BMS2062 - W3: Genomic Variation and Disease

What are some approaches to determining the function of a gene product/ protein?

• location of gene

• comparative analysis

• structure function analysis

• biomolecule interaction analysis

• consequences of over/ under expression

• consequences of mutation

Location of gene expression - analysis

Genome contains the same genetic material in all cells but are expressed differently in different cells.

• gene being expressed in a particular cell = protein’s function is required in some way by that cell

• transcriptomics can tell us where genes are being expressed (which RNA are present)

• proteomics can also tell us what collection of protein are present within a cell/ group of cells at any one time

The expression atlas: a database that contains the transcriptomics and proteomic data regarding genes expression in specific tissues for specific disease states

Comparative analysis

Have paralogues or orthologues previously been characterised for the gene of interest

• can infer that genes which haven’t been researched yet function similar to homologues

• could use web BLAST to find homologues (as they are likely to have a high number of sequence similarity)

Homologues:

Orthologues: genes which have been evolved from a common ancestor gene that have retained similar functions in different species

Paralogues: Genes which have evolved from the same ancestral gene in different regions of an organism’s genome

Structure function analsyis

Through the structure of a protein, we can determine the functionally important regions

• sequence of a protein can help understand how a protein might function - particular domains/ regions which can be used to infer function (can compare with already known proteins)

• X-ray crystallography, NRM or cryo-electron microscopy can be used to help understand the structure of a protein

  • can look for binding pockets

  • amino acid patterns (charged residues which bind to things)

Biomolecule interactions analysis

Based on the structure of the protein, what is it likely to interact with

Can be detected by:

• NMR - to collect structural data

• fluorescence experiment (two proteins coming close together produces a fluorophore)

• interactions proteomics

Bioinformatic Tools:

• STRING (protein-protein interaction database)

Consequences of under/ overexpression

Common approach of determining function

• can use model organisms to see this

consequences of mutation

• Individuals with mutations can be used to study how mutation in that region of the gene causes dysfunction in the protein and cellular level

• can create mutations in model organisms to see changes → understand function

Applications of genomics for humans

• diagnostic testing

• linking genetic variations to disease

• prenatal genetic testing

• cellular function

• cancer therapy

• pharmacogenomics

• gene editing/ therapy

How can genomics be used to differentiate between healthy and cancerous tissue?

• tumour suppressor genes and Proto-oncogenes

• type of mutation, location of mutation, percentage chance people develop cancer with the mutation

• some mutations have higher penetrance than others (more likely to cause cancer)

ClinVar

A bioinformatics tool that can assess an individual’s mutations against known mutations in the ClinVar database to assess pathogenicity

How can genomics enable gene editing?

• genomics provides a map of where genes of interest are located (tells us where genes are and their sequence)

• can identify desirable traits and find location of genomic variants associated with those traits

• allows us to possibly add desirable traits into an embryo → desirable traits can get passed on

What is gene editing?

What techniques allow us to edit genes?

Making changes to the genetic material of an organism

techniques:

• CRISPR-Cas9

• ZFNs

• TALENs

These techniques involve creating a double stranded break in the DNA and adding genes of interest