Lecture 17. Ageing 2. Genetics

Question 1

Are there mutations that decrease lifespan?

Answer 1

Yes
Hutchinson-Gilford progeria syndrome
Werner syndrome
Down’s syndrome

Question 2

What is the incidence of HGPS?

Answer 2

Extremely rare, 1 in 4,000,000 to 1 in 8,000,000

Question 3

What is the lifespan of those with HGPS?

Answer 3

7-30 years old: average age of death ~14.5 years

Question 4

What are the symptoms of HGPS?

Answer 4

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

Question 5

Where can the HGPS phenotype be mapped to?

Answer 5

Chromosome 1q

Question 6

What mutation results in HGPS?

Answer 6

Mutation in the LMNA gene that encodes the nuclear lamin A protein

Question 7

What do the mutations in exon 11 result in within patients of HGPS?

Answer 7

Activate a cryptic splice site resulting in production of a lamin A protein product that deletes 50 amino acids near the C terminus

Question 8

What does lamin A do?

Answer 8

Forms intermediate filaments, part of the cytoskeleton
It forms a network (the nuclear lamina) with other lamins inside the nuclear envelope

Question 9

What is passage?

Answer 9

Transfer of cells from one flask to another for growth

Question 10

What does passage show in HGPS fibroblasts?

Answer 10

Change in nuclear shape

Question 11

What do A-type lamins promote?

Answer 11

Genetic stability by maintaining levels of proteins that have key roles in repair of DNA double strand breaks

Question 12

When do the symptoms of Werner syndrome start to show?

Answer 12

Puberty

Question 13

What does Werner syndrome result in?

Answer 13

Accelerated ageing in twenties
Lack of growth spurt
Thin arms and legs and a thick trunk due to abnormal fat deposition

Question 14

How is Werner syndrome inherited?

Answer 14

Autosomal recessive

Question 15

What is the incidence of Werner syndrome?

Answer 15

1 in 1,000,000 but in Japan and Sicily it is 1 in 30,000

Question 16

What is the life expectancy of those with Werner syndrome?

Answer 16

Usually live into their late forties or early fifties

Question 17

What are the most common causes of death in Werner syndrome patients?

Answer 17

Cancer and atherosclerosis

Question 18

How many cell doublings do Werner fibroblasts achieve in tissue culture?

Answer 18

~20 compared to normal human fibroblasts that achieve ~60 cell doublings

Question 19

What gene is associated with Werner syndrome and what do mutations in this gene cause?

Answer 19

WRN, a DNA helicase
Mutations are typically loss of function/null mutations

Question 20

What is the mechanism of Werner syndrome?

Answer 20

Faulty DNA replication at the telomeres
Overexpression of telomerase in vitro counteracts WRN mutation

Question 21

How common is Down’s syndrome?

Answer 21

1 in 700 births

Question 22

What is the current life expectancy (as of 2017) of Down’s syndrome sufferers?

Answer 22

60 years

Question 23

What are the three types of Down’s syndrome?

Answer 23

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

Question 24

How many people have Down’s syndrome worldwide?

Answer 24

~5.8 million

Question 25

How many genes are there in the 'Down's critical region'?

Answer 25

About 30

Question 26

What is Ts65Dn?

Answer 26

A mouse model that is partially trisomic for 132 genes homologous to genes on human chromosome 21

Question 27

What is over-expressed in Down's syndrome?

Answer 27

Protein Usp16 which reduces the growth rate of human fibroblast cell lines

Question 28

What does Usp16 normally do?

Answer 28

Usp16 removes ubiquitin from histones and is therefore a critical regulator of the DNA damage response

Question 29

What does the nuclear lamina seem to control?

Answer 29

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

Question 30

What are examples of Human Ageing Genomic Resources (HAGR) databases?

Answer 30

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.

Question 31

How many known genes are there that influence lifespan in model organisms?

Answer 31

~2150

Question 32

What was the first mutation found to increase animal longevity?

Answer 32

age-1 gene in Caenorhabditis elegans increasing average lifespan by 69% and maximum lifespan by 110%

Question 33

What did age-1 null mutations in C. elegans result in?

Answer 33

Extending life 10-fold

Question 34

When does lifespan increase by loss of PI-3K occur in C. elegans?

Answer 34

In the absence of glucose

Question 35

What can daf-2 mutants do in C. elegans?

Answer 35

Form dauers above 25 °C but bypass the dauer 12h state below 20 °C with a doubling of lifespan

Question 36

Why was there a dip in over 90 year olds from 2007-2010?

Answer 36

Low birth rate triggered by WW1

Question 37

How many more people are over 90 now when compared with 1990?

Answer 37

2.6 fold increase

Question 38

Compared with younger adults, what do centenarians have?

Answer 38

Lower body mass index (BMI) Lower body fat Lower plasma triglycerides Lower oxidative stress levels

Question 39

What is a genome-wide association study (GWAS)?

Answer 39

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

Question 40

What allele is a risk factor for Alzheimer’s and increases the risk in homozygotes 15-fold?

Answer 40

APOE-4

Question 41

What are the roles of ApoE?

Answer 41

Regulates lipid homeostasis by mediating lipid transport from one tissue or cell type to another

Question 42

What is the ApoE4 isoform assocaited with?

Answer 42

Hyperlipidaemia and hypercholesterolemia, which lead to atherosclerosis, coronary heart disease and stroke (all diseases associated with ageing)

Question 43

What does ApoE4 promote?

Answer 43

ApoE4 promotes the polymerization of amyloid-β into plaque-forming fibrils

Question 44

What is significantly less frequent in centenarians?

Answer 44

ApoE4 allele

Question 45

What is significantly less frequent in centenarians?

Answer 45

ApoE2 allele

Question 46

What does ApoE2 protect against?

Answer 46

ApoE2 protects against cardiovascular disease and Alzheimer’s disease

Question 47

What do FOXO genes encode?

Answer 47

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

Question 48

What variant FOXO gene is strongly associated with centenarians and human longevity?

Answer 48

FOXO3A GG

Question 49

What regulates FOXO3?

Answer 49

Insulin-dependent Akt phosphorylation