Consolidating the Scientific Basis of Genomics

Details

Title

Consolidating the Scientific Basis of Genomics

Type

Stage One

Module code

HBI100

Requirement

Compulsory

Module objective

By the end of this module the Clinical Scientist in HSST will be able to analyse, synthesise and apply their knowledge and understanding of genomic structure and variation to their clinical practice. This knowledge and understanding will inform their ability to provide state-of-the-art analysis of inherited or somatic (e.g. in cancer) sequence variants observed in whole-genome sequence data. The Clinical Scientist in HSST will also be expected to consistently demonstrate the attitudes and behaviours necessary for the role of a CCS.

Knowledge and understanding

By the end of this module the Clinical Scientist in HSST will be able to analyse, synthesise, evaluate and critically apply their expert knowledge to genomic data interpretation including:

High-level genome structure:

• the extent of the human genome, and how it is partitioned into amino acid coding (1.2%), other exonic (1%) and transposable element (>50%) sequence. Variants in <10% of the human genome affect fitness;
• genome modification (methylation, epigenetics);
• chromosomes and histones;
• genome folding

The transcribed genome:

• characteristics of a generic protein-coding gene;
• the likely impact of mutations falling within its different regions (synonymous versus nonsynonymous sites, splice sites versus introns, Untranslated Regions (UTRs);
• molecular pathology: functional sites, malfolding of proteins, protein gain-of-function, mis- spliced transcripts, rapidly degraded transcripts

The regulatory genome:

• gene regulatory elements;
• our current inability to accurately predict impact of mutations in non-protein-coding sequence

Variation at individual level:

• how frequently spontaneous (de novo, non-inherited) mutations cause rare disease;
• common evolutionary trajectories of cancer genomes, including mosaicism;
• recessive vs dominant inheritance, mitochondrial disease, karyotypes, aneuploidy, loss of heterozygosity, copy number variation

Variation at family level:

• how recombination segregates variants and how variants are co-inherited (linkage disequilibrium).

Variation at population level:

• how human genome sequences differ among subpopulations and in cancer

Implications in clinical genomics:

• genomic variants that do not affect clinical phenotypes;
• biochemical activity – functionality relationships: much transcription and many protein-binding events have no downstream consequences;
• how the finite error rates of sequencing affect predictions;
• accounting for multiple statistical tests in genomics.

Technical and clinical skills

By the end of this module the Clinical Scientist in HSST will be expected to critically reflect and apply their knowledge of the fundamentals of genomics in a range of clinical practice scenarios to solve problems and identify new and innovative approaches.