This document contains a wide range of subjects in the field of level 6 clinical genetics. I have put an index at the start of the document so you can get your intended subject quickly and efficiently. Key words are written in bold or underline in order to separate them from their descriptions. The...
22-24 – Single cell analysis (approaches for single cell)
24-26 – Genetic counselling
26-29 – Epigenetics
29-33 – Metabolomics
, Clinical genetics revision
- Research interpatient heterogeneity
Diagnostics
- Mass spectrometry (measure molecular or atomic weight to identify the amount and
type of chemicals present in a sample)
Top down proteomics – The analysis of entire proteins
Bottom up proteomics – The analysis of peptides that were broken down from proteins
after proteolytic digestion
Shotgun proteomics – Aims to recognise all proteins in a complex sample
Tandem mass-spectrometry (used after fragmentation, so it analyses the fragments)
Liquid chromograph mass spectrometry - Utilizes fragmentation within the process
Label-free mass-spectrometry - determines the relative amount of proteins in two or
more biological samples
Labelled mass spectrometry - identifies and quantifies relative differential changes in
complex protein samples
Targeted proteomics - useful when predetermined sets of proteins need to be
measured across multiple samples
Matrix-assisted laser desorption/ionization (MALDI) - most popular ionization
technique for MSI (Types of imaging: Desorption electrospray ionization (DESI),
secondary ion mass spectrometry (SIMS), and easy ambient sonic spray ionization (EASI))
- Next generation sequencing (Massive parallel processing. Allows sequence profiling of
transcriptomes and genomes)
Roche, 454 (pyrosequencing)
SOLiD (Supported Oligo Ligation Detection
Solexa sequencing, Illumina – CHEAPEST
Ion Torrent
SMRT (Single Molecule Real-Time) sequencing
Nanopore
Flow-cell cytometry
- Sanger sequencing (determines the sequence of a sample one section at a time)
- Whole genome sequencing – process of determining the entirety, or nearly the entirety,
of the DNA sequence of an organism's genome at a single time
- Genome-wide association studies (GWAS) (rapid scanning of markers across genomes to
find genetic variations associated with a particular trait)
- Micro-array (used to detect thousands of gene sequences at a time)
- RNA sequencing (provides a far more precise measurement of levels of transcripts and
their isoforms)
- Mass cytometry (used to detect and measure physical and chemical characteristics of a
population of cells or particles)
- Single cell RNA sequencing (scRNA-seq) (generated via cell lysis, good in the treatment
and diagnostics of melanomas)
- Single-cell analysis (
, Non-efficient methods - Limiting dilution, micromanipulation, and flow-activated cell
sorting (FACS)
Microfluidic technology - Microdroplet-based microfluidics (e.g., Drop-Seq)
Cell Search – isolates rare circulating tumour cells (CTCs) - a system to enumerate CTCs
in patient blood samples
Cell barcoding - individual cells are labelled with unique nucleic acid sequences, so they
can be tracked
Template switching - anneal to a template switching oligo (TSO) with a known sequence,
prompting the reverse transcriptase to switch template from RNA to the TSO.
- Solid-phase extraction (SPE) (A purification technique, compounds which are dissolved
or suspended in a liquid mixture are separated from other compounds according to their
chemical and physical properties)
- Chromatography (Separates individual metabolites from a mixture)
restriction enzymes have advanced genomic analysis, and trypsin has advanced proteomic
analysis, there has been no equivalent enzyme for universal polysaccharide digestion
LOD score (logarithm of the odds) - a statistical estimate of whether two genes are likely to
be located near each other on a chromosome and are therefore likely to be inherited.
- A score of 3+ means they’re linked, but 3- means they’re not
Recombination occurs mostly between loci that are far from each other (50% chance of
recombination)
- If recombination rate is less than 50%, we say the loci are linked (genetic linkage)
- Genetic distance is measured in Centimorgans (cM)
Haplotype - A haplotype (haploid genotype) is a group of alleles in an organism that are
inherited together from a single parent
Sequencing – to determine the primary structure
Modes of inheritance:
- autosome – Non-sex chromosome, members of an autosome pair in a diploid cell have
the same morphology
- X-linked – sex chromosome
- Mitochondrial – from the mother
mRNA is the strand of DNA created in the nucleus by RNA polymerase
tRNA is the complex that finds a corresponding amino acid to the mRNA strand in translation
nucleotide monomers:
Hydrogen bonds found between nucleotides and monomers
, Gene regulation, how it works:
Heterochromatin – not that active (not transcribed, mainly because it’s always condensed),
long stretches of satellite DNA, usually condensed in interphase
Euchromatin – Not condensed in interphase, quite active
DNA primer - short single-stranded nucleic acid utilized by all living organisms in the
initiation of DNA synthesis
Tandem repeats – A pattern of one of more nucleotides is repeated, and the repetitions are
directly adjacent to each other
- Short tandem repeats are known to have more replication slippage
In DNA synthesis, there are mechanisms to correct any errors (like the insertion of an
incorrect base) like DNA polymerase proof-reading, and DNA repair pathways
DNA polymerase slippage (replication slippage) – the DP can stall and dissociate from the
DNA, causing the DNA to come apart, but then come together in the wrong place (like the
Velcro with the loop) – this can case insertion and deletion mutations
Genome wide associated studies (GWAS) - observational study of a genome-wide set of
genetic variants in different individuals to see if any variant is associated with a trait
- Is that how they discovered schizophrenia to be inheritable and not just a mental
disorder
Next generation sequencing (massive parallel sequencing) – Allow for the sequencing of DNA
and RNA much more cheaply and quickly as sangar sequencing (included in the 1000
genomes project)
Transcriptomics – Analysis of RNA transcripts that are produced by the genotype at a given
time, which may provide a link between the genome, the proteome, and the cellular
phenotype
Proteomics – Large-scale study of proteins, and being able to identify the increasing
numbers of proteins
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