Identifying Genetic Causes of Disease Flashcards
Why is it important to understand how disease is inherited?
For genetic testing and counselling
For risk prediction
Why is it important to elucidate the molecular basis of disease?
To identify drug targets
For ‘personalised medicine’
For gene therapy
Define allele
A version of a gene
Humans are diploid so have two alleles
Define homozygous
Two copies of the same allele (AA or aa)
Define heterozygous
Two copies of different alleles (Aa)
Define hemizygous
The state when only one allele is present
Define autosomal inheritance
A trait carried on one of the autosomes (non sex chromosome)
Define sex-linked inheritance
A trait carried on either the X or Y chromosome
Define mitochondrial inheritance
A trait carried within the mitochondrial (non nuclear) DNA and is maternally inherited
Define monogenic trait
Alterations to one gene causes phenotype
Define polygenic trait
More than one gene determines phenotype
Define multifactoral/complex trait
More than one gene determines phenotype and environmental factors may also have a role
Define dominance
Only one copy of an allele is required to cause a phenotype (heterozygous and homozygous individuals are affected)
What does a solid shape in a pedigree indicate?
An affected indivual
Define incomplete penetrance
Where individuals who have the ‘faulty’ copy of the gene do not display the disease or phenotype
This can show as skipped generations in pedigree analysis
Give an example of a codominant trait
Human blood group
Define codominance
Both phenotypes are expressed
What can monogenic traits be seen by?
Pedigree analysis
What type of inheritance do monogenic traits follow?
Simple Mendelian inheritance
How can you tell if a disease is genetically determined?
See if the disease runs in families
What can we deduce about parents if an affected individual has an autosomal dominant disease?
They must have at least one affected parent
What percentage of offspring will be affected if a parent has an autosomal dominant disease?
Approx. 50%
What is the ratio of males and females affected by an autosomal dominant disease?
Equal
Both males and females can transmit an autosomal dominant phenotype to their offspring, true or false?
True
What percentage of offspring are unaffected when both parents are heterozygous and affected by an autosomal dominant disease?
~25%
What percentage of offspring are affected when both parents are heterozygous and affected by an autosomal dominant disease?
~75%
What percentage of offspring have one copy of the dominant allele when both parents are heterozygous and affected by an autosomal dominant disease?
~50%
What percentage of offspring have two copies of the dominant allele when both parents are heterozygous and affected by an autosomal dominant disease?
~25%
For a carrier and unaffected parent of an autosomal recessive disease, what is the ratio of unaffected, affected and carrier offspring?
50% unaffected
50% carrier
For an affected and unaffected parent of an autosomal recessive disease, what is the ratio of unaffected, affected and carrier offspring?
100% carrier
When both parents are carriers of an autosomal recessive disease, what is the ratio of unaffected, affected and carrier offspring?
50% carrier
25% affected
25% unaffected
X-linked recessive diseases have the same principle as autosomal recessive diseases, but what else should be considered?
The inheritance restrictions of sex chromosomes
Males only have one copy of X so will show the recessive phenotype
For an affected father and carrier mother of an X-linked recessive disease, what is the ratio of unaffected, affected and carrier offspring?
Females: ~50% affected ~50% carrier Males: 50% affected 50% unaffected
For an unaffected father and carrier mother of an X-linked recessive disease, what is the ratio of unaffected, affected and carrier offspring?
Females: ~50% unaffected ~50% carrier Males: 50% affected 50% unaffected
For an unaffected father and affected mother of an X-linked recessive disease, what is the ratio of unaffected, affected and carrier offspring?
Females:
100% carrier
Males:
100% affected
List the types of genetic variation
Chromosomal abnormality, e.g. translocations, trisomy
SNPs (single/simple nucleotide polymorphisms), e.g. A to T
Copy number variation (CNV)
Indels (insertions or deletions)
What is the candidate gene approach for identifying genetic causes of disease?
Look for/type variants in gene regions where known biology predicts involvement
Sequence (whole genome or exome) genes
What is the downside to the candidate gene approach for identifying genetic causes of disease?
It is biased as it relies on prior knowledge of disease biology
What do regional association plots show?
The linkage relationship between SNPs
How can the location of a SNP influence disease?
Could be…
In a coding region (changes protein produced)
Intronic (splicing)
In a regulatory region (promoter, enhancer)
Do common diseases often run in families?
Yes
Do complex traits follow Mendelian ratios of inheritance?
No
How many genes are involved in complex traits?
Multiple
Complex traits are purely genetic, true or false?
False, they also have environmental determinants
What is now the most common method for investigating the genetic basis of complex diseases?
Genome-wide association studies (GWAS)
Why is GWAS unbiased?
Because the whole genome is tested
What does GWAS allow the discovery of?
Genetic regions with previously unknown disease biology
What do modern GWAS arrays type individuals for?
SNPs, indels and CNVs
How many variants per individual have been identified using GWAS arrays and imputation?
~10 million
How can you analyse the genes that may potentially be involved with a disease?
Using case-control analysis
What is the basis for case-control analysis?
Compare individuals with the disease (case) to healthy individuals (control)
What is the standard threshold for genome-wide significance and what is this based on?
p < 5E-8
Based on Bonferroni correction for 1 million independent tests
What is the false discovery rate for genome-wide significance?
1% or 5%
FDR 0.01 - 1 in every 100 loci incorrect
FDR 0.05 - 5 in every 100 loci incorrect
How many variants is genome-wide significance testing?
Millions of variants across thousands of people
Why do you need to control for multiple testing of genome-wide significance?
To reduce false positive results
How does the location of the gene influence disease?
Most disease associated SNPs affect genes in close proximity (~200kb)
How does the location of the SNP influence disease?
Knowing/predicting which SNP is having the effect can help identify the gene involved
What questions can bioinformatics analysis answer to help predict the function of a SNP?
Is a protein coding change deleterious to protein function?
Is a transcription factor binding site altered?
Is there evidence of changes in gene expression linked to the SNP?
Why is bioinformatics analysis helpful?
As there is an increasing amount of publically available data and online tools
Understanding how a disease is inherited can help identify whether it is…
Monogenic or complex
GWAS is a common and unbiased approach now widely used to identify genetic causes of disease, true or false?
True
What does GWAS help us to identify about a disease?
Risk prediction Biological mechanisms involved Personalised medicine (in the future)
