The document discusses approaches for identifying genes associated with neurological disorders. It describes several methods: linkage studies, homozygosity mapping, exome and whole genome sequencing, genome-wide association studies, detection of structural variation, and transcriptomics. Each method is summarized, with examples provided of neurological genes identified through various approaches such as exome sequencing. The human genome is also briefly described to provide context. In summary, the document outlines strategies for pinpointing genes underlying neurological conditions.
Los días 11 y 12 de diciembre de 2014, la Fundación Ramón Areces celebró el Simposio Internacional 'Neuropatías periféricas hereditarias. Desde la biología a la terapéutica' en colaboración con CIBERER-ISCIII y el Centro de Investigación Príncipe Felipe. El tipo más común de estas patologías es la enfermedad de Charcot-Marie-Tooth, un trastorno neuromuscular hereditario con una prevalencia estimada de 17-40 afectados por 100.000 habitantes. Durante estos dos días, investigadores mostraron sus avances en la mejora del diagnóstico y el tratamiento y, por ende, de la aproximación clínica y la calidad de vida de las personas afectadas por estas patologías.
The document summarizes Huntington's disease (HD), including that it is a genetic neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin gene. It describes the clinical features and progression of HD and discusses the role of mutant huntingtin. It also summarizes the pathology of HD in the brain and basal ganglia. Various animal models of HD are described, including toxin models, genetic mouse models expressing mutant huntingtin fragments or full-length protein, and non-human primate models.
Genomics is the study of all nucleotide sequences in an organism, including genes, noncoding regions, and regulatory elements. Determining the human genome sequence involved forming DNA libraries, sequencing clones, and ordering sequences using computational analysis. Genomics has applications in medicine like gene testing for inherited disorders and understanding drug responses. Pharmacogenomics studies how genetic differences impact individual drug metabolism and effects, aiming to prevent adverse drug reactions by screening for risk alleles.
This document provides an overview of DNA methylation analysis. It begins with background on DNA methylation functions and diseases. It then discusses methods for measuring DNA methylation status, including bisulfite sequencing. The document reviews steps for DNA methylation data analysis using tools like methylKit in R. It presents a case study example of analyzing DNA methylation data from human stem cells and fibroblasts. Alignment, quality control, differential methylation analysis and visualization are discussed.
Gene therapy involves inserting normal genes into cells to treat genetic diseases. The first successful gene therapy trial treated a patient with severe combined immunodeficiency (SCID) caused by adenosine deaminase (ADA) deficiency. The procedure involved removing the patient's lymphocytes, infecting them with a retrovirus carrying the normal ADA gene, allowing the gene to integrate and express ADA, and returning the modified lymphocytes to the patient to permanently produce the enzyme. This landmark trial established gene therapy as a viable treatment approach for genetic diseases.
Gene therapy aims to treat Parkinson's disease by inserting genes into cells to correct deficiencies. It has advantages over traditional treatments by potentially targeting the underlying causes and slowing disease progression. Two main approaches are ex vivo gene therapy, where cells are modified outside the body, and in vivo gene therapy through direct brain injection. Viral vectors are commonly used to deliver genes but carry risks. Ongoing research is exploring using gene therapy to restore dopamine synthesis, modulate basal ganglia activity, or provide neuroprotection for Parkinson's.
Los días 11 y 12 de diciembre de 2014, la Fundación Ramón Areces celebró el Simposio Internacional 'Neuropatías periféricas hereditarias. Desde la biología a la terapéutica' en colaboración con CIBERER-ISCIII y el Centro de Investigación Príncipe Felipe. El tipo más común de estas patologías es la enfermedad de Charcot-Marie-Tooth, un trastorno neuromuscular hereditario con una prevalencia estimada de 17-40 afectados por 100.000 habitantes. Durante estos dos días, investigadores mostraron sus avances en la mejora del diagnóstico y el tratamiento y, por ende, de la aproximación clínica y la calidad de vida de las personas afectadas por estas patologías.
The document summarizes Huntington's disease (HD), including that it is a genetic neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin gene. It describes the clinical features and progression of HD and discusses the role of mutant huntingtin. It also summarizes the pathology of HD in the brain and basal ganglia. Various animal models of HD are described, including toxin models, genetic mouse models expressing mutant huntingtin fragments or full-length protein, and non-human primate models.
Genomics is the study of all nucleotide sequences in an organism, including genes, noncoding regions, and regulatory elements. Determining the human genome sequence involved forming DNA libraries, sequencing clones, and ordering sequences using computational analysis. Genomics has applications in medicine like gene testing for inherited disorders and understanding drug responses. Pharmacogenomics studies how genetic differences impact individual drug metabolism and effects, aiming to prevent adverse drug reactions by screening for risk alleles.
This document provides an overview of DNA methylation analysis. It begins with background on DNA methylation functions and diseases. It then discusses methods for measuring DNA methylation status, including bisulfite sequencing. The document reviews steps for DNA methylation data analysis using tools like methylKit in R. It presents a case study example of analyzing DNA methylation data from human stem cells and fibroblasts. Alignment, quality control, differential methylation analysis and visualization are discussed.
Gene therapy involves inserting normal genes into cells to treat genetic diseases. The first successful gene therapy trial treated a patient with severe combined immunodeficiency (SCID) caused by adenosine deaminase (ADA) deficiency. The procedure involved removing the patient's lymphocytes, infecting them with a retrovirus carrying the normal ADA gene, allowing the gene to integrate and express ADA, and returning the modified lymphocytes to the patient to permanently produce the enzyme. This landmark trial established gene therapy as a viable treatment approach for genetic diseases.
Gene therapy aims to treat Parkinson's disease by inserting genes into cells to correct deficiencies. It has advantages over traditional treatments by potentially targeting the underlying causes and slowing disease progression. Two main approaches are ex vivo gene therapy, where cells are modified outside the body, and in vivo gene therapy through direct brain injection. Viral vectors are commonly used to deliver genes but carry risks. Ongoing research is exploring using gene therapy to restore dopamine synthesis, modulate basal ganglia activity, or provide neuroprotection for Parkinson's.
This document describes a study that used exome sequencing to identify genetic causes of adult-onset mitochondrial diseases. The study sequenced the exomes of 8 patients with progressive external ophthalmoplegia (PEO) and identified novel variants in the RRM1 and TOP3A genes. Sanger sequencing confirmed the variants and identified a TOP3A variant (p.M100V) in another patient but not in 102 controls. The study concludes that RRM1 and TOP3A may cause mitochondrial disease but further work is needed to verify candidate genes and variants.
Gene Therapy: Central concept of gene therapy, basic molecular mechanism of gene transfer, prerequisite of human gene therapy, biological basis of gene therapy strategies, vehicles for gene transfer, Antisence oligonucleotides and RNAi, clinical gene therapy studies, gene therapy for hereditary disease, gene therapy for cancer, gene therapy for HIV.
Gene therapy is the science of making specific changes to the human genome to improve it or achieve therapeutic effects for gene-related diseases. This document discusses gene therapy in three sentences: it defines gene therapy, describes the three main types (germline, somatic, vaccination), and explains that somatic gene therapy aims to treat body cells without affecting future generations. The document then discusses the process of gene therapy including identifying defective genes, creating a replacement gene, and delivering the new gene into the body.
The document summarizes Pierre Zwiegers' thesis defense for a Master of Science degree. Zwiegers investigated targeted lentiviral-mediated delivery of progranulin cDNA in a genetic model of amyotrophic lateral sclerosis (ALS). The thesis included background on ALS and the neurotrophic properties of progranulin. Experiments assessed whether early-stage progranulin upregulation could lessen behavioral and neuropathological symptoms in transgenic mSOD1 mice. Results found no effect on disease onset, survival, neuronal loss or inflammation. Discussion addressed limitations of mSOD1 models for clinical translation and need for replicative pre-clinical studies.
This document discusses gene therapy for the treatment of cancer. It begins by explaining what genes are and how they relate to cancer development. It then describes the process of making gene therapy medicine, which involves using a modified adenovirus to deliver a tumor suppressor gene like p53 into cancer cells. The document explains how gene therapy works by having the adenovirus deliver the tumor suppressor gene into the cancer cell nucleus, where it causes the cancer cell to self-destruct. It notes that gene therapy can be administered directly into tumors or systemically via injection. The document concludes by presenting examples of patients who were
This document provides an overview of gene therapy, including types, approaches, vectors used, methods of delivery, advantages, disadvantages, applications, and recent advances. It discusses somatic cell gene therapy, which aims to correct genetic defects in non-reproductive cells, and germline gene therapy, which could pass alterations to future generations but poses more risks. Ex vivo and in vivo gene therapy approaches are described. Viral and non-viral vectors as well as various delivery methods are outlined. Some applications including cystic fibrosis and cancer are highlighted. Risks and ethical considerations are also mentioned.
Genome Editing & Gene Therapy by Eric KelsicImpact.Tech
Slides from the Genome editing & gene therapy Impact.tech seminar, hosted by Eric Kelsic on June 11th, 2019.
The seminar covers the experiments and inventions that led to the development of genome editing technologies. These inventions were derived from life itself: isolated from natural organisms and adapted for scientific and therapeutic goals. You will learn the history of how genome engineering tools, including CRISPR, and delivery technology, including AAV capsids, were created in their modern form. The seminar explores how genome editing and gene therapy technologies are giving individuals control over their own genomes, focusing on the treatment of genetic diseases. It will describe major companies and emerging trends in the gene therapy industry. Finally, the seminar will discuss how and where new discoveries, including accelerated algorithms for genetic engineering, will lead us in the near and distant future.
Eric Kelsic, PhD, is the founder and CEO of Dyno Therapeutics, a VC-backed biotech located in Cambridge, Massachusetts. Dyno is leading a machine learning revolution to develop enhanced capsid proteins that enable new gene and genome editing therapies. Eric co-developed the technology underlying Dyno’s machine-guided protein engineering platform as a Staff Scientist in George Church’s lab at the Wyss Institute of Harvard Medical School. He holds a PhD in Systems Biology from Harvard University and a BS in Physics from Caltech.
Gene therapy is an experimental technique that uses genes to treat disease by inserting genes into patients' cells instead of using drugs or surgery. Recent research has shown promising advances in gene therapy to treat various diseases. However, gene therapy still faces technical challenges such as safely delivering genes to target cells and tissues, potential immune responses, and difficulty treating complex multigenic disorders. While still experimental, gene therapy offers hope for treating currently incurable conditions.
Ultra-High-Field 1H MRS as a Prognostic Precision Medicine Biomarker Detectio...Uzay Emir
Ultra-high-field MRS can directly identify molecular markers like IDH1 and IDH2 mutations in gliomas in less than 5 minutes with high sensitivity and specificity. It detected 2-HG in two case studies of patients with gliomas, leading to a diagnosis of IDH2 mutation in one case. Compared to standard 3T MRS, 7T MRS using a double spin echo technique had improved detection of 2-HG. Ultra-high-field MRS provides a non-invasive method for prognostic precision medicine by stratifying and monitoring IDH mutant glioma patients through detection of genetic and metabolic biomarkers.
Gene therapy involves introducing genetic material into host cells to treat diseases caused by genetic mutations. It has been used to treat several conditions like ADA-SCID, cystic fibrosis, and inherited retinal diseases. Various gene delivery systems exist including viral vectors like adenovirus, AAV, and retroviruses. Strategies for gene therapy include gene augmentation, inhibition, targeting, assisted killing, and prodrug therapy. While promising, gene therapy still faces challenges like improving delivery methods and reducing immune responses.
Gene therapy involves transferring nucleic acids into cells to treat disease. The first approved gene therapy procedure was performed in 1990 on 4-year-old Ashanthi DeSilva who had severe combined immunodeficiency. Doctors removed her white blood cells, inserted the missing gene, and reinfused the cells. There are two main types of gene therapy: somatic and germline. Viral and non-viral vectors are used to deliver therapeutic genes. While gene therapy holds promise, safety issues remain due to potential short-lived effects, immune responses, and risks from viral vectors.
Gene therapy refers to the insertion of genetic material to correct a genetic defect.
In gene therapy, a "normal" gene is inserted into the genome to replace an "abnormal," disease-causing gene
Primary Mitochondrial Disease and Secondary Mitochondrial Dysfunctionmitoaction
This document summarizes a presentation by Dr. Richard E. Frye on mitochondrial dysfunction in neurodevelopmental disorders and autism. The presentation covers:
- Evidence that mitochondrial dysfunction is involved in many diseases and now believed to be important in autism based on studies showing abnormalities in electron transport chain complexes in autistic children.
- Further studies demonstrating differences in mitochondrial reserve capacity between autistic children and controls, and associations with environmental exposures like air pollution.
- Research into mechanisms of dysfunction including effects of the gut microbiome, genes, and potential treatments like mitochondrial cocktails.
This document provides an overview of gene therapy. It defines key terms like genetics, genes, chromosomes, and therapy. It explains that gene therapy involves inserting a normal gene to replace an abnormal gene causing disease. Viruses and non-viral methods can be used as vectors to deliver therapeutic genes. While some gene therapies have shown promise for diseases like Parkinson's and immune deficiencies, the field has also faced challenges. Safety issues in early trials halted some research, but recent studies demonstrate progress in refining methods and potentially treating diseases like sickle cell anemia.
In this slide, You will get to learn abut Gene Therapy and different types of gene therapy. Various method of Gene Therapy and Advantage & Disadvantage and Recent advances in Gene Therapy.
Introduction
Approaches to Gene Therapy
Vectors in Gene Therapy
Non-viral Methods
Physical Methods for Improving DNA Transfer
Chemical Methods for Improving DNA Transfer
Advantages and Disadvantages of Gene Therapy
Applications of Gene Therapy
Challenges
Présentation de Michel Pucéat réalisée durant le cours du réseau international des instituts Pasteur de "Médecine Génomique: du diagnostic à la thérapie " (17-21 octobre 2016)
Gene therapy involves inserting a normal gene to replace an abnormal gene that causes a genetic disease. It can replace or inactivate mutated genes, or introduce new genes to fight disease. Common applications include treating cystic fibrosis, hemophilia, cancer, and HIV. Viral vectors like retroviruses and adenoviruses are often used to deliver genes, but they can cause immune reactions. Non-viral methods like nanoparticles, electroporation, and ultrasound show promise for safer gene delivery. Overall, gene therapy holds potential for treating many currently incurable genetic disorders and diseases.
Gene therapy is an experimental technique that involves inserting a normal gene to replace a defective gene responsible for disease. It can replace a mutated disease-causing gene with a healthy copy or inactivate a mutated gene functioning improperly. Common diseases targeted include severe combined immunodeficiency, hemophilia, cystic fibrosis, hemoglobinopathies like thalassemia and sickle cell anemia, Parkinson's disease, and cancer. The first approved gene therapy case occurred in 1990 treating a girl with immune deficiency. Since then, gene therapy has been used to treat metastatic melanoma. Gene therapy can affect the germline permanently or somatic cells temporarily.
"From the Chromosome...Everything". My Inaugural Lecture at the Blizard Institute, Barts & The London School of Medicine & Dentistry, Queen Mary University of London. 10th May 2010.
Cancer is characterized by abnormal cell growth and division. The hallmarks of cancer include self-sufficiency in growth signals, insensitivity to growth inhibition, evading apoptosis, limitless replicative potential, sustained angiogenesis, and ability to invade and metastasize. Cancer results from mutations in oncogenes and tumor suppressor genes caused by factors such as viruses, bacteria, chemicals, and radiation.
This document describes a study that used exome sequencing to identify genetic causes of adult-onset mitochondrial diseases. The study sequenced the exomes of 8 patients with progressive external ophthalmoplegia (PEO) and identified novel variants in the RRM1 and TOP3A genes. Sanger sequencing confirmed the variants and identified a TOP3A variant (p.M100V) in another patient but not in 102 controls. The study concludes that RRM1 and TOP3A may cause mitochondrial disease but further work is needed to verify candidate genes and variants.
Gene Therapy: Central concept of gene therapy, basic molecular mechanism of gene transfer, prerequisite of human gene therapy, biological basis of gene therapy strategies, vehicles for gene transfer, Antisence oligonucleotides and RNAi, clinical gene therapy studies, gene therapy for hereditary disease, gene therapy for cancer, gene therapy for HIV.
Gene therapy is the science of making specific changes to the human genome to improve it or achieve therapeutic effects for gene-related diseases. This document discusses gene therapy in three sentences: it defines gene therapy, describes the three main types (germline, somatic, vaccination), and explains that somatic gene therapy aims to treat body cells without affecting future generations. The document then discusses the process of gene therapy including identifying defective genes, creating a replacement gene, and delivering the new gene into the body.
The document summarizes Pierre Zwiegers' thesis defense for a Master of Science degree. Zwiegers investigated targeted lentiviral-mediated delivery of progranulin cDNA in a genetic model of amyotrophic lateral sclerosis (ALS). The thesis included background on ALS and the neurotrophic properties of progranulin. Experiments assessed whether early-stage progranulin upregulation could lessen behavioral and neuropathological symptoms in transgenic mSOD1 mice. Results found no effect on disease onset, survival, neuronal loss or inflammation. Discussion addressed limitations of mSOD1 models for clinical translation and need for replicative pre-clinical studies.
This document discusses gene therapy for the treatment of cancer. It begins by explaining what genes are and how they relate to cancer development. It then describes the process of making gene therapy medicine, which involves using a modified adenovirus to deliver a tumor suppressor gene like p53 into cancer cells. The document explains how gene therapy works by having the adenovirus deliver the tumor suppressor gene into the cancer cell nucleus, where it causes the cancer cell to self-destruct. It notes that gene therapy can be administered directly into tumors or systemically via injection. The document concludes by presenting examples of patients who were
This document provides an overview of gene therapy, including types, approaches, vectors used, methods of delivery, advantages, disadvantages, applications, and recent advances. It discusses somatic cell gene therapy, which aims to correct genetic defects in non-reproductive cells, and germline gene therapy, which could pass alterations to future generations but poses more risks. Ex vivo and in vivo gene therapy approaches are described. Viral and non-viral vectors as well as various delivery methods are outlined. Some applications including cystic fibrosis and cancer are highlighted. Risks and ethical considerations are also mentioned.
Genome Editing & Gene Therapy by Eric KelsicImpact.Tech
Slides from the Genome editing & gene therapy Impact.tech seminar, hosted by Eric Kelsic on June 11th, 2019.
The seminar covers the experiments and inventions that led to the development of genome editing technologies. These inventions were derived from life itself: isolated from natural organisms and adapted for scientific and therapeutic goals. You will learn the history of how genome engineering tools, including CRISPR, and delivery technology, including AAV capsids, were created in their modern form. The seminar explores how genome editing and gene therapy technologies are giving individuals control over their own genomes, focusing on the treatment of genetic diseases. It will describe major companies and emerging trends in the gene therapy industry. Finally, the seminar will discuss how and where new discoveries, including accelerated algorithms for genetic engineering, will lead us in the near and distant future.
Eric Kelsic, PhD, is the founder and CEO of Dyno Therapeutics, a VC-backed biotech located in Cambridge, Massachusetts. Dyno is leading a machine learning revolution to develop enhanced capsid proteins that enable new gene and genome editing therapies. Eric co-developed the technology underlying Dyno’s machine-guided protein engineering platform as a Staff Scientist in George Church’s lab at the Wyss Institute of Harvard Medical School. He holds a PhD in Systems Biology from Harvard University and a BS in Physics from Caltech.
Gene therapy is an experimental technique that uses genes to treat disease by inserting genes into patients' cells instead of using drugs or surgery. Recent research has shown promising advances in gene therapy to treat various diseases. However, gene therapy still faces technical challenges such as safely delivering genes to target cells and tissues, potential immune responses, and difficulty treating complex multigenic disorders. While still experimental, gene therapy offers hope for treating currently incurable conditions.
Ultra-High-Field 1H MRS as a Prognostic Precision Medicine Biomarker Detectio...Uzay Emir
Ultra-high-field MRS can directly identify molecular markers like IDH1 and IDH2 mutations in gliomas in less than 5 minutes with high sensitivity and specificity. It detected 2-HG in two case studies of patients with gliomas, leading to a diagnosis of IDH2 mutation in one case. Compared to standard 3T MRS, 7T MRS using a double spin echo technique had improved detection of 2-HG. Ultra-high-field MRS provides a non-invasive method for prognostic precision medicine by stratifying and monitoring IDH mutant glioma patients through detection of genetic and metabolic biomarkers.
Gene therapy involves introducing genetic material into host cells to treat diseases caused by genetic mutations. It has been used to treat several conditions like ADA-SCID, cystic fibrosis, and inherited retinal diseases. Various gene delivery systems exist including viral vectors like adenovirus, AAV, and retroviruses. Strategies for gene therapy include gene augmentation, inhibition, targeting, assisted killing, and prodrug therapy. While promising, gene therapy still faces challenges like improving delivery methods and reducing immune responses.
Gene therapy involves transferring nucleic acids into cells to treat disease. The first approved gene therapy procedure was performed in 1990 on 4-year-old Ashanthi DeSilva who had severe combined immunodeficiency. Doctors removed her white blood cells, inserted the missing gene, and reinfused the cells. There are two main types of gene therapy: somatic and germline. Viral and non-viral vectors are used to deliver therapeutic genes. While gene therapy holds promise, safety issues remain due to potential short-lived effects, immune responses, and risks from viral vectors.
Gene therapy refers to the insertion of genetic material to correct a genetic defect.
In gene therapy, a "normal" gene is inserted into the genome to replace an "abnormal," disease-causing gene
Primary Mitochondrial Disease and Secondary Mitochondrial Dysfunctionmitoaction
This document summarizes a presentation by Dr. Richard E. Frye on mitochondrial dysfunction in neurodevelopmental disorders and autism. The presentation covers:
- Evidence that mitochondrial dysfunction is involved in many diseases and now believed to be important in autism based on studies showing abnormalities in electron transport chain complexes in autistic children.
- Further studies demonstrating differences in mitochondrial reserve capacity between autistic children and controls, and associations with environmental exposures like air pollution.
- Research into mechanisms of dysfunction including effects of the gut microbiome, genes, and potential treatments like mitochondrial cocktails.
This document provides an overview of gene therapy. It defines key terms like genetics, genes, chromosomes, and therapy. It explains that gene therapy involves inserting a normal gene to replace an abnormal gene causing disease. Viruses and non-viral methods can be used as vectors to deliver therapeutic genes. While some gene therapies have shown promise for diseases like Parkinson's and immune deficiencies, the field has also faced challenges. Safety issues in early trials halted some research, but recent studies demonstrate progress in refining methods and potentially treating diseases like sickle cell anemia.
In this slide, You will get to learn abut Gene Therapy and different types of gene therapy. Various method of Gene Therapy and Advantage & Disadvantage and Recent advances in Gene Therapy.
Introduction
Approaches to Gene Therapy
Vectors in Gene Therapy
Non-viral Methods
Physical Methods for Improving DNA Transfer
Chemical Methods for Improving DNA Transfer
Advantages and Disadvantages of Gene Therapy
Applications of Gene Therapy
Challenges
Présentation de Michel Pucéat réalisée durant le cours du réseau international des instituts Pasteur de "Médecine Génomique: du diagnostic à la thérapie " (17-21 octobre 2016)
Gene therapy involves inserting a normal gene to replace an abnormal gene that causes a genetic disease. It can replace or inactivate mutated genes, or introduce new genes to fight disease. Common applications include treating cystic fibrosis, hemophilia, cancer, and HIV. Viral vectors like retroviruses and adenoviruses are often used to deliver genes, but they can cause immune reactions. Non-viral methods like nanoparticles, electroporation, and ultrasound show promise for safer gene delivery. Overall, gene therapy holds potential for treating many currently incurable genetic disorders and diseases.
Gene therapy is an experimental technique that involves inserting a normal gene to replace a defective gene responsible for disease. It can replace a mutated disease-causing gene with a healthy copy or inactivate a mutated gene functioning improperly. Common diseases targeted include severe combined immunodeficiency, hemophilia, cystic fibrosis, hemoglobinopathies like thalassemia and sickle cell anemia, Parkinson's disease, and cancer. The first approved gene therapy case occurred in 1990 treating a girl with immune deficiency. Since then, gene therapy has been used to treat metastatic melanoma. Gene therapy can affect the germline permanently or somatic cells temporarily.
"From the Chromosome...Everything". My Inaugural Lecture at the Blizard Institute, Barts & The London School of Medicine & Dentistry, Queen Mary University of London. 10th May 2010.
Cancer is characterized by abnormal cell growth and division. The hallmarks of cancer include self-sufficiency in growth signals, insensitivity to growth inhibition, evading apoptosis, limitless replicative potential, sustained angiogenesis, and ability to invade and metastasize. Cancer results from mutations in oncogenes and tumor suppressor genes caused by factors such as viruses, bacteria, chemicals, and radiation.
The document discusses various methods for SNP genotyping including hybridization-based methods, enzyme-based methods, and other post-amplification methods. It focuses on tetra-arm PCR, describing how it works by deliberately introducing mismatches in the primers to distinguish alleles. Instructions are provided on how to design tetra-arm PCR primers for any SNP using input of the sequence, SNP position and alleles. Students are assigned practical work designing tetra-arm PCR and RFLP tests using bioinformatics tools.
The document discusses the hallmarks of cancer. It describes six fundamental changes or hallmarks in cancer cells that allow them to grow uncontrollably and potentially spread throughout the body. These hallmarks are: self-sufficiency in growth signals, insensitivity to anti-growth signals, evading programmed cell death (apoptosis), limitless replicative potential, sustained angiogenesis, and tissue invasion and metastasis. The document provides details on each of these hallmarks and how they enable cancerous behavior in cells.
This document provides an overview of the molecular foundations of cancer. It discusses how cancer arises from genetic and epigenetic aberrations that accumulate in cells and lead to altered gene expression and the acquisition of hallmark capabilities that allow tumors to form and progress. Key points covered include the types of genomic changes like mutations and chromosome defects that occur; the roles of oncogenes and tumor suppressor genes; how cancer risk can be inherited; and the uses of genomics in cancer diagnosis and targeted treatment.
New Study Identifies High-Risk Variants Associated with Autism Spectrum Disor...Golden Helix Inc
A study identified 24 new genetic variants associated with autism spectrum disorders (ASDs), each conferring over a 2-fold increased risk of developing ASDs. The study analyzed data from over 9,000 subjects to validate these novel genetic variants, in addition to validating 31 previously reported variants. This represents a significant increase in understanding the genetic risk factors involved in ASDs.
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Stephan Züchner discusses major developments in human genetics including improved genome sequencing capabilities and declining costs. He summarizes research on inherited axonopathies like hereditary spastic paraplegias and Charcot-Marie-Tooth disease, which are clinically and genetically heterogeneous. Züchner leads a large international collaborative effort called GEM.app involving over 450 investigators that has identified numerous genes for various neurodegenerative and neuromuscular disorders through shared exome and genome data.
Dan Geschwind, MD, PhD: Advances in Genetics 2016Semel Admin
Advances in genetics have identified hundreds of genes associated with autism spectrum disorder (ASD) risk. Knowing the genetic causes has implications for treatment, recurrence risk, and prevention. While ASD has extreme genetic heterogeneity, studies in animal models, human cells, and post-mortem tissue aim to identify convergent biological pathways and circuits impacted across various genetic mutations. This research seeks to develop targeted therapies for ASD and demonstrates the potential of precision medicine approaches for neurodevelopmental disorders.
Los días 11 y 12 de diciembre de 2014, la Fundación Ramón Areces celebró el Simposio Internacional 'Neuropatías periféricas hereditarias. Desde la biología a la terapéutica' en colaboración con CIBERER-ISCIII y el Centro de Investigación Príncipe Felipe. El tipo más común de estas patologías es la enfermedad de Charcot-Marie-Tooth, un trastorno neuromuscular hereditario con una prevalencia estimada de 17-40 afectados por 100.000 habitantes. Durante estos dos días, investigadores mostraron sus avances en la mejora del diagnóstico y el tratamiento y, por ende, de la aproximación clínica y la calidad de vida de las personas afectadas por estas patologías.
This document discusses oligodendrocytes, the cells that form myelin in the central nervous system. It describes their role in development, diseases like multiple sclerosis where remyelination fails, and potential therapies to promote remyelination. A clinical trial was conducted using neural progenitor cell transplantation to treat Pelizaeus-Merzbacher disease, a fatal leukodystrophy caused by myelin deficiency. Research suggests the Wnt signaling pathway inhibits oligodendrocyte differentiation and myelination, and a small molecule Wnt inhibitor was found to accelerate remyelination in mice.
Hereditary neuropathies are a diverse group of inherited conditions affecting the peripheral nervous system. They are frequently underdiagnosed due to their indolent onset over decades and lack of clear family history in some cases. Charcot-Marie-Tooth disease is the most common inherited neuropathy, with two main types - CMT1 characterized by demyelination and CMT2 characterized by axonal loss. CMT1 results from mutations affecting myelin protein zero or peripheral myelin protein 22 genes, causing demyelination and onion bulb formation. Accurate diagnosis relies on detailed family history, neurological examination, and electrodiagnostic testing to distinguish inherited from acquired neuropathies.
Amyotrophic lateral sclerosis (ALS) is a rare neurological disease that primarily affects the nerve cells (neurons) responsible for controlling voluntary muscle movement (those muscles we choose to move). Voluntary muscles produce movements like chewing, walking, and talking.
Peripheral neuropathy can be classified based on the number and distribution of affected nerves, type of nerve fiber involved, and cause. Giant axonal neuropathy is a rare genetic disorder characterized by abnormal intermediate filament organization in axons, leading to focal axonal enlargements. It presents in childhood with signs of central and peripheral nervous system involvement such as cerebellar ataxia, muscle weakness, and loss of sensation. Diagnosis involves nerve biopsy and genetic testing. Management focuses on preventing complications and optimizing development, though most patients become wheelchair-bound by their teens and deceased by their 20s.
A single-nucleotide polymorphism (SNP) is a variation in a single DNA building block (nucleotide) that differs between members of a species. SNPs are the most common type of genetic variation among humans, with around 0.1% of bases differing between individuals. They can occur in coding regions, where they may alter the resulting protein, or non-coding regions. SNPs are significant for mapping genes and studying an individual's predisposition to diseases like cancer or response to medications. They can be identified by comparing DNA sequences from many individuals or through laboratory techniques like SNP genotyping.
Секвенирование как инструмент исследования сложных фенотипов человека: от ген...BioinformaticsInstitute
This document summarizes genetic analyses of complex human phenotypes. It describes whole genome sequencing of individuals from bipolar disorder families and finding an association between genetic variation in a chromosome 6 region and amygdala volume. It also discusses rare variant sequencing of metabolic syndrome-related genes in Finnish cohorts, identifying new signals beyond existing GWAS hits. Additionally, it outlines exome and targeted sequencing of Tourette syndrome pedigrees, with a genome-wide significant result in a long non-coding RNA gene linked to the trait.
NRSF regulates hcn1 after an insult that leads to epilepsy through its physical binding to the gene. Enduring repression of hcn1 expression by NRSF involves epigenetic changes of the chromatin of the gene. Blocking NRSF function after an insult that provokes epilepsy markedly attenuates the development of epilepsy. The prevention of epilepsy is a result of rescuing ~30 genes, (in addition to hcn1) whose repression contribute to epilepsy.
Motor neuron disease (MND) refers to conditions characterized by degeneration of upper and lower motor neurons. Amyotrophic lateral sclerosis (ALS) is the most common form of MND and involves both upper and lower motor neurons. ALS is clinically defined based on involvement of motor neurons and includes features such as muscle weakness, atrophy, fasciculations, and stiffness. The pathology of ALS involves degeneration and death of motor neurons in the brain, brainstem, and spinal cord leading to muscle denervation and atrophy. While the cause of ALS is largely unknown, factors such as oxidative stress, protein aggregation, mitochondrial dysfunction, and glutamate excitotoxicity are hypothesized to contribute to motor neuron de
This document discusses the genetics of psychiatric disorders such as depression, bipolar disorder, schizophrenia, autism, and Tourette syndrome. It covers patterns of inheritance such as autosomal dominant, recessive, and X-linked traits. Specific genes have been identified for some conditions, like DISC1 for bipolar disorder and mutations in multiple small effect genes contribute to conditions like autism and schizophrenia. Genome-wide association studies and copy number variation analysis have also provided insights but most psychiatric conditions are genetically complex with both genetic and environmental factors involved.
The document discusses prion diseases, which are neurodegenerative disorders caused by abnormal prion proteins. It covers the discovery of prions, the different forms of human and animal prion diseases, and the molecular pathogenesis involving the conversion of normal prion protein (PrPc) to abnormal disease-causing prion protein (PrPsc). Clinical features of various human prion diseases like CJD are described. Diagnosis involves neuroimaging, EEG, CSF analysis and detection of PrPsc in brain tissue. Histopathology shows vacuolation, gliosis and prion plaques. Variant CJD results from eating meat from cows with BSE.
1. Genetic testing can be used for several purposes including making a diagnosis, validating a difficult clinical diagnosis, choosing appropriate therapy, establishing genotype-phenotype correlations, and identifying individuals at risk of disease.
2. It is important that the request for genetic testing be clinically driven and that the potential usefulness and impact on the patient be considered first.
3. High quality testing, as well as pre- and post-test counseling, are critical to ensure proper diagnosis and management based on genetic testing results.
1. DNA polymorphisms, such as single nucleotide polymorphisms (SNPs) and variable number tandem repeats (VNTRs), are natural variations in DNA sequences among individuals.
2. These polymorphisms can be used for indirect DNA diagnosis of genetic diseases through detection of restriction fragment length polymorphisms (RFLPs). DNA from family members is digested with restriction enzymes and analyzed through gel electrophoresis and Southern blotting.
3. If a polymorphism is found near a disease-causing mutation and is linked to it, its inheritance pattern can help determine which family members have inherited the mutation and are at risk for the associated genetic disease.
1. DNA polymorphisms, such as single nucleotide polymorphisms (SNPs) and variable number tandem repeats (VNTRs), are natural variations in DNA sequences among individuals.
2. These polymorphisms can be used for indirect DNA diagnosis of genetic diseases through detection of restriction fragment length polymorphisms (RFLPs) near mutated genes.
3. Examples of gene mutations include substitutions, insertions, and deletions that can alter protein products and cause disease if in coding regions. Indirect diagnosis uses linked polymorphisms to infer whether individuals carry disease-causing mutations.
This document summarizes 22 PhD theses defended in 2011 at the Faculty of Medicine, Ss. Cyril and Methodius University in Skopje, Republic of Macedonia. It provides English abstracts of the theses, including topics studied, methods, results, and conclusions. The theses covered areas like juvenile myoclonic epilepsy, treatment of lung cancer, dermatophytoses, and more. 9 theses lacked keywords and most (12) had structured abstracts. The editorial board did not verify the quality or content of the abstracts.
Altered proliferation and networks in neural cells derived from idiopathic au...Masuma Sani
Autism Spectrum Disorders; heterogeneous nature of genetic and brain pathology in ASD– which makes it difficult to produce relevant animal and cell models
Schizophrenia Research Forum Live Webinar - June 28, 2017 - Rusty Gage wef
1) The document describes a study using induced pluripotent stem cells (iPSCs) derived from bipolar disorder (BD) patients to model the disease in vitro.
2) Hippocampal dentate gyrus-like neurons were differentiated from iPSCs and showed hyper-excitability at both the molecular and functional levels in BD-derived neurons.
3) Treatment with lithium rescued the hyper-excitability phenotype in neurons derived from lithium-responsive BD patients but not lithium non-responsive patients, suggesting patient-specific responses.
Similar to Genes in complex neurological disorders (20)
Cell Therapy Expansion and Challenges in Autoimmune DiseaseHealth Advances
There is increasing confidence that cell therapies will soon play a role in the treatment of autoimmune disorders, but the extent of this impact remains to be seen. Early readouts on autologous CAR-Ts in lupus are encouraging, but manufacturing and cost limitations are likely to restrict access to highly refractory patients. Allogeneic CAR-Ts have the potential to broaden access to earlier lines of treatment due to their inherent cost benefits, however they will need to demonstrate comparable or improved efficacy to established modalities.
In addition to infrastructure and capacity constraints, CAR-Ts face a very different risk-benefit dynamic in autoimmune compared to oncology, highlighting the need for tolerable therapies with low adverse event risk. CAR-NK and Treg-based therapies are also being developed in certain autoimmune disorders and may demonstrate favorable safety profiles. Several novel non-cell therapies such as bispecific antibodies, nanobodies, and RNAi drugs, may also offer future alternative competitive solutions with variable value propositions.
Widespread adoption of cell therapies will not only require strong efficacy and safety data, but also adapted pricing and access strategies. At oncology-based price points, CAR-Ts are unlikely to achieve broad market access in autoimmune disorders, with eligible patient populations that are potentially orders of magnitude greater than the number of currently addressable cancer patients. Developers have made strides towards reducing cell therapy COGS while improving manufacturing efficiency, but payors will inevitably restrict access until more sustainable pricing is achieved.
Despite these headwinds, industry leaders and investors remain confident that cell therapies are poised to address significant unmet need in patients suffering from autoimmune disorders. However, the extent of this impact on the treatment landscape remains to be seen, as the industry rapidly approaches an inflection point.
ABDOMINAL TRAUMA in pediatrics part one.drhasanrajab
Abdominal trauma in pediatrics refers to injuries or damage to the abdominal organs in children. It can occur due to various causes such as falls, motor vehicle accidents, sports-related injuries, and physical abuse. Children are more vulnerable to abdominal trauma due to their unique anatomical and physiological characteristics. Signs and symptoms include abdominal pain, tenderness, distension, vomiting, and signs of shock. Diagnosis involves physical examination, imaging studies, and laboratory tests. Management depends on the severity and may involve conservative treatment or surgical intervention. Prevention is crucial in reducing the incidence of abdominal trauma in children.
Basavarajeeyam is a Sreshta Sangraha grantha (Compiled book ), written by Neelkanta kotturu Basavaraja Virachita. It contains 25 Prakaranas, First 24 Chapters related to Rogas& 25th to Rasadravyas.
Local Advanced Lung Cancer: Artificial Intelligence, Synergetics, Complex Sys...Oleg Kshivets
Overall life span (LS) was 1671.7±1721.6 days and cumulative 5YS reached 62.4%, 10 years – 50.4%, 20 years – 44.6%. 94 LCP lived more than 5 years without cancer (LS=2958.6±1723.6 days), 22 – more than 10 years (LS=5571±1841.8 days). 67 LCP died because of LC (LS=471.9±344 days). AT significantly improved 5YS (68% vs. 53.7%) (P=0.028 by log-rank test). Cox modeling displayed that 5YS of LCP significantly depended on: N0-N12, T3-4, blood cell circuit, cell ratio factors (ratio between cancer cells-CC and blood cells subpopulations), LC cell dynamics, recalcification time, heparin tolerance, prothrombin index, protein, AT, procedure type (P=0.000-0.031). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and N0-12 (rank=1), thrombocytes/CC (rank=2), segmented neutrophils/CC (3), eosinophils/CC (4), erythrocytes/CC (5), healthy cells/CC (6), lymphocytes/CC (7), stick neutrophils/CC (8), leucocytes/CC (9), monocytes/CC (10). Correct prediction of 5YS was 100% by neural networks computing (error=0.000; area under ROC curve=1.0).
Integrating Ayurveda into Parkinson’s Management: A Holistic ApproachAyurveda ForAll
Explore the benefits of combining Ayurveda with conventional Parkinson's treatments. Learn how a holistic approach can manage symptoms, enhance well-being, and balance body energies. Discover the steps to safely integrate Ayurvedic practices into your Parkinson’s care plan, including expert guidance on diet, herbal remedies, and lifestyle modifications.
8 Surprising Reasons To Meditate 40 Minutes A Day That Can Change Your Life.pptxHolistified Wellness
We’re talking about Vedic Meditation, a form of meditation that has been around for at least 5,000 years. Back then, the people who lived in the Indus Valley, now known as India and Pakistan, practised meditation as a fundamental part of daily life. This knowledge that has given us yoga and Ayurveda, was known as Veda, hence the name Vedic. And though there are some written records, the practice has been passed down verbally from generation to generation.
Recomendações da OMS sobre cuidados maternos e neonatais para uma experiência pós-natal positiva.
Em consonância com os ODS – Objetivos do Desenvolvimento Sustentável e a Estratégia Global para a Saúde das Mulheres, Crianças e Adolescentes, e aplicando uma abordagem baseada nos direitos humanos, os esforços de cuidados pós-natais devem expandir-se para além da cobertura e da simples sobrevivência, de modo a incluir cuidados de qualidade.
Estas diretrizes visam melhorar a qualidade dos cuidados pós-natais essenciais e de rotina prestados às mulheres e aos recém-nascidos, com o objetivo final de melhorar a saúde e o bem-estar materno e neonatal.
Uma “experiência pós-natal positiva” é um resultado importante para todas as mulheres que dão à luz e para os seus recém-nascidos, estabelecendo as bases para a melhoria da saúde e do bem-estar a curto e longo prazo. Uma experiência pós-natal positiva é definida como aquela em que as mulheres, pessoas que gestam, os recém-nascidos, os casais, os pais, os cuidadores e as famílias recebem informação consistente, garantia e apoio de profissionais de saúde motivados; e onde um sistema de saúde flexível e com recursos reconheça as necessidades das mulheres e dos bebês e respeite o seu contexto cultural.
Estas diretrizes consolidadas apresentam algumas recomendações novas e já bem fundamentadas sobre cuidados pós-natais de rotina para mulheres e neonatos que recebem cuidados no pós-parto em unidades de saúde ou na comunidade, independentemente dos recursos disponíveis.
É fornecido um conjunto abrangente de recomendações para cuidados durante o período puerperal, com ênfase nos cuidados essenciais que todas as mulheres e recém-nascidos devem receber, e com a devida atenção à qualidade dos cuidados; isto é, a entrega e a experiência do cuidado recebido. Estas diretrizes atualizam e ampliam as recomendações da OMS de 2014 sobre cuidados pós-natais da mãe e do recém-nascido e complementam as atuais diretrizes da OMS sobre a gestão de complicações pós-natais.
O estabelecimento da amamentação e o manejo das principais intercorrências é contemplada.
Recomendamos muito.
Vamos discutir essas recomendações no nosso curso de pós-graduação em Aleitamento no Instituto Ciclos.
Esta publicação só está disponível em inglês até o momento.
Prof. Marcus Renato de Carvalho
www.agostodourado.com
Histololgy of Female Reproductive System.pptxAyeshaZaid1
Dive into an in-depth exploration of the histological structure of female reproductive system with this comprehensive lecture. Presented by Dr. Ayesha Irfan, Assistant Professor of Anatomy, this presentation covers the Gross anatomy and functional histology of the female reproductive organs. Ideal for students, educators, and anyone interested in medical science, this lecture provides clear explanations, detailed diagrams, and valuable insights into female reproductive system. Enhance your knowledge and understanding of this essential aspect of human biology.
2. Overview
• Types
of
gene0c
aberra0ons
that
can
cause
neurological
disorders
• Approaches
for
iden0fying
genes
associated
with
neurological
disorders:
1. Linkage
studies
2. Homozygosity
mapping
3. Exome
&
whole
genome
sequencing
4. Genome-‐wide
associa0on
studies
5. Detec0on
of
structural
varia0on
6. Transcriptomics
3. 46
chromosomes
2m
DNA
3
x
109
base
pairs
~
22,000
genes
The
human
genome
4. Muta'ons
of
various
types
cause
neurological
disease
Muta'on
type
Muta'on
subtype
Example(s)
SINGLE
NUCLEOTIDE
Point
muta0ons,
inser0ons,
dele0ons
Missense,
nonsense,
frameshiU,
splice
site,
addi0on
or
dele0on
of
amino
acid(s)
Many
neurological
disorders
with
a
gene0c
basis
MICROSATELLITE
EXPANSION
Triplet
repeat
(polyglutamine)
Hun0ngton
disease
(HTT)
Triplet
repeat
(polyanaline)
Congenital
central
hypoven0la0on
syndrome
(PHOXB2)
Triplet
repeat
(other)
Fragile
X
mental
retarda0on
syndrome
(CGG
repeat
expansion
in
FMR
5’UTR)
Myotonic
dystrophy
1
(CTG
repeat
expansion
in
DMPK
3’UTR)
Adapted from P.M.Boone et al, Hum Genet 2011
5. Muta'ons
of
various
types
cause
neurological
disease
Muta'on
type
Muta'on
subtype
Example(s)
STRUCTURAL
VARIATION
Karyotypic
Aneuploidy
Down
syndrome
Transloca0on
X-‐linked
mental
retarda0on
58
Copy
number
Genomic
dele0on
Hereditary
neuropathy
with
liability
to
pressure
palsies
Genomic
duplica0on
Charcot-‐Marie-‐Tooth
disease,
type
1A
Whole
gene
dele0on
Autosomal
recessive
early
onset
Parkinson
disease
6
(PINK1)
Whole
gene
duplica0on
Early
onset
Alzheimer
disease
with
cerebral
amyloid
angiopathy
(APP)
Intragenic
dele0on
Duchenne
muscular
dystrophy
(DMD)
Intragenic
duplica0on
Autosomal
dominant
dopa-‐responsive
dystonia
(GCH1)
Non-‐coding
X-‐linked
spas0c
paraplegia
type
2
(near
PLP1)
Inversion
-‐
Duchenne
muscular
dystrophy
and
other
features
inv(X)(p21.2q22.2)
Adapted from P.M.Boone et al, Hum Genet 2011
7. Applica'on
of
current
methods
for
disease
gene
iden'fica'on
A.B. Singleton, Trends in Genetics 2010
(based
on
T.A.
Manolio,
Nature
2009)
High
risk,
rare
alleles
APP,
PS
mut
in
AD
LRKK2
mut
in
PD
Moderate
risk,
low
frequency
alleles
GBA
mut
in
PD
Low
risk,
common
alleles
CLU,
PICALM,
CR1
mut
in
AD
SNCA,
MAPT
mut
in
PD
8. T.A.
Manolio,
Nature
2009
Feasibility
of
iden'fying
gene'c
variants
by
strength
of
gene'c
effect
(odds
ra'o)
and
risk
allele
frequency
9. Phenotypic variation
Wilt Chamberlain, NBA basketball player
7 feet, 1 inch; 275 pounds
Willie Shoemaker, horse racing jockey
4 feet, 11 inches; barely 100 pounds
1.
Linkage
studies
10. In human beings, 99.9% of the DNA sequence is the same
Remaining 0.1% makes a person unique
- Different attributes/characteristics traits
- Diseases he/she develops
These variations can be:
- Harmless (change in phenotype)
- Harmful (diabetes, cancer, heart disease, Huntington's
disease, and hemophilia )
- Latent (variations in coding and regulatory regions, are
not harmful on their own, and the change in each gene
only becomes apparent under certain conditions)
Genetic variation underlies phenotypic differences
11. Single Nucleotide Polymorphism - SNP
- Variation in DNA sequence (substitutions, deletions,
insertion, etc) that is present at a frequency greater than
1% in a population.
Mutation
- Variation in DNA sequence (substitutions, deletions, etc)
that is present at a frequency lower than 1% in a
population.
ATTGGCCTTAACCCCCGATTATCAGGAT
ATTGGCCTTAACCTCCGATTATCAGGAT
Allele
A
Allele
B
12.
13. Linkage
studies
• Loci
are
linked
if
they
are
close
to
each
other
• Search
for
co-‐inheritance
of
the
disease
with
polymorphic
markers
• Obtain
loca0on
of
gene
• Sequence
• Limited
applica0on
for
late-‐onset
diseases
12
PARK8/LRRK2
Leucine-‐Rich
Repeat
Kinase
2
Autosomal
Dominant
Parkinson’s
Disease
C. Paysan-Ruiz et al, Neuron 2004
14. 2.
Homozygosity
mapping
• Genome-‐wide
genotyping
using
high
density
SNP
microarrays
• Autosomal
recessive
diseases
Frontotemporal
Demen'a
–
like
disease
AA
AA
AB
Adapted from J.Bras et al, Nat Rev Neurosc 2012
15. Homozygosity
mapping
C. Paysan-Ruiz et al, Ann Neurol 2009
p.R747W
+/+
Dystonia-‐Parkinsonism
• PLA2G6
• Phospholipase
A2,
group
VI
22
PLA2G6
rs7288109
rs16996781
16. 3.
Exome
&
whole
genome
sequencing
Exon 1 Exon 2 Exon 3
Intron
1
Intron
2
DNA
Transcription
start site
Protein
Pre-mRNA
Transcription
Splicing
Translation
mRNA
Intergenic regionPromoterEnhancer
Gene
17. Exome
&
whole
genome
sequencing
Adapted from J.Bras et al, Nat Rev Neurosc 2012
18. Examples
of
neurological
disease
genes
iden'fied
by
exome
sequencing
Disorder
Gene
Au0s0c
spectrum
disorder
Mul0ple,
CHD8,
KATNAL2
Au0sm
UBE3B,
CLTCL1,NCKAP5L,
ZNF18,
ANK2,
SCN2A
AD
cerebellar
ataxia,
deafness
&
narcolepsy
DNMT1
AD
early
onset
Alzheimer’s
disease
SORL1
AD
spinocerebellar
ataxia
PRKCG,
TGM6
AR
infan0le
onset
spinocerebellar
ataxia
CC10orf2
AR
pontocerebellar
hypoplasia
and
spinal
motor
neuron
degenera0on
EXOSC3
Brown-‐Vialeho-‐Van
Laere
syndrome
(early
onset
ALS)
SLC52A3
Charcot-‐Marie-‐Tooth
neuropathy
Mul0ple
heterozygous
variants
Essen0al
tremor
FUS
Adapted from Handel et al, Exp Rev Neuropath 2013AD,
AR:
Autosomal
dominant,
recessive
19. Clinical
Whole-‐Exome
Sequencing
for
the
Diagnosis
of
Mendelian
Disorders,
Yang
et
al,
NEJM
2013
250
pa0ents:
80%
were
children
with
neurologic
phenotypes
24. Neurological
disease
genes
iden'fied
by
whole
genome
sequencing
Disorder
Gene
Charcot-‐Marie-‐
Tooth
neuropathy
SH3TC2
Familial
Amyotrophic
Lateral
Sclerosis
C9orf72
Infan0le
epilep0c
encephalopathy
and
SUDEP
SCN8A
Complex
motor
and
sensory
axonal
neuropathy
plus
microcephaly
VRK1
Adapted from:
Handel et al, Exp Rev Neuropath 2013 & C. Gonzaga-Jauregui et al, JAMA Neurol 2013
25. Whole
genome
sequencing
in
a
pa'ent
with
Charcot-‐Marie-‐Tooth
neuropathy,
Lupski
et
al,
NEJM
2010
26. Whole
genome
sequencing
in
a
pa'ent
with
Charcot-‐Marie-‐Tooth
neuropathy,
Lupski
et
al,
NEJM
2010
Professor
James
R
Lupski,
Baylor
College
of
Medicine
27. Whole
genome
sequencing
in
a
pa'ent
with
Charcot-‐Marie-‐Tooth
neuropathy,
Lupski
et
al,
NEJM
2010
Charcot-‐Marie-‐Tooth
neuropathy
• Childhood
onset
neurodenera0ve
disease
• Characterised
by
demyelina0on
of
motor
and
sensory
nerves
• Most
common
inherited
disorder
of
the
peripheral
nervous
system
• Two
major
phenotypic
types
according
to
electrophysiological,
clinical,
and
nerve-‐biopsy
evalua0ons
•
glial
myelinopathy
(CMT
type
1)
• neuronal
axonopathy
(CMT
type
2)
• Each
type
can
be
inherited
in
a
dominant,
recessive
or
X-‐linked
manner
• PMP22
duplica0on
accounts
for
70%
of
cases
• Many
other
genes
associated
with
remaining
cases
• CMT4C
is
caused
by
homozygous
or
compound
heterozygous
muta0ons
in
SH3TC2
gene
28. Whole
genome
sequencing
in
a
pa'ent
with
Charcot-‐Marie-‐Tooth
neuropathy,
Lupski
et
al,
NEJM
2010
CMT:
Charcot-‐Marie-‐Tooth
neuropathy
MMM:
mild
mononeuropathy
of
the
median
nerve
29. Whole
genome
sequencing
in
a
pa'ent
with
Charcot-‐Marie-‐Tooth
neuropathy,
Lupski
et
al,
NEJM
2010
Muta0ons
in
the
SH3TC2
gene
R954X,
with
or
without
Y169H
muta0on,
muta0on
was
associated
with
Carpal
Tunnel
Syndrome
30. Whole
genome
sequencing
in
a
pa'ent
with
Charcot-‐Marie-‐Tooth
neuropathy,
Lupski
et
al,
NEJM
2010
SH3TC2
• SH3
domain
and
tetratricopep0de
repeats-‐containing
protein
2
• Expressed
in
Schwann
cells
• Localises
in
plasma
membrane
and
to
the
perinuclear
endocy0c
recycling
compartment
• Proposed
to
be
an
adaptor
or
docking
molecule
• Presumed
role
in
myelina'on
• Numerous
homozygous
and
compound
heterozygous
muta0ons
have
been
iden0fied
in
CMT4C
• Nonsense
variant:
p.R954X
• Missense
variant:
p.Y169H
31. SH3TC2:
A
role
in
endocy'c
recycling
Adapted from R.C.Roberts et al, Hum Mol Genet 2010
Y169H
R954X
Muta0ons
iden0fied
in
Lupski
et
al,
2010
Muta0ons
in
CMT4C
found
to
mistarget
SH3TC2
away
from
the
recycling
endosome
32. Whole
genome
sequencing
in
a
pa'ent
with
Charcot-‐Marie-‐Tooth
neuropathy,
Lupski
et
al,
NEJM
2010
SH3TC2
• Nonsense
variant:
p.R954X
• Missense
variant:
p.Y169H
• High
degree
of
conserva0on
of
Y169
in
vertebrates
33. 4.
Genome-‐wide
associa'on
studies
-‐
GWAS
Direct
Associa0on
Indirect
Associa0on
Disease
gene
SNP
• Examine
a
large
number
of
SNPs
in
large
numbers
of
affected
and
control
cases
• Iden0fy
SNPs
that
associate
with
the
disease
Common
Disease,
Common
Variant
hypothesis:
A
common
variable
(i.e.
with
a
high
minor
allele
frequency
that
can
therefore
be
seen
in
most
individuals)
modulates
risk
to
disease
development
35. GWAS
analysis
of
Parkinson’s
disease
MulZple
genes
at
a
single
locus
GAK:
cyclin
G
associated
kinase
TMEM175:
transmembrane
protein
175
DGKQ:
diacylglycerol
kinase
theta
110
kDa
M.A.Nalls
et
al,
Lancet
2011;
J.Bras
et
al,
Nat
Rev
Neurosc
2012
39. 5.
Detec'on
of
structural
varia'on
M.E.Hurles
et
al,
TIG
2008
40. ALTERED
GENE
DOSAGE
ALTERED
STRUCTURE
OF
REGULATORY
ELEMENTS
enhancer
represser
exons
Inser'on
Dele'on
of
repressor
Exon
duplica'on
Gene
duplica'on
Adapted
from
M.E.Hurles
et
al,
TIG
2008
Impact
of
structural
varia'on
on
gene
func'on
41. Structural
varia'on
Copy
number
varia0on
(CNV)
• Array
CGH/high
density
SNP
microarrays
All
structural
varia0on
• Exome
and
whole
genome
sequencing
Reference
DNA
Test
DNA
42. Examples
of
CNVs
in
neurodevelopmental
syndromes
CGS:
con0guous
gene
dele0on/duplica0on
syndrome
UPD:
uniparental
disomy
Syndrome
Locus
Aberra'on
Gene(s)
Neurodevelopmental
Williams-‐Beuren
del(7)q11.23;
dup(7)q11.23
17q11.23
Dele0on;
Duplica0on
CGS
incl
ELN
Angelman;
Prader-‐Willi
15q11-‐
q12
Mat
dele0on,
pat
UPD15;
Pat
dele0on,
mat
UPD15
UBE3A;
CGS
Smith-‐Magenis;
Potocki-‐Lupski
17p11.2
Dele0on;
Duplica0on
GCS
incl
RAI1;
RAI1
Reh;
Reh-‐like
Xq28
Dele0on;
Duplica0on,
triplica0on
MECP2;
MECP2
Pelizaeus-‐Merzbacher
Xq22.2
Duplica0on,
dele0on
PLP1
Adapted
from
Stankiewicz
&
Lupski,
Ann
Rev
Med
2010
43. Neurodegenera've
Parkinson’s
4q21
Duplica0on,
triplica0on
SNCA
Spinal
muscular
dystrophy
5q13
Dele0on,
gene
conversion
SMN1,
SMN2
CMT1A;
HNPP
17p12
Duplica0on;
Dele0on
PMP22
Alzheimer’s
21q21
Duplica0on
APP
Examples
of
CNVs
in
neurodegenera've
syndromes
Adapted
from
Stankiewicz
&
Lupski,
Ann
Rev
Med
2010
44. Peripheral
myelin
protein-‐22
(PMP22)
J.Li
et
al,
Mol
Neurobiol
2013
Gene
structure
• Ex
1a
in
myelina0ng
Schwann
cells
• Ex
1b
in
non-‐
neuronal
cells
Predicted
Protein
Structure
45. J.Li
et
al,
Mol
Neurobiol
2013
Hypothe'cal
mechanisms
involving
PMP22
in
CMT1a,
HNPP
&
CMT1E
46. Complex
rearrangements
at
the
PMP22
locus
Adapted
from
Zhang
et
al,
Nat
Genet
2009
PMP22:
peripheral
myelin
protein
22
RAI1:
re0noic
acid
induced
1
48. Examples
of
transcriptomic
approaches
to
complex
neurological
diseases
Disease
RNA-‐seq
experimental
design
Gene
Alzheimer’s
disease
Human
brain
0ssue
APOE
Amyotrophic
lateral
sclerosis
Drosophila
TBPH
Au0sm
Human
brain
0ssue
Adenosine-‐to-‐inosine
edi0ng
Au0sm
Human
primary
neural
stem
cells
RBFOX1
splicing
network
Canine
neonatal
cerebellar
cor0cal
degenera0on
Dogs
SPTBN2
Mul0ple
sclerosis
Primary
human
CD4+
cells
CD6
Schizophrenia,
bipolar
disorder,
au0sm
Cultured
neurons
Noncoding
RNA
Adapted from Handel et al, Exp Rev Neuropath 2013
49. Mosaic
copy
number
varia'on
in
human
neurons,
M.J.McConnell
et
al,
Science
2013
Human
frontal
cortex
neurons
DNA
copy
number
analysis
&
single-‐cell
sequencing
13-‐41%
have
at
least
one
de
novo
CNV
Dele0ons
twice
as
common
as
duplica0ons
Subset
of
neurons
has
mul0ple
genomic
altera0ons
50. M.J.McConnell et al, Science 2013
Copy
number
varia'on
in
postmortem
human
neurons
using
single
cell
sequencing
Male
Female
51. Transmitting genomes
Deletions, duplications, and other mutations may arise at
different places in a developmental lineage.
M.J.McConnell et al, Science 2013 Macosko & McCarroll Science 2013