Genetic variation and Treating genetic disease Flashcards
what is human genetic variation
- This is the genetic differences both within and among populatiosn
what is genetic variation caused by
- There may be multiple variants of any given gene in the human populations leading to polymorphism/mutation and alleles
What is new variations and new mutations due to
- New mutations are due to shuffling of parent genes during sex
what type of variation are there
- variation in how we sense things and communicate
- why we are prone to certain diseases
- height
- eye colour
- skin colour
- hair loss
- no nails
what are the facts about the genome
- 21000 genes in the human genome that code for protien (1.5% of the whole genome)
The rest includes - DNA transcribed to form RNA molecules which are not translated into protein such as non coding RNA and miRNA
- Evolutionarily conserved non-coding regions, enhancer functions, transposons and microsatellites
what is single gene disorders
- Mutation in a single gene leading to disease
what are transposons
this is a DNA sequence that can change its position within a genome which can create or reverse mutations and alter the cells genetic identity and genome size
what are microsatellites
this is a set of short repeated DNA sequences at a particular locus on a chromosome which vary in number and different individuals and so can be used for genetic fingerprinting
name an example of a single gene disorder
cystic fibrosis
give 4 types of genetic disorders
- single gene disorders
- chromosomal disorders
- polygenic disorders
- somatic disorders
what do chromosomal disorders happen
- A change, gain, loss or exchange of chromosome elements
what is a polygenic disorder
- Due to the combined effects of many genes or in combination with environmental factors
what is a somatic disorder
these are disorders of the Body cells that happen during early development
describe an example of a chromosomal disorder
Turner syndrome
describe an example of a polygenic disorder
diabetes
describe an example of a somatic disorder
cancer
what is a splice site mutation
- Leads to an insertion or deletion of a number of nucleotides in the specific site at which splicing of an intron takes place - this may mean that the intron is not taken away from the gene or the exon can be deleted
How do you detect DNA variation
- Polymerase chain reaction
- sequencing
describe the polymerase chain reaction process
- denature the DNA do this by heating at 94 degrees at 1 minute
- anneal - foward adn reverse primers are added and you spend 45 seconds at 54 degrees
3, extension - this is when Taq DNA polymerase and dNTPs add nucleotides to it - repeat this many times then analyse it, add a floursent dye in it
How do you carry out sequencing
- have the PCR product from the gene you want to analyse
- get the complementary primers that bind to the DNA
- add ACTG which are added as they go along
- ddNTPs stop the reading of the sequence, they happen at different places shows us the gene code
what do ddNTPs lead to
dideoxynucleotides lead to chain termination
what is Exome sequencing
- this allows you to sequence every single gene in one reaction
- a profile variation across all protein coding regions of the genome
how do you analyse the genetic data
- database
- bioinformatic tools
- biological interpretation
Genomics England what does it do
100,000 whole genome sequences in NHS patients with rare inherited disease, cancers and pathogens from the NHS in England
Aim is to:
Create an ethical and transparent programme based on consent
Bring benefit to patients and set up genomic medicine service for NHS
Enable scientific discovery and medical insight
Kick start the development of UK genomics industry
describe what the east London genes and health initiative is doing
Stage 1
- 100,000 volunteers split in a tube, health records
Stage 2
- Recall of 1000 volunteers a year – whitechapel centre
- Recall based on genetic results and health records
- Volunteer can agree or decline each further stage 2 study
- Work with local, national, international researchers
what are the long term aims for sequencing genes
- Resource research programmes to improve, diabetes, cholesterol, heart disease and new treatments
- Genomics is the further of medicine
- Tackle under representation of south Asians in genetic studies and health research in general
- Increase health awareness
How do you make a designer babies
- need to know what the genetic mutation is that you want
- needs to be legal
- IVF followed by preimplantation genetic diagnosis
how does pre implantation genetic diagnosis work
- take egg and sperm to IVF
- Get formation of blastomere
- remove one or two cells from the blastomere
- test DNA for chromosomes
- if genetic disorder is detected the embryo is discarded
- if the genetic disorder is excluded then the embryo is implanted
How could whole genome sequencing effect us
- Healthcare: diagnosis, risk management and pharmacogenomics
- ethics - is it ethically right to sequence our genomes, and who can access this information and what can they do
- insurance
- web dating - marriage by DNA
- designer babies
- alter the way we look after ourselves
How do you correct a mutant gene
- Correct mutant gene in patients’ cells and deliver via stem cell (iPSCs/MSCs)
- Use virus constructs, introduce normal gene into patient cells
What is genome editing
altering removing or adding nucleotides to the genome after cutting with engineered nucleases and then DNA repair
why don’t drugs work in all patients
- Variation in absorption
- Distribution
- Metabolism
- Elimination
- Variability of target receptors
- Plus the same disease can be due to independent and diverse pathological and genetic processes
what is the most common allele type
wild type
What is determined by a genetic variation
- complex development and maintenance
- How we sense things
- How we communicate
- Diseases we are prone to
describe the human genome
- 3.2x109 base pairs of DNA
- Between individuals 99% of DNA is identical
- Variations that occur with >1% frequency are polymorphisms
- Polymorphism which are pathological are mutations
- Copy number variation (CNVs)
what are copy number variations
these are sections of genomes which are repeated and number of repeats vary between individuals
describe rare disease statistics
- <5% of the population which is 3 million in the UK
- 7000 rare disorders
- 855 have a single gene defect
- early knowledge may avoid disability and better clinical care
- due to consanguinity and recessive conditions
- common recessive mutation such as sickle cell
what is the overview of PCR
- Have to already know the DNA fragment you want already
- Amplify the section of the DNA, makes multiple copies of it
- this undergoes electrophoresis
- measures the number and magnitude of DNA fragments from the sample
what is a primer
– this is a single strand of DNA 20-30 bases long which initiates elongation, this is then repeated 30 times to produce lots of copies
where does this variation arise
- crossing over - two homogenous chromosomes are paired at prophase I, they undergo crossing over and this produces 2 recombinant chromatids with allele on different sides
- mixing of the chromosoems
what are common variants
- found to exist in coding and regulatory sequences of genes
what are common disease variants
predicts that common disease causing alleles or variants will be found in all human populations which manifest a given disease
what are rare variants
alternative forms of a gene that are present with a minor allele frequency of less than 1%
what are functional rare variants
functional rare variants - alters gene function which occurs at low frequency in a population - this can have a role in complex disease and mendelian conditions
what does PCR use
Taq polymerase
primers
free nucleotides
segment which needs to be replicated
Polymorphism in the cytochrome P450 enzymic an effect how anaesthetic work
Patients with deficiency in P450 2D6 will have less analgesia
what is genome editing
this is the idea that some genetic variation can lead to disease but the use of new techniques can alter these variations
for example CRISPR Cas9
why is genome sequencing now cheaper
- introduction of better techniques which allow sequencing under a few hours
- companies that now do if for you
