found to be able to correctly adjust the bias in genetic variance component estimation and gain power in QTL mapping in terms of precision. Double hierarchical generalized linear models, and a non-iterative simplified version, were implemented and applied to fit data of an entire genome. These whole genome models were shown to have good performance in both QTL mapping and genomic prediction. A re-analysis of a publicly available GWAS data set identified significant loci in Arabidopsis that control phenotypic variance instead of mean, which validated the idea of variance-controlling genes. The works in the thesis are accompanied by R packages available online, including a general statistical tool for fitting random effects models (hglm), an efficient generalized ridge regression for high-dimensional data (bigRR), a double-layer mixed model for genomic data analysis (iQTL), a stochastic IBD matrix calculator (MCIBD), a computational interface for QTL mapping (qtl.outbred), and a GWAS analysis tool for mapping variance-controlling loci (vGWAS).
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Overall, Andrew David James. "The geographic scale of human genetic variation at short tandem repeat loci". Thesis, Queen Mary, University of London, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.325035.
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Liu, Yan Tat. "Detection of genetic variation in the human α- and β-globin loci". Thesis, University of Oxford, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.433372.
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Lu, Yue. "Genetic mapping of quantitative trait loci for slow-rusting traits in wheat". Diss., Kansas State University, 2016. http://hdl.handle.net/2097/32179.
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Doctor of PhilosophyDepartment of Agronomy
Guihua Bai
Allan K. Fritz
Wheat leaf rust, caused by Puccinia triticina, is an important fungal disease worldwide. Growing resistant cultivars is an effective practice to reduce the losses caused by the disease, and using slow-rusting resistance genes can improve the durability of rust resistance in the cultivars. CI13227 is a winter wheat line that shows a high level of slow-rusting resistance to leaf rust and has been studied extensively. In this research, two recombinant inbreed line (RIL) populations derived from CI13227 x Suwon (104 RILs) and CI13227 x Everest (184 RILs) and one doubled haploid (DH) population derived from CI13227 x Lakin with 181 lines were used to identify quantitative trait loci (QTLs) for slow leaf rusting resistance. Each population and its parents were evaluated for slow-rusting traits in two greenhouse experiments. A selected set of 384 simple sequence repeat markers (SSRs), single nucleotide polymorphism markers (SNPs) derived from genotyping-by-sequencing (GBS-SNPs) or 90K-SNP chip (90K-SNPs) were analyzed in the three populations. Six QTLs for slow-rusting resistance, QLr.hwwgru-2DS, QLr.hwwgru-7BL, QLr.hwwgru-7AL, QLr.hwwgru-3B_1, QLr.hwwgru-3B_2, and QLr.hwwgru-1D were detected in the three populations with three stable QTLs, QLr.hwwgru-2DS, QLr.hwwgru-7BL and QLr.hwwgru-7AL. These were detected and validated by Kompetitive Allele-Specific PCR (KASP) markers converted from GBS-SNPs and 90K-SNPs in at least two populations. Another three QTLs were detected only in a single population, and either showed a minor effect or came from the susceptible parents. The KASP markers tightly linked to QLr.hwwgru-2DS (IWB34642, IWB8545 and GBS_snpj2228), QLr.hwwgru-7BL (GBS_snp1637 and IWB24039) and QLr.hwwgru-7AL (IWB73053 and IWB42182) are ready to be used in marker-assisted selection (MAS) to transfer these QTLs into wheat varieties to improve slow-rusting resistance in wheat.
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Stone, Hillarey. "Enrichment of Transcriptional Regulators at Steroid Sensitive Nephrotic Syndrome Genetic Risk Loci". University of Cincinnati / OhioLINK, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=ucin160199291391191.
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Preston, E. Lynn. "Isolation and Characterization of Polymorphic Loci from the Caribbean Flamingo (Phoenicopterus ruber ruber): New Tools for Wildlife Management". Thesis, University of North Texas, 2005. https://digital.library.unt.edu/ark:/67531/metadc4908/.
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Methods to determine genetic diversity and relatedness within populations are essential tools for proper wildlife management. Today the approach of choice is polymerase chain reaction-based microsatellite analysis. Seven new polymorphic loci were isolated from a microsatellite-enriched Caribbean flamingo genomic library and used to characterize survey populations of Caribbean and African greater flamingos. In addition, four of these loci were used to verify parentage relationships within a captive-breeding population of African greater flamingos. Parentage predictions based upon gamekeeper observations of breeding and nesting did not always agree with genetic-based parentage analyses of the nine suggested family groups. Four family groups were supported (groups I, II, III and VI) by there results. However, an analysis of the remaining five suggested groups, with a total of eight offspring/dam and eight offspring/sire suggested relationships, yielded seven exclusions of the suggested dam and six exclusions of the suggested sire. This put the overall suggested dam exclusion rate at 35% and exclusion rate for suggested sires at 29%. Although the keeper observation data for our family groups must be considered a variable of concern at this time, these findings are certainly suggestive that more carefully controlled studies may reveal that flamingos are not monogamous as long accepted, but rather socially monogamous or even promiscuous. Thus we have now been able to both characterize and demonstrate the utility of our polymorphic microsatellite loci. We hope these results will interest additional wildlife facilities in further parentage and behavioral studies that will collectively aid to improve monitoring and maintenance of genetic diversity, and as provide better insight into breeding habits of both wild and captive populations.
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Silva, Heyder Diniz. "Aspectos biométricos da detecção de QTL'S ("Quantitative Trait Loci") em espécies cultivadas". Universidade de São Paulo, 2001. http://www.teses.usp.br/teses/disponiveis/11/11134/tde-18102002-162652/.
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O mapeamento de QTL's difere dos demais tipos de pesquisas conduzida em genética. Por se tratar basicamente de um procedimento de testes múltiplos, surge, neste contexto, um problema que se refere ao nível de significância conjunto da análise, e consequentemente, seu poder. Deste modo, avaliou-se, via simulação computacional de dados, o poder de detecção de QTL's da análise de marcas simples, realizada por meio de regressão linear múltipla, utilizando o procedimento stepwise" para seleção das marcas e procedimentos baseados em testes individuais, utilizando os critérios FDR e de Bonferroni para determinação nível de significância conjunto. Os resultados mostraram que o procedimento baseado em regressão múltipla, utilizando o procedimento stepwise" foi mais poderoso em identificar as marcas associadas a QTL's e, mesmo nos casos em que este procedimento apresentou poder ligeiramente inferior aos demais, verificou-se que o mesmo tem como grande vantagem selecionar apenas as marcas mais fortemente ligadas aos QTL's. Dentre os critérios FDR e de Bonferroni, o primeiro mostrou-se, em geral, mais poderoso, devendo ser adotado nos procedimentos de mapeamento por intervalo. Outro problema encontrado na análise de QTL's refere-se µa abordagem da interação QTL's x ambientes. Neste contexto, apresentou-se uma partição da variância da interação genótipos x ambientes em efeitos explicados pelos marcadores e desvios, a partir da qual obtiveram-se os estimadores da proporção da variância genética (pm), e da variância da interação genótipos x ambientes (pms), explicadas pelos marcadores moleculares. Estes estimadores independem de desvios das frequências alélicas dos marcadores em relação µ as esperadas (1:2:1 em uma geração F2, 1:1 em um retrocruzamento, etc.), porém, apresentam uma alta probabilidade de obtenção de estimativas fora do intervalo paramétrico, principalmente para valores elevados destas proporções. Contudo, estas probabilidades podem ser reduzidas com o aumento do número de repetições e/ou de ambientes nos quais as progênies são avaliadas. A partir de um conjunto de dados de produtividade de grãos, referentes µ a avaliação de 68 progênies de milho, genotipadas para 77 marcadores moleculares codominantes e avaliadas em quatro ambientes, verificou-se que as metodologias apresentadas permitiram estimar as proporções pm e pms, bem como classificar as marcas associadas a QTL's, conforme seu nível de interação. O procedimento permitiu ainda a identificação de regiões cromossômicas envolvidas no controle genético do caractere sob estudo conforme sua maior ou menor estabilidade ao longo dos ambientes.In general terms, QTL mapping di®ers from other research ac-tivities in genetics. Being basically a multiple test procedure, problems arise which are related to the joint level of signi¯cance of the analysis, and consequently, to its power. Using computational simulation of data, the power of simple marker analysis, carried out through multiple linear regression, using stepwise procedures to select the markers was obtained. Procedures based on single tests, using both the FDR and the Bonferroni criteria to determinate the joint level of signi¯cance were also used. Results showed that the procedure based on multiple regression, using the stepwise technique, was the most powerful in identifying markers associated to QTL's. However, in cases where its power was smaller, its advantage was the ability to detect only markers strongly associates with QTL's. In comparision with the Bonferroni method, the FDR criterion was in general more powerful, and should be adopted in the interval mapping procedures. Additional problems found in the QTL analysis refer to the QTL x environment interaction. We consider this aspect by par-titioning the genotype x environment interaction variance in components explained by the molecular markers and deviations. This alowed estimating the proportion of the genetic variance (pm), and genotype x environment variance (pms), explained by the markers. These estimators are not a®ected by deviations of allelic frequencies of the markers in relation to the expected values (1:2:1 in a F2 generation, 1:1 in a backcross , etc). However, there is a high probability of obtaining estimates out of the parametric range, specially for high values of this proportion. Nevertheless, these probabilities can be reduced by increasing the number of replications and/or environments where the progenies are evaluated. Based on a set of grain yield data, obtained from the evaluation of 68 maize progenies genotyped for 77 codominant molecular markers, and evaluated as top crosses in four environments, the presented methodologies allowed estimating proportions pm and pms as well the classification of markers associated to QTL's, with respect to its level of genotype x environment interaction. The procedure also allowed the identification of chromosomic regions, involved in the genetical control of the considered trait, according to its stability, in relation to the observed environmental variation.
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Saunders, Barbara Ann. "Investigation of the inheritance of RAPD loci in Daphnia Pulex /". Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape10/PQDD_0002/MQ42439.pdf.
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Antonella, Galvan. "Mapping of loci providing genetic resistance to tumorigenesis and characterization of candidate genes". Thesis, Open University, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.491913.
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Genome-wide screening by genetic marker analysis in crosses between well-characterized mouse strains may allow the identification of loci responsible for susceptibility and resistance to specific tumour types. The aim of this project was to carry out the mapping of cancer modifier loci controlling both skin and lung tumour phenotypes in a SWR x (SWR x Car-R) backcross population by genome-wide analysis of single nucleotide polymorphisms (SNPs). Through different experimental approaches, such as SNP library genotyping, genomic DNA subtraction and SNP array analysis we identified cancer modifier loci involved in skin or lung cancer susceptibility and characterized cancer modifier genes mapping in these associated regions. SNP library genotyping detected an association of the Par4 locus with lung tumorigenesis. Candidate gene analysis in this region revealed a nonconservative variation in Met gene, that highlighted its candidacy for the Par4 locus. Genomic subtraction identified a Chr.1 region, where genetic linkage analysis of 17 SNPs in individual mice confirmed the significant association of this region to skin and lung tumour susceptibility. By a candidate gene approach we focused on Igfbp5. In vitro characterization detected -4.0-fold inhibition of clonogenicity by Igfbp5 over-expression in human lung cancer cell lines and expression analysis in normal lung tissue revealed -2.0-fold higher transcript levels in resistant Car-R compared with susceptible SWR mice, revealing a 3 Supplied by The British Library - 'The world's knowledge' 1I .! j. f Abstract potential role of Igfbp5 gene in modulating lung tumorigenesis. Preliminary analysis of genome-wide scans using SNP arrays confirmed the Chr.1 and Chr.6 loci; the present pedigree analysis in the remaining genome may allow the identification of additional loci affecting lung and skin tumorigenesis, thus demonstrating that the susceptibility to both tumorigenesis result from a combination of several weak genetic loci. . In conclusion, genome-wide analysis in well-defined mice allowed the identification of QTLs and genes affecting lung and skin cancer susceptibility through a combination of methodologies.
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Baron, Gerald Stephen. "Isolation and characterization of two genetic loci from the intracellular pathogen Francisella novicida". Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp02/NQ36628.pdf.
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Sieh, Weiva. "Genetic susceptibility to prostate cancer : the androgen receptor and prostate-specific antigen loci /". Thesis, Connect to this title online; UW restricted, 2003. http://hdl.handle.net/1773/10875.
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Selladurai, Surendran. "Genetic mapping and molecular characterisation of Russian wheat aphid resistance loci in wheat". Thesis, Selladurai, Surendran (2016) Genetic mapping and molecular characterisation of Russian wheat aphid resistance loci in wheat. PhD thesis, Murdoch University, 2016. https://researchrepository.murdoch.edu.au/id/eprint/33781/.
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The Russian wheat aphid (RWA, Diuraphis noxia Kurdmojov) is considered as one of the most destructive pest of wheat around the world, causing significant yield loss in wheat cultivation. A continuous process of searching for novel resistance loci (Dn) to combat evolving new RWA biotypes has been successful in providing RWA resistance to breeding programs. Australia was declared as a RWA free country but Infestation of RWA was first time reported in Tarlee, South Australia in April, 2016. A novel resistance source, PI94365 with expressing resistance to several biotypes found in other countries was selected to incorporate its resistance into the Australian cultivar EGA Gregory. A double haploid (DH) population developed through the microspore technique was phenotyped in South Africa, Turkey and Morocco with respective biotypes. A genetic linkage map was constructed with 4053 molecular markers including simple sequence repeats (SSR), genome by sequencing (GBS) and Diversity array technology (DArT) molecular markers. Major QTLs to RWA resistance were mapped on 1DS, 7DS and 7BL and minor QTLs were mapped on 3BL, 4AS and 4DL. POPSEQ genetic map distances for the QTLs identified on chromosomes 1DS and 7DS were determined by comparative genomics studies with published consensus and POPSEQ maps. A large number of molecular markers have been identified in the region of RWA resistance loci for the marker assisted plant breeding.
Proteomics studies in the absence of live aphids (due to quarantine restriction in Australia) were carried out in order to reveal the resistance mechanism driven by constitutive genes. Ten proteins were significantly differentially expressed between resistance and susceptible lines selected from the double haploid population that was mapped in detail through haplotype analysis. These proteins were annotated using the current wheat genome assembly and functional annotation in relation to RWA resistance.
Studies identified several induced proteins with RWA infestations. Differentially expressed genes identified in these studies annotated to the wheat genome together with their genetic map location assigned some of the genes to major RWA resistance QTLs and thus this study provided some new insights into RWA resistance. Over all, the work carried out in this study delivered RWA resistant wheat lines for breeding resistance cultivars that are well characterized by a broad range of molecular markers in the regions of the RWA resistance loci. The high density of new molecular markers provides for the efficient tracking of RWA resistance loci in the pipe-line of cultivar development within the framework of quarantine restrictions.
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Morona, Judy Kay. "Characterisation of the capsular polysaccharide biosynthesis loci of streptococcus pneumoniae serogroup 19 /". Title page, contents and abstract only, 1998. http://web4.library.adelaide.edu.au/theses/09PH/09phm8678.pdf.
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Dierks, Claudia. "Molecular genetic analysis of quantitative trait loci (QTL) for osteochondrosis in Hanoverian warmblood horses". [S.l.] : [s.n.], 2006. http://deposit.ddb.de/cgi-bin/dokserv?idn=980656702.
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Roca, Ayats Neus. "Identification and functional characterization of genetic loci involved in osteoporosis and atypical femoral fracture". Doctoral thesis, Universitat de Barcelona, 2019. http://hdl.handle.net/10803/668311.
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Osteoporosis is a complex disease, determined by genetic and environmental factors, characterized by a low bone mass and microarchitectural deterioration of bone tissue, with a consequent decrease of bone strength and increase in bone fragility and fracture risk. It is the most common bone metabolic disorder, and a major worldwide public health concern.
Bone mineral density (BMD) heritability ranges from 50% to 85% and genetic factors have a crucial role in the pathogenesis of osteoporosis. To date, many genes and variants associated with osteoporosis have been identified, but they only explain 20% of the phenotypic variance. In addition, the underlying mechanisms of these associations are poorly understood. Hence, it is necessary to identify new variants/genes and to deepen the knowledge about osteoporosis pathogenesis.
Nitrogen-containing bisphosphonates (N-BPs) are the first-line pharmacological treatment for osteoporosis. They are cost-effective anti-resorptive drugs that inhibit the mevalonate pathway, preventing osteoclasts’ function and promoting their apoptosis. Very rarely, atypical femoral fractures (AFFs) can occur after a long-term therapy with N-BPs. AFFs are located in the subtrochanteric region or the femoral diaphysis and arise after minimal or no trauma. The pathogenic mechanisms underlying AFF remain largely unknown.
This PhD thesis aimed at contributing to the elucidation of the genetic determinants of osteoporosis and AFF.
On the one side, we deeply studied a GWAS signal in the C7ORF76 locus, in 7q21.3, including its dissection in the BARCOS cohort of Spanish postmenopausal women and the functional characterization of the associated variants and regulatory elements within the locus. We identified 2 variants associated with BMD and osteoporotic fracture and showed that they are cis-eQTLs for the neighbouring gene SLC25A13 in human primary osteoblasts. One of the associated variants lay in an upstream putative regulatory element, which we named UPE. We have demonstrated the regulatory capacity of UPE in bone cells, and its interaction with a lncRNA and other regulatory elements within the region.
We also studied a previously described mouse Dlx5/6 enhancer (eDlx#18) within the C7ORF76 locus. We demonstrated that it is able to activate transcription in an osteoblastic context and that it interacts with the DLX5 promoter, as well as with other tissue-specific DLX5/6 enhancers. An SNP within this enhancer has been shown to be a cis-eQTL for DLX6 in human primary osteoblasts. Finally, the homozygous deletion of eDlx#18 in mice resulted in a reduced viability, a decreased Dlx5 expression in otic vesicle and branchial arches in E11.5 embryos. In E17.5 embryos, skeletal defects were noted, including a smaller dentary and deficient ossification at several sites.
On the other side, a small cohort of N-BP-associated AFF patients was analyzed by whole exome sequencing, and the most conserved and interesting mutation found, in the GGPS1 gene, was functionally characterized using molecular and cellular approaches. We found 37 rare mutations in 34 genes shared by 3 sisters with N-BP-associated AFF, including mutations in GGPS1 and CYP1A1, which was also mutated in one unrelated patient. The p.Asp188Tyr mutation in GGPS1 affected oligomerization of the enzyme, leading to a severe reduction in enzyme activity. GGPS1 depletion in osteoblastic cells resulted in a strong mineralization reduction and a decreased expression of some osteoblastic markers, such as osteocalcin, osterix and RANKL. The depletion in osteoclast precursors led to increased osteoclast number but with reduced resorption activity.
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Zhu, Hong. "Genetic and expression analysis of candidate tumor loci in non-small cell lung cancer". Click to view the E-thesis via HKUTO, 2005. http://sunzi.lib.hku.hk/hkuto/record/B35328368.
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Mikko, Sofia. "A comparative analysis of genetic diversity at Mhc DRB loci in some ruminant species /". Uppsala : Swedish Univ. of Agricultural Sciences (Sveriges lantbruksuniv.), 1997. http://epsilon.slu.se/avh/1997/91-576-5237-6.gif.
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Case, Richard Alan James. "Population genetic structure of Atlantic cod (Gadus morhua) : applications of neutral and selected loci". Thesis, University of Hull, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.440646.
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Zhu, Hong, i 朱紅. "Genetic and expression analysis of candidate tumor loci in non-small cell lung cancer". Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2005. http://hub.hku.hk/bib/B35328368.
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