Genetics and genomics in clinical practice - 3 Flashcards Preview

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What is genomic variation?

Varying effects on health depending on where they occur and whether they alter the function of essential genes and/or their controlling elements


How can variation within the human genome arise?

- alterations in the sequence of bases in a specific section of DNA
- Microsatellites - tandem repeats of 2-6bp
- Minisatellites - tandem repeats of 10-60bp - can span several Kb
- larger deletions/duplications of DNA segments - may include one to many genes
- changes in the number or structure of chromosomes


What factors are important in determining the impact of variation in the genome?

depends on the type and where the change is
- some changes result in no or little effect while others cause medical conditions


What does variation in the genome lead to?

Normal human variation - eye colour
Differences in response to medications - effects of antidepressants
Influences likelihood of disease - diabetes
Directly result in a genetic condition e.g sickle cell anaemia


What is mendelian inheritance?

Caused by mutation in a single nuclear gene
Classical inheritance patterns:
- dominant/recessive
- autosomal/X-linked


What is non-mendelian inheritance?

Polygenic - vast majority of diseases
Multifactorial (common complex)
Maternal inheritance (mitochondrial)
Unsure what combination of genes leads to disease


In a group of patients with a common condition, what are the patterns of inheritance likely to be like?

A few will have the condition through mendelian inheritance but the majority will be due to multifactorial inheritance
Environmental factors are important in both


What are some examples of mendelian conditions?

Marfan syndrome
Cystic fibrosis
Sickle cell disease
Duchenne muscular dystrophy

Genetic components highlighted by pedigree pattern and recurrence risk


What are some examples of common conditions?

Coronary artery disease
Diabetes mellitus
Cerebrovascular disease
Breast and bowel cancer
some congenital anomalies

Genetic component suggested by clustering of cases in some families but no obvious inheritance pattern


What are the differences between genetic and environmental conditions?

- rare
- genetics simple
- uni-factorial
- high recurrence rate

- common
- genetics complex
- multifactorial
- low recurrence rate


How do you identify genetic and environmental influences?

observational studies of the incidence of diseases in different groups of people - need much larger groups of people to study


How is evidence on diseases gathered?

Familial clustering - not hereditary under these conditions
Twin studies
Adoption studies - split up siblings and place them in different environments
Population and migration studies - moving from high area of prevalence to low area at about age 16, means you end up taking on the environmental factors of the low prevalence area


Why are twin studies useful?

MZ= share all their genes and environment
DZ= share 50% of their genes and environment
Determining the incidence of a disease in twins helps delineate whether there are genetic and environmental components


Why is it useful to do large observation studies of families where they was a multifactorial condition?

Probabilities of recurrence for relatives can be calculated for general use- By observing the number of relatives with the same condition in the families


What are continuous traits and what is the basis of their inheritance?

Typically, polygenic inheritance is the basis for continuous traits which follow a normal distribution in the population
eg. blood pressure, height
Large number of genetic factors, each making a small contribution to the final phenotype


What is the basis of multifactorial inheritance?

Inheritance controlled by many genes with small additive effects = polygenic
plus the effects of the environment


How can genetic and environmental factors combine to produce a liability to a multifactorial condition?

Produces a liability curve
Above a certain threshold liability a person will develop the multifactorial disorder - individuals with the same mutations and combinations of mutations will develop the condition


What are the genetic factors contributing to a person's liability to neural tube defects?

celtic origin
specific variant in MTHFR gene - many people with have this mutation but they won't have the disease


What are the environmental factors contributing to a person's liability to neural tube defects?

poor socioeconomic status
valproic acid embryopathy

By understanding the environmental factors it means there is a greater possibility of reducing the recurrence risk by altering the environment
e.g. peri-conceptual folic acid reduces the probability of recurrence by about 75%


What is the threshold model of multifactorial inheritance and what other models are there?

Genes and environmental factors causing a particular multifactorial trait may vary from person to person
Other models:
- major gene of large effect acting on multifactorial background
- small number of genes act together


How do you determine if a child will inherit a multifactorial disease?

the recurrence risk for multifactorial disorders has been determined through family studies
Observe the number of affected siblings in many families (empiric risk)
This "look and see" approach is different from mendelian conditions where probabilities are the result of segregation of alleles on chromosomes


What is the observed recurrence risk of NTD in UK population?

observed recurrence risk after one baby with NTD in the UK population is about 4% (1 in 25)


How can we identify genes involved in mendelian conditions?

Use families
Identified by:
- a pedigree pattern indicative of a known mode of inheritance
- the diagnosis of a single gene disorder with a known mode of inheritance


How are the genetic components of common conditions identified?

Genes for common disorders have to be identified through association studies in large populations
- cross over during meiosis creates variation within the human population, therefore it makes it challenging to identify all the genes involved in a multifactorial disease


What are SNPs?

SNPs are changes of a single base in a particular DNA sequence (in genes or non-coding sequences)
- the physical locations of SNPs are known


What is one method of identifying the genetic components of common complex conditions?

Through genome wide association studies (GWAS_
Thousands of people - individuals need to be as similar as possible
Test up to 500,000 (nowadays its probably more like 3 million) in each person


What is considered to be the use of SNPs in future clinical practice?

SNPs associated with several genes maybe used together to give estimate of susceptibility
- most relative risks associated with particular SNP genotype are usually low
- therefore other genes and environmental factors involved


What is a risk locus for type 2 diabetes and what is the RR?

RR = 2.4 - low therefore other genes and environmental factors must be involved


What is a risk locus for MI and what is the RR?

RR = 2.5 - low therefore other genes and environmental factors must be involved


What is a risk locus for essential hypertension and what is the RR?

RR = 1.6 - low therefore other genes and environmental factors must be involved