L13: Intro to Genetics

Question 1

What is genetics?

Answer 1

Genetics is the study of the genetic material inside an organism and how this material controls what the organism looks like and how it works

Question 2

What is genetics fundamental to?

Answer 2

The understanding of how populations and species have evolved

Question 3

What do classical genetic studies involve?

Answer 3

Involved analysis of genetic variants or mutants that lead to abnormal genetic function, from this make deductions as to what the importance of the gene was to the organism/cells and any manipulation that can be made to alter function

Question 4

When was the Human Genome Project published?

Answer 4

2003

Question 5

Why has the cost in genome sequencing declined so much?

Answer 5

• Prior to the 2003 publication of the Human Genome project the cost of genome sequencing was very high
• Developments in technology now means it costs significantly less to do

Question 6

What were Big Data Projects?

Answer 6

• e.g. the 1000 Genome project - sequenced 1000 genomes of individuals across different populations - set out to describe common human genetic variation by applying whole genome sequencing across multiple diverse populations
• To identify variations, you have to know the genetic diversity of different populations to understand the frequency of the particular variation sequence that may be found

Question 7

What are genomics?

Answer 7

Genomics is the study of the body’s genes, their functions and their influence on the growth, development and working of the body

Question 8

How can genomic data be used?

Answer 8

Can be used in the development of cutting edge genomic technologies to predict and diagnose inherited and acquired disease, and to personalise treatments and interventions

Question 9

What is meant by the ‘double hit’ with regards to cancer?

Answer 9

• Often do not get familial cancer syndromes - if there is a mutation you will go on to develop a particular type of cancer
• Normally a combination of different mutations- can be born with the germline cancer/gene mutation and not until somatic events after birth that the abnormal pathology is developed - known as a double hit
• The double hit can be in a particular tumour type

Question 10

Why is understanding combinations of mutations that occur in different tumour tyoes important?

Answer 10

Important for understanding the tumour and finding genetic susceptibility genes, to choose the best treatment and personalised medicine

Question 11

What are some examples of important genomic databases?

Answer 11

• COSMIC - Catalogue of somatic mutations in cancer
• The Cancer Genome Atlas (TCGA) - researchers are mapping the genetic changes in 33 cancers selected for study

Question 12

What characterises most mutations?

Answer 12

• Most mutations in cancer are somatic (occur de novo in the precursor cells of the tumour)
• But inheriting mutations can also predispose to cancer (germline)

Question 13

How can the effect of inherited mutations vary with frequency?

Answer 13

• Small effects are seen where the genetic variant is common (frequent)
• Large effects in the case of very rare mutations

Question 14

Give some examples of risk penetrance profiles for genetic susceptibility factors

Answer 14

• Breast cancer - clear genetic susceptibility genes where having the variant makes someone very susceptible to that cancer
• e.g. Braca 1 and 2 - these genes mean a high susceptibility to develop breast cancer
• Risk SNPs on the graphs have a high allele frequency so the risk of developing cancer is low
• The MLH1, 2 and 6 have a high susceptibility to develop colorectal cancer- not repaired can lead to change in cancer and tumour progression
• APC the most high risk gene in causing colorectal cancer

Question 15

Which genes should be tested for?

Answer 15

• Use a panel of genes for inherited cancer gene mutations - include the most high risk genes for susceptibility
• The genes to be included are decided by national government genetic services

Question 16

What do somatic mutations in particular genes indicate?

Answer 16

In cancers a somatic mutation in particular genes indicated a specific biochemical pathways has been disrupted, for which there might be a treatment

Question 17

What does the graph show?

Answer 17

• As the mutations per megabase increase, this means the risk of having the type of somatic cancer is more frequent/prevalent and has a higher number of coding mutations per tumour
• Below the graph is the % way in which the mutation may occur e.g. melanoma causes skin cancer which is predominantly due to the effect of UV rays

Question 18

What can happen to some cancers?

Answer 18

• Can be sporadic and disappear
• Sometimes no familial susceptibility

Question 19

Why is sequencing of genes done?

Answer 19

• Can identify a particular germline cancer predisposition in an individual and can do targeted screening
• Preventative surgery can remove cancerous tissue
• Personalised medicine/treatment can be informed by gene variants causing base change e.g. mutated mismatch repair genes - can target these specific variants/bases

Question 20

What plot can be done to show genetic susceptibility for genes?

Answer 20

• Manhattan plot
• Shows risk susceptibility on the Y axis and the chromosome number on the X axis

Question 21

Give an example of some clinical problems that can be genetically linked

Answer 21

• Type 2 diabetes
• Cardiovascular disease
• Psychiatric disorders

Question 22

How has type 2 diabetes been linked to genetic factors?

Answer 22

• Compelling evidence that the individual risk of type 2 diabetes is strongly influenced by genetic factors
• Successive waves of T2D genome wide association studies—with ever larger samples— have delivered more than 80 robust association signals (80 different loci across the genome)
• However, in these studies, the alleles associated with T2D were predominantly common (minor allele frequency (MAF) >5%), with individually modest impacts on T2D risk

Question 23

How has coronary heart disease been linked to genetic factors?

Answer 23

• Myocardial infarction (MI), a leading cause of death around the world, displays a complex pattern of inheritance
• When MI occurs early in life, genetic inheritance is a major component to risk
• Rare mutations in low-density lipoprotein (LDL) genes have been shown to contribute to Ml risk in individual families
• Common variants at more than 45 loci have been associated with Ml risk in the population
• Susceptibility on chromosome 9 can lead to coronary heart disease

Question 24

How has psychiatric disease been linked to genetic factors?

Answer 24

There are confirmed associations between genetic variants that increase the risk of
- schizophrenia (SCZ),
- autism spectrum disorder (ASD),
- major depression,
- Bipolar disorder (BPD),
and in some cases the underlying gene(s) have been identified
- Considered multigenic

Question 25

What projects were done to discover the genetics behind many Mendelian disorders?

Answer 25

• Deciphering Developmental Disorders Project (DDD)
• 100 000 Genomes Project
• Split genes into 3 main categories - cancer susceptibility, infectious disease and rare diseases

Question 26

What was an outcome from the 100 000 Genome Project?

Answer 26

• Aimed to prevent diseases by earlier detection to improve chances of survival
• Allowed for fast track diagnosis for critically ill babies and children - using whole exome sequencing to reduce waiting time and doubles the chance of diagnosis

Question 27

What is whole exome sequencing?

Answer 27

• Can sequence 1.5% of the coding variation of a genome
• Removes any junk DNA

Question 28

How does the age of a father at the conception of a child affect the number of de novo mutations?

Answer 28

• With age the risk of developing mutations increases
• So the next generation are more likely to develop a mutation

Question 29

What was the UK biobank?

Answer 29

• A prospective cohort study with deep genetic and phenotypic data collected on approximately 500,000 individuals from across the United Kingdom, aged between 40 and 69
• The open resource is unique in its size and scope
• Rich variety of phenotypic and health-related data available on each participant, including biological measurements, lifestyle indicators, biomarkers in blood and urine, and imaging of the body and brain
• Follow-up information is provided by linking health and medical records
• Genome-wide genotype data have been collected on all participants, providing many opportunities for the discovery of new genetic associations and the genetic bases of complex traits

Question 30

How can traces of the Neanderthal shape the appearance and health of living people?

Answer 30

• Genome wide studies
• Can study different populations and identify where different variants originate from
• E.g. Scandinavia has a very different genetic profile to Spain - they are geographically distinct - tell us the different genetic makeups and shows how different populations have evolved