Module 6--Human Genetics Flashcards
What is exon skipping?
Creates functional proteins from faulty genes by skipping faulty codes
What is Huntington’s disease?
Autosomal dominant inheritance
- Cause: CAG repeat leads to faulty protein
- Repeat number is inversely correlated with age of onset (more repeats lead to early onset)
- More CAG repeats, more polyglutamine, more toxic faulty protein in brain
- Symptom: Progressive degeneration of nerve cells
- Diagnosis (detection using PCR) but no cure
What is Down syndrome, or trisomy 21?
Chromosomal disorders
- Cause: meiotic nondisjunction; an extra copy of chromosome 21
- Crucial genes were identified (one extra copy of specific genes has an impact)
- Some therapies are being developed
What is BRCA gene?
If you have this gene, you have a much higher change of developing breast cancer
What is the significance of differential diagnosis of cancer?
Molecular profile leads to informed treatment choice
What is the Beery Twin Story?
- Fraternal twins struggled from birth with a host of medical problems, but no diagnosis
- Genome sequencing found mutations on the SPR gene
- And treatment could be prescribed
What are the influences of different types of genetic disease on a lifetime of an indivudal?
- Chromosomal diseases are not compatible to life; often die as fetus
- Single gene disorder has a high influence on phenotype
- Multifactorial disease may take some time to appear
What is the complexity of diseases?
Genetic Spectrum
What is sickle cell anemia?
Recessive disorders
-Cause: single nucleotide polymorphism; a missense mutation, change the protein sequence, the mutant protein leads to the sickle-shaped red blood cells
How to test for sickle cell anemia?
What is cystic fibrosis?
Autosomal recessive disorder
- Cause: mutations in CF gene which encodes an ion channel; defects in this ion channel cause the salt and fluid imbalances across eipthelial cell membrane
- Symptoms: salty sweat; accumulation of mucus in lungs, pancreas, and liver; frequent respiratory infections
How to identify disease genes?
- Old approach: positional cloning
- Modern approach: GWAS and whole-genome sequencing
What is positional cloning?
Mapping a gene of interest precisely and searching for a clone of the gene using procedures that depend on its location in the genome
What is the complex inheritance of predisposition for heart disease?
- Multiple loci involved
- Family history of cariovascular disease
- Risk of developing disease is related to the combination of allels (in multiple genes) inherited by an individual
What is hemochromatosis?
-Hereditary disease
=Excess iron in body
- Excess iron can lead to life-threatening conditions
- Has complex inheritance
- Only a minority of people who have the risk alleles in implicated genes will develop serious problems
- Symptoms appear in midlife
- Treatment: regularly removing blood
How to identify implicated genes in multifactorial genetic disorders?
Genome Wide Association Studies (GWAS)
What kinds of abnormalities lead to chromosomal disorders?
Numerical and structural abnormalities
What kinds of cell do chromosome disorders occur in?
Germline cells or somatic cells
How do chromosomal disorders occur?
Non-disjunction in meiosis and mitosis
What is aneuploid?
An organism or cell having a chromosome number that is not an exact multiple of the monoploid, e.g. 2n+1, 2n-1
What is trisomy?
An otherwise diploid cell or organsim that has an extra chromosome of one pair (2n+1)
Draw a diagram representing aneuploidy and non-disjunction in meiosis
What is Turner syndrome?
- Sex chromosome aneuploidy
- XO
- Partly or completely missing an X leading to various symptoms
What is Klinefelter syndrome?
- Sex chromosome aneuploidy
- XXY
- Primary features: sterility and small testicles (maybe subtle and people don’t realize they are affected)
- Extra copies of genes on the X chromosome interfere with male sexual development, testes function and reduce testosterone levels
- X chromosome has Androgen Receptor (AR) gene, which is the receptor for testosterone
What is Triple X syndrome?
- Sex chromosome aneuploidy
- XXX
- Females are mostly normal; some with learning disabilities
What is XYY syndrome?
- Sex chromosome aneuploidy
- XYY
- Less symptoms because Y chromosome is smaller than X chromosome (less impacts)
What is the problem of having extra X and Y chromosomes, XXYY?
Extra X and Y chromosomes prevent testes from functioning normally and reduce levels of testosterone
What is SRY gene?
-Found on Y chromosome
=Testis determining factor
When does chromosomal changes usually occur?
Occur randomly during eggs and sperm formation in a parent, producing gametes with chromosome anomalies
What is monosomy?
A form of aneuploidy with the presence of only one chromosome from a pair
What kinds of structural abnormalities can chromosomes have?
- Deletions
- Duplications
- Inversions
- Translocations
Give an example of chromosome disorder caused by deletion.
Cri-du-chat syndrome
- Cause: deletion of part of the short arm in chromosome 5
- Symptoms: severe impairment and catlike crying in infancy
- This deletion occurs most often as a random event during germline formation
What is Copy Number Variation (CNV)?
-A type of structural variation in chromosome
=Duplication or Deletion event that affects a considerable number of base pairs
-Associated with both various neurocognitive diseases in humans and human evolution
What is Attention Deficit Hyperactivity Disorder (ADHD)?
- Deletion of GRM5 is exclusive to ADHD cases
- GRMs = G-protein-coupled receptors involved in modulation of excitatory synaptic transmission
What is chromosome translocations?
Change in position of a segment of a chromosome to another part of the same chromosome or a different chromosome
Give an example of disease caused by chromosome translocations.
Chronic myeloid leukaemia
- Philadelphia chromosome = result of a reciprocal translocation between chromosome 9 and 22 with breakpoints in the c-abl on chromosome 9 and the bcr gene on chromosome 22
- Fusion gene created encodes a tyrosine kinase that promotes cancer in white blood cells
Can a chromosomal structure diagnosis improve the prognosis of a patient?
No, it may not be enough, full genome sequencing is still required to figure out what gene is causing the disease
Cancer is a _____ disease
genetic
Cancer arises as a _____ _____ _____ _____
consequence of multiple mutations
Cancer-causing mutations may be _____ or _____ or both
germline or somatic
What are the types of cancer gene?
- Oncogenes
- Tumour suppressor genes
What increases risk of cancer?
-Age due to accumulation of mutations
How many mutations usually result in the formation of a tumour?
>7 driver mutations
Most tumours display _____ _____ _____
significant genomic instability
What are the types of agents of mutations?
- Mutagen: causes genetic mutation
- Carcinogen: irreversibly transforms normal cells into cancerous cells
- Anuegen: causes changes in the number of chromosomes
- Teratogen: causes malformation of an embryo
Cancer results rom an accumulation of _____ and _____ gene mutations
germline and somatic
Cancer is a _____ process
multi-step
-Multiple carcinogenic events – exposure to chemicals, radiation, viruses
Cancer affects _____ _____ _____
multiple cellular pathways
What are oncogenes?
- Genes that promote conversion of a cell to a malignant state
- Often dominant
- Actively promote pathways that lead to tumor development
What are tumour suppressor genes?
- Prevent malignancy
- Often recessive
- When mutated, fail to repress pathways that lead to cancer
What happens when tumor suppressor genes are mutated?
A predisposition to develop cancer often follows a dominant pattern of inheritance
What mutation usually occur in tumor suppressor gene?
Loss-of-function mutation
Mutation in tumor suprressor gene does not cause cancer to develop, what else need to happen in order for cancer to develop?
A second mutation in somatic cells knocking out the function of the wild-type allele
What kind of mutation occur in tumor suppressor gene?
Germline mutation
What somatic mutations can occur in cancer genes?
- Point mutation
- Small insertions or deletions (indels)
- Gene amplification
- Gene deletion or duplication and CNVs
- Chromosome rearrangements
What mutations may activate oncogenes?
- Point mutations
- Small insertions or deletions (indels)
- Gene amplifications
- Chromosome translocations
What mutations may inactivate tumor suppressor genes?
- Point mutations
- Small insertions or deletions (indels)
- Gene deletions
Each tumor generally contains a _____ set of _____ _____
different set of genetic lesions
What are the purposes of illustrating genomic lanscape of cancer?
- Identify common gene mutations
- Profile genetic signatures for specific types or stages of cancer
Transcript profiling of cancer can enable _____ _____
differential diagnosis
What treatment is avaialbe for chronic myeloid leukaemia?
Gleevec, a specific drug that targets the pathway activated by the fusion protein and stops tumour from growing
What treatment is available ofr melanoma?
B-Raf inhibitors
What is the goal of isolating human disease genes?
Having better diagnostics and clinical outcomes
What is Genome-wide Association Study?
- Complex traits –> multiple genes
- Genetic markers across the genome (50,000 to 1 million SNP, mostly SNPs)
- Discover significant SNP (risk alleles associated to disease)
- Starting point to map disease genes
What is Manhattan plot?
It is commonly used in genome-wide association studies (GWAS) to display significant SNPs
What is Next Generation Sequencing (NGS)?
- A DNA sequencing technology which has revolutionised genomic research
- Can sequence an entire human genome within a single day
What is bioinformatics?
=Study of genetic and other biological information using computer and statistical techniques
- It is used to compile and analyze biological data
- It can be used to predict biological experiments = in silico experiments
=Application of computational tools to solve biological questions
Bioinformatic approaches can be used to determine:
- If the sequence similar is to other known genes
- If the sequence contain ‘sequence motifs’ that are found in other disease genes
- If the sequence, or regions of the sequence, evolutionarily conserved (if highly conserved, have significant role in physiology/metabolism)
- Gene expression and co-expression (gene networks)
- Functional Genomics
What techniques determine where and when a gene is expressed?
- RNA analysis
- Protein analysis
What technique determines where and when a gene’s promoter is active?
Reporter assays
What is Green Fluorescent Protein used for?
GFP is used to determine where and when a gene’s promoter is active
What are transgenic mice used for and how?
They are used to visualize when and where genes are expressed:
- which cells/tissues
- what developmental time point
How:
- In transgenic factors, endogenous protein coding sequences are replaced by sequences encoding the EGFP reporter gene
- Mice express a reporter gene in the same environment as the native gene
–> study cell migration and development
–> isolate specific cells using flow cytometry
–> target cells for electrophysiology
–> evaluate drug treatments
What is RNA interference?
=Blocking gene expression with double-stranded RNA
-Can be used to dissect biological processes by inhibiting the functions of specific genes
What are the clinical applications of analysing other part of human genome?
Using genome level data for:
- Disease management
- Personalized diagnosis and treatment
- Early diagnosis
- Gene therapies
