Lecture 17. Ageing 2. Genetics Flashcards
Are there mutations that decrease lifespan?
Yes
Hutchinson-Gilford progeria syndrome
Werner syndrome
Down’s syndrome
What is the incidence of HGPS?
Extremely rare, 1 in 4,000,000 to 1 in 8,000,000
What is the lifespan of those with HGPS?
7-30 years old: average age of death ~14.5 years
What are the symptoms of HGPS?
Slow growth, dwarfism, fragile bodies
Generally a senile appearance
Early loss of hair (complete body alopecia)
Disproportionately large head
Small face, shallow recessed jaw, ‘pinched’ nose
Scleroderma (a hardening and tightening of the skin)
Lipodystrophy (almost complete absence of subcutaneous fat)
Incomplete extension at the knees and elbows - stiff joints
Coronary artery disease. Usually die in teens, typically of heart disease
Where can the HGPS phenotype be mapped to?
Chromosome 1q
What mutation results in HGPS?
Mutation in the LMNA gene that encodes the nuclear lamin A protein
What do the mutations in exon 11 result in within patients of HGPS?
Activate a cryptic splice site resulting in production of a lamin A protein product that deletes 50 amino acids near the C terminus
What does lamin A do?
Forms intermediate filaments, part of the cytoskeleton
It forms a network (the nuclear lamina) with other lamins inside the nuclear envelope
What is passage?
Transfer of cells from one flask to another for growth
What does passage show in HGPS fibroblasts?
Change in nuclear shape
What do A-type lamins promote?
Genetic stability by maintaining levels of proteins that have key roles in repair of DNA double strand breaks
When do the symptoms of Werner syndrome start to show?
Puberty
What does Werner syndrome result in?
Accelerated ageing in twenties
Lack of growth spurt
Thin arms and legs and a thick trunk due to abnormal fat deposition
How is Werner syndrome inherited?
Autosomal recessive
What is the incidence of Werner syndrome?
1 in 1,000,000 but in Japan and Sicily it is 1 in 30,000
What is the life expectancy of those with Werner syndrome?
Usually live into their late forties or early fifties
What are the most common causes of death in Werner syndrome patients?
Cancer and atherosclerosis
How many cell doublings do Werner fibroblasts achieve in tissue culture?
~20 compared to normal human fibroblasts that achieve ~60 cell doublings
What gene is associated with Werner syndrome and what do mutations in this gene cause?
WRN, a DNA helicase
Mutations are typically loss of function/null mutations
What is the mechanism of Werner syndrome?
Faulty DNA replication at the telomeres
Overexpression of telomerase in vitro counteracts WRN mutation
How common is Down’s syndrome?
1 in 700 births
What is the current life expectancy (as of 2017) of Down’s syndrome sufferers?
60 years
What are the three types of Down’s syndrome?
Trisomy 21 (nondisjunction), 95% cases, extra chromosome 21
Translocation Down’s, ~4% cases, extra chromosome 21 attached to another chromosome
Mosaic Down’s, ~1% of cases, some cells trisomic, others are not
How many people have Down’s syndrome worldwide?
~5.8 million
How many genes are there in the ‘Down’s critical region’?
About 30
What is Ts65Dn?
A mouse model that is partially trisomic for 132 genes homologous to genes on human chromosome 21
What is over-expressed in Down’s syndrome?
Protein Usp16 which reduces the growth rate of human fibroblast cell lines
What does Usp16 normally do?
Usp16 removes ubiquitin from histones and is therefore a critical regulator of the DNA damage response
What does the nuclear lamina seem to control?
DNA double break repair and also to control telomerase action. Accumulation of DNA damage and loss of telomeres takes us into the area of genetic instability
What are examples of Human Ageing Genomic Resources (HAGR) databases?
GenAge: a database of genes related to human ageing and a database of ageing- and longevity- associated genes in model organisms
GenDR: a database of genes associated with dietary restriction based on genetic manipulation experiments and gene expression profiling
CellAge: is a database of senescence-associated genes taken from studies using various human cell types.
How many known genes are there that influence lifespan in model organisms?
~2150
What was the first mutation found to increase animal longevity?
age-1 gene in Caenorhabditis elegans increasing average lifespan by 69% and maximum lifespan by 110%
What did age-1 null mutations in C. elegans result in?
Extending life 10-fold
When does lifespan increase by loss of PI-3K occur in C. elegans?
In the absence of glucose
What can daf-2 mutants do in C. elegans?
Form dauers above 25 °C but bypass the dauer 12h
state below 20 °C with a doubling of lifespan
Why was there a dip in over 90 year olds from 2007-2010?
Low birth rate triggered by WW1
How many more people are over 90 now when compared with 1990?
2.6 fold increase
Compared with younger adults, what do centenarians have?
Lower body mass index (BMI)
Lower body fat
Lower plasma triglycerides
Lower oxidative stress levels
What is a genome-wide association study (GWAS)?
An examination of a genome-wide set of genetic variants in different individuals to see if any variant is associated with a trait. The most frequent type of variation in our genome is the single nucleotide polymorphism (SNP), a variation at a single site in DNA
What allele is a risk factor for Alzheimer’s and increases the risk in homozygotes 15-fold?
APOE-4
What are the roles of ApoE?
Regulates lipid homeostasis by mediating lipid transport from one tissue or cell type to another
What is the ApoE4 isoform assocaited with?
Hyperlipidaemia and hypercholesterolemia, which lead to atherosclerosis, coronary heart disease and stroke (all diseases associated with ageing)
What does ApoE4 promote?
ApoE4 promotes the polymerization of amyloid-β into plaque-forming fibrils
What is significantly less frequent in centenarians?
ApoE4 allele
What is significantly less frequent in centenarians?
ApoE2 allele
What does ApoE2 protect against?
ApoE2 protects against cardiovascular disease and Alzheimer’s disease
What do FOXO genes encode?
Transcription factors that control expression of genes that regulate energy metabolism, oxidative stress, proteostasis, apoptosis, cell cycle regulation, metabolic processes, immunity, inflammation and stem cell maintenance
What variant FOXO gene is strongly associated with centenarians and human longevity?
FOXO3A GG
What regulates FOXO3?
Insulin-dependent Akt phosphorylation
