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FTIB > systems to cells part 2 > Flashcards

systems to cells part 2 Flashcards

1
Q

how could we go about finding a gene for a trait e.g. cystic fibrosis - what do we need to do this

A

we need:

  • the trait segregating in large families
  • the trait needs to behave as a mendelian, single gene trait
  • genetic differences across the genome (SNPs)
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2
Q

when gene mapping what are the 3 milestones towards finding a single gene responsible for a trait

A
  1. phenotype
  2. small chromosomal region
  3. single gene
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3
Q

when you get down to a region of the chromosome in gene mapping how many genes are usually in the this region

A

usually around 50

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4
Q

what are mendels 2 laws

A

law of segregation

law of independent assortment

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5
Q

what is the law of segregation

A

alleles of a given locus separate into different gametes during meiosis

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6
Q

what is the law of independent assortment

A

when homologous pairs of chromosomes orient independently of each other at the metaphase plate of meiosis 1
probability of inheriting an allele at one locus is independent of inheriting an allele at a second locus
the allele a gamete receives from one gene doesn’t influence the allele received for another gene

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7
Q

if genes are close to each other, are we likely to get parental or recombinant genotypes in a dihybrid cross

A

more parental because the genes will have strong linkage

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8
Q

what is the difference between parental and recombinant genotypes

A
  • a parental genotype is the same as one of the parents - a combination of alleles inherited from parents
  • a recombinant genotype is different to both of the parent genotypes - a different combination of alleles than possessed by the parents
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9
Q

the .…….. is blind to what a gene is

A

spindle

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10
Q

how can pieces of the same chromosome segregate independently

A

we get homologous recombination (crossover) at meiosis 1

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11
Q

what is crossing over

A

crossing over generates gametes with recombinant genotypes
this enables alleles at different loci on the same chromosome to be re-associated
by creating new genotypes it creates genetic diversity in the population

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12
Q

give 2 characteristics about crossing over sites on chromosomes

A

they are fairly randomly distributed

they occur 1-2 times per chromosome in each meiosis

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13
Q

the further away genes are on a chromosome, the greater/lower the probability of crossing over

A

greater

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14
Q

what is the recombination frequency

A

the measure of the distance between 2 genes

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15
Q

how do we calculate recombination frequency

A

no. recombinants/ total no. chromosomes or total offspring

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16
Q

if we have independently segregating genes what is our RF value likely to be

A

RF=50%

no. parental = no. recombinants

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17
Q

what happens to recombination frequency as genes get closer together on the same chromosome

A

the recombination frequency decreases RF = <50% and the parental dominate

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18
Q

when mendel was studying peas he looked at dihybrid crosses where the genes of interest were very close/far

A

far apart - saw recombination

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19
Q

if our RF <5% what does this tell us about the genes

A

they must be linked on the same chromosome

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20
Q

we see linkage is genes are between ………… of the genome

A

1.6%

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21
Q

1% recombination = 1 ??

A

centi morgan (cm)

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22
Q

genetic distance = ???

A

physical distance

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23
Q

1 centi morgan = …. bp

A

1 million

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24
Q

1 million bp = …… genes

A

6

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25
Q

what is the maximum observaleb RF

A

50% = 50cm

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26
Q

1.6% genome = ……. bp

A

50 million

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27
Q

define linkage

A

when alleles of nearby loci tend to be inherited together

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28
Q

what is a haplotype

A

a chromosome

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29
Q

we inherit one chromosome from each parent each with a different combination of ………..

A

alleles/polymorphisms

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30
Q

crossing over generates new haplotypes but blocks of ……..… remain

A

old ones

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31
Q

describe the inheritance of a causative allele (allele that causes a trait)

A
  1. lots of SNPs will be located around the causative allele
  2. recombination will occur and some of these SNPs will be lost
  3. the SNPs very close to the causative allele will be inherited by descendants due to linkage
  4. the chromosome is passed on containing the causative mutation and the tightly linked SNPs
  5. these SNPs will feature in every person with the causative allele
  6. using this knowledge we can try to determine where a causative locus is - if we know where SNPs are located we can estimate where the disease locus is likely to be
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32
Q

what is the only chromosome that never recombines

A

y chromosome

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33
Q

how can you be a descendant of someone and not be related to them

A

parts of haplotypes are lost during recombination so you may no longer share common sequence

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34
Q

how many SNPs does one person have

A

> 10,000

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35
Q

genetic linkage results in random/non-random segregation

A

non-random

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36
Q

……. are generally linked to a trait locus and all those with the trait will have the same ones

A

SNPs

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37
Q

why has most genetic analysis so far been on traits like cystic fibrosis

A

it is caused by a single gene
large effect size - if you have the allele you have the trait
little to no environmental effect
runs in families in clear mendelian patters/ratios
we can find a gene that explains all the variability

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38
Q

give examples of 2 traits that are not inherited in clear mendelian pattern

A
  • complex trait like diabetes, depression etc

- quantitative traits like height etc

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39
Q

why do some trait not follow simple mendelian patterns

A

there could be multiple genes involved
there could be no genetic basis
if genes are involved they may only affect the risk of developing the trait, it is not necessarily pre-determined
environmental factors can also have a role

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40
Q

what is heritability

A

the contribution of genetics to a trait under current conditions

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41
Q

what is grave’s disease

A

an autoimmune disorder that leads to hyperthyroidism (overactivity of the thyroid)

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42
Q

why are identical twins good for studying genetics

A

because they have the same genetics and they are generally exposed to the same environment unless separated

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43
Q

when looking at the heritability of a trait we need to separate the genes from the environment - how can we do this with twins

A

identical twins - same genes, same environment
fraternal twins - different genes. same environment
heritability = identical twin trait probability id the other has it - fraternal twin probability of trait if other has it x2

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44
Q

for huntington’s disease what is the probability that if one twin is affected the other will be too and what is the estimate of heritability

A

identical twins - 100%
fraternal twins - 50%
estimate of heritability 100-50 x2 = 100%

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45
Q

what would be better than looking at fraternal twins but isn’t necessarily ethical

A

separating identical twins at birth - they would have same genes but different environment

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46
Q

what does 40% heritability mean

A

for a population:

  • 40% of the risk is attributable to genetics
  • 60% of the risk is non-genetic
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47
Q

what is a gwas

A

a genome-wide association study (GWAS) is an observational study of a genome-wide set of genetic variants in different individuals to see if any variant is associated with a trait.
GWASs typically focus on associations between single-nucleotide polymorphisms (SNPs) and traits like major human diseases, but can equally be applied to any other genetic variants and any other organisms.
used to identify loci contributing to complex traits

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48
Q

when doing a gwas do we sample a population or a family

A

population - they can look at >100,00 0 people

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49
Q

……. can be used to test for association with disease alleles

A

SNPs

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50
Q

if SNPs are not associated in the population what do we see

A

the state of one SNP does not influence the state of the other - the SNPs are not associated in the population - the SNPs are very far apart

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51
Q

if SNPs area associated in the population what do we see

A

the 2 SNPs are very close together and the state of one SNP influences the other - they are in a common haplotype block in the population

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52
Q

if two SNPs are linked and the state of one SNP confers disease what do we see

A

because there is linkage we will see a higher frequency of the linked SNP in those with the disease SNP - the other SNP behaves as though it is genetically linked to the pre-disposing SNP

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53
Q

we can find loci contributing to complex risks even if multiple genes contribute. each genes contributes a …. ……. and so we need …………. numbers

A

small risk huge

54
Q

what are association statistics important for

A

determining if a SNP is linked to an allele

55
Q

what is the method of association analysis

A
  1. collect large population sample
  2. separate into trait and no trait groups taking care to match the groups for other features that have a genetic component e.g. age, sex, ethnicity
  3. genotype 100,000 SNPs in each person
  4. check the population is in hardy Weinberg equilibrium
  5. determine if the allele frequency of each SNP is different between groups
  6. if there is a difference, check to see if it is statistically significant
56
Q

do practice calculations

A

khan academy

57
Q

how can we determine is there is a significant difference between allele frequencies

A

chi squared test - if there is a significant difference then the more frequent allele in the trait group is associated with the trait

58
Q

analysing SNPs for association is very prone to what and what extra measure do we take to avoid these

A

multiple testing and false positives

p value threshold is lowered to p<5x10-8 - decreases the chance of a false positive

59
Q

why were many early gwas prone to false positives

A

because there were too few people in the study and the stats were less well understood so the p-value threshold was higher
groups were also not well matched for other features that have a genetic components

60
Q

why were early gwas also prone to finding nothing

A

too few participants in studies meant only SNPs associated with large effects could be found

61
Q

a SNP on which gene is associated with autism

A

CDH10 - this could shed light on the development of autism and possible therapies

62
Q

where were the most highly associated SNPs for autism found

A

between CDH9 and CDH10

63
Q

how can SNP gwas results be effectively displayed

A

in manhattan plots - the number of dots highlight the strength of the association and the position on the chromosome is also shown

64
Q

what are the hallmarks of diabetes

A

fat distribution, obesity, hepatic lipid metabolism –> insulin resistance –> hyperglycaemia
autoimmune B cell dysfunction, low insulin synthesis, low insulin secretion –> insulin deficiency –> hyperglycaemia

65
Q

what are the 3 variations of diabetes

A

T1D, T2D, MODY

66
Q

T1D and MODY are normally diagnosed in …….. people whereas T2D is normally diagnosed in ……….. people

A

younger

older

67
Q

what does MODY stand for and what is it

A

monogenic onset diabetes in the young
it is a very rare mendelian trait and often misdiagnosed as T1D or T2D
there are multiple versions with a different mutated gene in each
the two most common mutations affect GCK and HNF1A

68
Q

what does GCK encode and what does the MODY mutation cause

A

glucokinase which is responsible for catalysing the first step in glycolysis (glucose –> glucose-6-phosphate)
the mutation is recessive showing loss of function
glucose becomes trapped in cells as it is still being taken up but not being metabolised in glycolysis

69
Q

what does HNF1A encode and what dies the MODY mutation cause

A

a transcription factor that drives expression of certain genes in the endoderm, including GLUT1 and 2
the mutation is recessive showing strong loss of function

70
Q

what % of diabetes cases does T1D account for and what % of the population does it affect

A

10% of cases

0.5% of the population

71
Q

what is T1D

A

an autoimmune disease that destroys the pancreatic B cells

the immune system destroys pancreatic B cells due to expression of insulin as self antigen

72
Q

what has genetic testing of t1D involved

A

looking at candidate genes chosen based on biology
gwas to search for risk loci
several gwas wee carried out - the HLA (human leukocyte antigen) region was implicated early. this encodes the major histocompatibility complex which regulates the immune system
the structure of the binding cleft of HLA DBQ1 determines what antigenic peptides are bound and presented to the immune system
insulin is presented and seen as non self

73
Q

T1D is the only organ specific autoimmune disease not to show a strong ……… bias

A

sex - most autoimmune diseases are more common in females

74
Q

what does T1D therapy involve

A

injections of recombinant human insulin

75
Q

describe the heritability of T1D

A

the probability of a twin having the disease if the other has it is:

  • identical - 20-40%
  • fraternal - 6%
76
Q

it has been found that there are ……………….. risks that are the same for multiple autoimmune diseases

A

pre-disposable

77
Q

why is early diagnosis of T1D difficult

A

because clinical signs are only evident after development of the disease

78
Q

how could we improve early diagnosis of T1D

A

genotyping could identify high risk children 2-5yrs before development of T1D

79
Q

are there environmental factors for T1D

A

yes

80
Q

it is thought that an …………… infection early in life could lead to multiple immune challenges which could cause T1D

A

enterovirus

81
Q

what % of diabetes cases does T2D account for and what % of the population does it affect

A

90%
6% of the population
one of the biggest health problems globally

82
Q

describe the heritability of T2D

A

the probability of a twin having the disease if the other has it is:
- identical - 70%
- fraternal - 20-30%
there is some extent of heritability but this extent is unclear because there are also definite environmental factors

83
Q

what is the biggest risk factor for T2D

A

obesity

84
Q

how may T2D genes affect behaviour

A

may affect food intake, fat accumulation, metabolism, BMI, glycaemic traits, liver processes, B cell responses/survival

85
Q

how much of the T2D risk has been explained using gwas

A

6% - the identified risk alleles feed into the same endophenotypes which are found in several different metabolic diseases e.g. B cell dysfunction, fat distribution, hepatic fluid metabolism and increased adiposity

86
Q

what is the strongest risk variant of T2D

A

the TCF7L2 gene which encode a transcription factor and acts in pancreatic B cells

87
Q

where are the majority of T2D risk variants found and what does this mean

A

ncRNA - the current idea is that these are regulating sites e.g. TF binding sites, meaning T2D would be a regulatory disorder

88
Q

what is the odds ratio

A

the odds for carriers of risk alleles divided by the odds of non-carriers of risk alleles

89
Q

look at odds ratio calcs

A

notes and khan academy

90
Q

what does an odds ratio of one mean

A

the allele has no affect on the probability of having the disease

91
Q

what does the odds ratio supply

A

the relative risk - this can be misleading

92
Q

what can be more informative than relative risk

A

absolute risk/incidence frequency

risk = cases/total

93
Q

do most T2D carry the TCF7L2 risk allele

A

no

94
Q

what environmental factors increase T2D risk

A

movement to a higher calorie diet
westernised lifestyle
movement of native populations to urban settings

95
Q

what is the polygenic risk score

A

it considers the population of variants together to look at individual people
it gives a percentile score which relates to relative risk of disease
it can be used to give preventative measures to those of high risk, however, for T2D this would be a lifestyle change and a PRS is generally not enough to motivate people

96
Q

is PRS reliable

A

not it is not very accurate or reliable so it is more effective when combined with tests for other factors
this has been effective for stroke and heart disease but PRS doesn’t enhance predictive risk of T2D

97
Q

is T2D predestined by genes alone

A

no

it is part heritable part non-genetic

98
Q

can heritability change with the environment

A

yes

99
Q

how many genes have alleles that contribute to T2D risk

A

100s if not 1000s

100
Q

what is the new theory for T2D risk

A

omni-genetic - whole genome contribution - not a single part

101
Q

what causes the mortality associated with diabetes, the disease itself or the associated conditions

A

the associated conditions

102
Q

what is diabetes now classified as

A

a global epidemic due to the increase in prevalence of T2D

103
Q

what conditions has diabetes caused increased mortality and morbidity in

A
  • CVD
  • PVD - peripheral vascular diseases - narrowing of the blood vessels that carry blood to leg and arm muscles the most common cause of which is atherosclerosis
  • renal dysfunction - poor kidney function that may be due to reduced kidney perfusion which can be caused by high blood pressure
  • neural dysfunction - loss of feeling in limbs
  • blindness - caused by high blood glucose concentration around the retina
  • vascular endothelial dysfunction - problems with blood vessels that supply our essential organs
104
Q

what is atherosclerosis

A

build up pf plaque inside the artery walls, reducing the flow of blood to the tissues resulting in reduced nutrient and oxygen transport

105
Q

what modifiable factor can prevent or delay the onset of diabetes

A

physical activity - an type of activity increases ATP use - increasing intensity drives fat burning
unfortunately most diabetics are physically inactive
barriers to exercise need to be reduced

106
Q

why does exercise help with diabetes

A 
hyperglycaemia results in 
- glucose toxicity 
- vascular endothelial dysfunction 
exercise results in 
- increased ATP consumption 
- substrate utilisation switches to carbohydrate with increasing intensity
107
Q

what is thought to be a barrier to exercise compliance

A

people lack time, access and interest
prescription of exercise modality, intensity and duration
we need to find ways to allow people to engage with physical activity and make it easily accessible

108
Q

T2D is characterised by reduced insulin sensitivity what are the acute and chronic responses of exercise

A 
acute 
- hyperglycaemia --> euglycaemia (normal blood glucose)
- improved insulin sensitivity 
chronic 
- blood glucose control
109
Q

at rest and postprandially, glucose transport into muscle is via …… which is modulated by …………. being released, allowing transport of glucose into cells. this is the insulin dependent/independent effect

A

GLUT4
insulin
dependent

110
Q

what is insulin independent glucose uptake

A

muscle contraction can modulate GLUT4

111
Q

how is muscle contraction of benefit for T1D and T2D

A

muscle contraction can modulate GLUT4 uptake to muscle cells and the effect lasts for hours

112
Q

what lasts longer muscle contraction uptake of GLUT4 or insulin dependent uptake

A

insulin dependent effect last longer than the muscle contraction (insulin independent effect)

113
Q

other than insulin injection what is the only other glycaemic control that T1D get

A

muscle contraction

114
Q

what are the effects of moderate intensity aerobic exercise on diabetics

A

during exercise, unlike healthy individuals where liver glucose production is matched peripheral glucose uptake, diabetics use more than is produced, reducing blood sugar during exercise
the effect last between 24-72 hours

115
Q

what are the effects of high intensity exercise on diabetics

A

high intensity exercise can cause hyperglycaemia due to catecholamine induced glycogen breakdown
the effect last 1-2 hours
may be sensitive to duration of intensity exercises

116
Q

how does resistance exercise affect diabetics

A

little of no data available on single bouts of resistance in diabetes
benefits have been shown in pre-diabetes (blood glucose elevated during fasting)
it can lower blood glucose for up to 24 hours and it responds to both volume and intensity

117
Q

what are the current exercise recommendations

A

150 min per week

  • moderate aerobic activity 2-3 times per week - has metabolic impact for up to 72 hours
  • resistance exercise - metabolic impact for up to 24 hours
  • increased muscle mass/strength for enhanced insulin independent affect
118
Q

what is a novel strategy to help those where time is an issue exercise

A

HIIT - high intensity interval training - might have the same effect as longer duration moderate intensity activity

119
Q

exercise isn’t enough, its all about energy balance what is meant by this

A

the balance between food intake and basal metabolism, thermic of food, physical activity, thermogenesis

120
Q

what is basal metabolisms

A

energy required at rest by endothermic animals

121
Q

what is the thermic effect of food

A

a reference to the increase in metabolic rate that occurs after ingestion of food

122
Q

what is physical activity

A

an body movement that works muscles and requires more energy than resting

123
Q

what is thermogenesis

A

the process of heat production -energy loss by heat production

124
Q

what we eat is important as well - what substrate is favoured at rest ATP generation

A

fatty acids

125
Q

high …………. content foods increase blood glucose and should be avoided

A

carbohydrate

126
Q

apart from the amount of carbohydrates in our food what else do we need to consider about them

A

type (amylose (straight chain) vs. amylopectin (branched)) - amylopectin more easily digested than amylose
preparation (cooking time or method) - frying is bad
processed vs fresh
- trans fatty acids are found in energy dense foods
- processed foods with long shelf lives are hard to break down

127
Q

a low carbohydrate diet is ineffective without ……… restriction to maintain energy balance

A

calorie

128
Q

define concomitant

A

naturally accompanying or associated with

129
Q

what are the concomitant conditions associated with obesity

A
  • hyperlipidaemia - elevated levels of lipids/lipoproteins in blood - can lead to endothelial dysfunction and atherosclerosis
  • hypertension - increased blood pressure
  • cancer
  • orthopaedic issues - bones and muscles
  • asthma - respiratory condition marked by spasms in the bronchi causing breathing difficulties
130
Q

give examples of some nutritional supplements and their effects

A

caffeine, ketone bodies, green tea - can be consumed as part of healthy diet - some people take them as weight loss pills but this is dangerous and generally doesn’t work

131
Q

other than supplements what other things are used for weight loss

A

synthetic amines and neoprene belts

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