neu400 exam 1

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1

gene

unit of storage

transmission and implementation of genetic information

2

mechanisms of genetics

- decipher genetic code
- analysis of transcription/translation
- function of gene-determined protein
- fine structure of genetic material
- DNA sequences outside genes

3

neurogenetics

area of specialization within medical genetics and neurology that focuses on hereditary neurologic conditions

use of genetic methodologies on studies of the normal and diseased NS

conditions include inherited forms of childhood and adult-onset:
- muscular dystrophies
- myopathies
- neuromuscular movement disorders
- learning and behavioral aspects

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muscular dystrophy

progressive weakness and loss of muscle mass

abnormal genes (mutations) interfere with production of proteins needed to form healthy muscle

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myopathy

muscle weakness due to dysfunction of muscle fiber

can be inherited or acquired

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neurogenetics objectives

1. identification of the genetic basis for diseases and pathologies of the brain and nervous system

2. identification of the genes associated with personality traits and abilities

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neurogenetics objective 1: identification of the genetic basis for diseases and pathologies of the brain and nervous system

relevance:
- allows exact diagnosis and helps prognosis
- identify risk factors for condition
- helps understand mechanism that underlies disease
- develop gene-based strategies to prevent onset or mitigate symptoms
- provide genetic counseling (protect the offspring)

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neurogenetics objective 2: identification of the genes associated with personality traits and abilities

relevance:
- clarify the actual biological mechanisms that underlie personality and social and health behaviors (knowledge of biological mechanisms acting in normal personality can contribute to understanding personality disorders)

- knowledge of individuals' genotypes could help in targeting social science interventions to those who stand to benefit from them the most (if appropriate candidate genes can be discovered, the ultimate goal is to develop drugs that act on specific targets)

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heredity

the passing on of physical or mental characteristics genetically from one generation to another

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heredity: 1865 Mendel's laws

breeding and counting of offspring

interpretation: random comb of basic units, concept of gene

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heredity: 1865 F. Galton

"hereditary talents and character" and "biometrics"

measure intelligence, behavior and stature as accurate as possible; know the relationship and do statistics to predict

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mosaic

carrier of the mutation in some but not all of their cells

"presence of two different genotypes in an individual
"As a result, the individual has two or more genetically different cell lines derived from a single zygote"

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23 and me

swab of cheek cells (epithelial cells) in saliva

can give genetic background and predisposition to genetic diseases

can also tell personality traits; ex: afraid of heights

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the human genome

needed to uncover the entire nucleotide sequence of the human genome - completed in 2004

to understand biological importance of the genetic information in health and disease

assign a particular phenotype to a particular genetic variant

total estimated # nucleotides in finished sequence (including gaps) = 3 billion, haploid; 23 pairs of chromosomes; length of human chromosome ranges from 46Mb to 247Mb

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functional elements of the genome

1. protein-coding genes sequences - account for only a small fraction of the genome (about 1.5%)

2. non-coding, RNA only genes

3. regions of transcription regulation

4. conserved elements not included in above categories for which no function has been discovered yet

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number of protein coding genes

is a moving target; depends on:
1. functional annotation of the genome
2. the comparative analysis with other species
3. experimental validation

on average, we say about 20-25000 genes (100,000 were predicted)

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gene image

card image

primary transcript - single stranded RNA product of transcription of DNA; processed to yield various mature RNA products (mRNA, tRNA, rRNA)

spliced transcripts - products of RNA splicing; introns cut out, exons remain

functional products - each gene codes for a functional product, molecule needed to perform a job in the cell

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genomic variability

the similarity between two human genomes in BPs sequence is 99.9%

human genome is polymorphic - many DNA sequence variants among different individuals
these variants are the molecular bases for phenotypic variability

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polymorphic

DNA sequence is common within the population with common changes (many DNA sequence variants among different individuals)

results in the occurrence of several different forms or types of individuals among the members of a single species

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HapMap Project

multi-country effort to identify and catalog genetic similarities and differences in human beings

using this info, researchers able to find genes that affect health, disease and individual responses to medications and environmental factors

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ENCODE Project

ENCyclopedia Of DNA Elements - ENCODE

project to identify all functional elements in the human genome sequence

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lessons from personal genomics: identical sequence

difference in identical BPs in humans is actually 99.5%, not the previously thought assumption that any two human individuals are 99.99% identical at the DNA level

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lessons from personal genomics: variability

there is a large amount of variation in BPs in humans and that's what makes us so different

on average, the genome of any individual will contain 20,000 to 25,000 coding variants, of which 9,000-11,000 are nonsynonymous, and a slightly higher number are synonymous

- 9,000-11,000 are differences in the AA

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coding variants

a sequence variant that changes the coding sequence; represented in the proteins

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nonsynonymous

nucleotide mutation that alters the amino acid sequence of a protein

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synonymous

nucleotide mutation that does not alter amino acid sequences

"evolutionary substitution of one base for another in an exon of a gene coding for a protein, such that the produced amino acid sequence is not modified"

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forms of genomic variability

- single nucleotide polymorphism (SNP)
- short sequence repeats
- insertion/deletion polymorphisms (indels)
- copy number variants (CNVs)
- inversions
- chromosomal abnormalities

28

genetic approaches to study pathogenesis of diseases related to the nervous system

animal models: (of neurological disease) have successfully/accurately recreated many aspects of human illness, for in-depth study of neuropathology

cell based-models:
cultured cells - primarily from a tissue
cell lines - transformed to never stop growing and given characteristics of transformed cells
stem cells - can give origin to many different lines
iPSc - induced pluripotent stem cells
organoids - miniaturized/simplified version of an organ produced in vitro

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cultured cells

primarily from a tissue

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cell lines

transformed to never stop growing and given characteristics of transformed cells

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stem cells

can give origin to many different lines

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iPSCs - induced pluripotent stem cells

type of pluripotent stem cell that can be generated directly from adult cells
- can be made in a patient-matched manner (each individual could have their own pluripotent stem cell line)

they can propagate indefinitely, as well as give rise to every other cell type in the body (neurons, heart, pancreatic, and liver cells); could be used to replace those lost to damage or disease

33

organoids

miniaturized/simplified version of an organ produced in vitro in 3D andshows realistic micro-anatomy

derived from: cells in a tissue, stem cells, iPSCs

can self-organize in 3D culture owing to their self-renewal and differentiation capacities

used to study disease and treatments in a lab

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animal models vs cell-based models

animal models reproduce basic pathological features of the disorders by mechanisms that may not necessarily occur in humans

cell-based models are based on known pathophysiological mechanisms but may not reproduce all the features seen in patiens

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what is a model

any experimental preparation developed for the purpose of studying a condition in the same or different species

typically they are preparations in animals that attempt to mimic a human condition

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what do we want to be represented in animal models?

and/or:
- underlying (neuro)biology
- the entire syndrome
- specific symptoms of a syndrome/disorder
- prediction of treatment efficacy

37

aims of animal models

- improve diagnosis and treatment of patients
- advance the understanding of biological systems and disease pathogenesis

38

animal models: validity

the similarity of what is observed in the animal model to what is observed in the human modeled organism

39

animal models: predicative

a model responds to treatments in a way that predicts the effects of those treatments in humans

determines the success of predictions made from the model and has generally referred to pharmacologic responses to drugs

40

animal models: construct (etiologic)

construct (or etiologic) refers to the relevance for the disease of the methods by which a model is constructed

ensures that there is a convincing theoretical rationale for the model and assesses the degree to which the characteristics of the animal model can unambiguously be interpreted as being similar to those of the clinical condition

"Do the internal workings of the model behave in a manner similar enough to the clinical situation being modeled that it will respond to experimental manipulations in the same manner as that clinical situation?"

41

reliability

reliability of an animal model is established by demonstrating that under defined testing conditions, results are the same from one time to another within the same laboratory and from one laboratory to another

- inter-laboratory reproduction
- test-retest reliability

42

construct 1: ideal situation

recreate in an animal the etiologic processes that cause a disease in humans to replicate neural and behavioral features of the illness

ex: knock in/out mice
- Knocking a known disease-causing (Mendelian) genetic mutation into a mouse
- inserting a highly, but not fully, penetrant genetic variant that markedly increases vulnerability for a human disease

very difficult for brain diseases because many disease-causing genes have not been determined with certainty and many diseases are very complex

43

construct 2

E xposure of an animal to a well-validated environmental risk factor or known disease-causing agent

Very difficult brain diseases; virtually all environmental contributions to mental illness, such as stress or childhood adversity are associated with multiple disorders and most often normal outcomes

44

endophenotypes - "intermediate phenotype"

card image

genetic epidemiology term which is used to separate behavioral symptoms into more stable phenotypes with a clear genetic connection

45

model validation

- Models are only as sound as the information currently available in the clinical literature
- Models assume a common basis for the behavior and physiology of various species
- Models should be reliable in terms of induction and outcome

Variability cannot always be considered an error

46

model validation - predictivity

The ability of the model to predict the human phenomenon
- If this refers to treatment : pharmacological isomorphism

this is the most important criterion since the scientific process requires the testing of predictions

47

orthologues genes

genes shared by 2 species

"genes that encode for the same protein in different organisms"

we share 44% of our DNA with fruit flies, but most of that are genes related to basic survival/DNA replication

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Orthologous phenotypes

different phenotypes in different species but related to the same molecular function/pathway

49

models most commonly utilized in neuroscience

cells (iPSCs) - cellular functions

yeast - interactors/pathways (mutating one gene then putting it back; complementation)

fruit flies/zebrafish - ideal for high throughput screenings (produce plenty of offspring; limitation is orthologue)

mice - more specific cases (can modify genome fairly easily; select which genes you want to work with later on in life)

50

complementation

card image

two strains of an organism with different homozygous recessive mutations that produce the same mutant phenotype produce offspring with the wild-type phenotype when mated or crossed

51

transgenesis

incorporating a gene from one species into another
- putting a piece of DNA not originally from a species into that species

52

pronuclear injection

card image

pronuclei - two nuclei that have not yet fused in the oocyte (each is haploid, 21 chromosomes)

- usually inject into the male nuclei because their nucleus is bigger
- usually more animals don't have the transgene than animals that do express it