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GGE > Genetics 11 - Genetic Diversity and Complex Genetic Diseases > Flashcards

Genetics 11 - Genetic Diversity and Complex Genetic Diseases Flashcards

1
Q

learning outcomes

A
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2
Q

monozygotic twins

A

single zygote that underwent mitosis post fertilisation

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3
Q

sources of genetic diversity

A

differing patterns of random X inactivation

somatic mutation/recombination (e.g. cells of the immune system)

different degrees of heteroplasmy (mtDNA)

copy number variants (CNVs)

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4
Q

CNVs

cause of…

relevance of variation it causes

A

very highly variable regions in human genome

cause of structural variation

comprised of variable number of repears (>90% identical) of a particular unit of sequence

contribute to human genetic variation (5-10% of genome)

play an important role in evolution

represent functional (disease causing) mutations as well as genomic polymorphisms of uncertain relevance (CNPs)

genes associated with disease are least affected by CNVs whereas paralogous genes are most affected (2+ genes descended from same ancestral gene but original gene was duplicated and received some type of mutation that gave rise to new function which is closely related to ancestral gene - usually changes in species - form of evolution)

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5
Q

paralogous genes

A

2+ genes descended from same ancestral gene but original gene was duplicated and received some type of mutation that gave rise to new fucntion which is closely related to ancestral gene - usually changes in species - form of evolution

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6
Q

categories of CNV

A

smaller CNVs (<10kb)

copy number polymorphisms (CNPs)

common in the general population (freq < 1%)

often encode proteins involved in drug metabolism and immunity

associated with susceptibility to complex inflammatory/immune disease e.g. psoriasis and Chron’s

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7
Q

larger CNVs

size

type of mutations

prevalence

associated with

A

10kb - 5Mb

microdeletions/microduplications

rare in general population

associated with susceptibility to neurocognitive diseases

autism, schizophrenia, behavioural, language, sleep, intellectual, complex types

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8
Q

William Syndrome

A

micro del 7q11.23

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9
Q

Smith-Magenis syndrome

A

micro del 17p11.2

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10
Q

Potocki-Lupski syndrome

A

micro dup 17p11.2

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11
Q

duplication vs deletion

A

Microdeletions are usually more severe than duplication syndromes

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12
Q

detection of larger CNVs (microdeletions) - SNP array

A

copy # - will tell us if there is something missing/extra

genotype - heterozygosity, along middle line - no dots on the middle line ⇒ LOH - may indicate deletion

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13
Q

immunoglobulin structure

how is it formed

A

2 heavy chains - (γ,α,μ,ε,δ - G, A, M, E, D)

2 light chains - either 2λ or 2κ

each chain (heavy and light) has both:

constant region (C)

variable region (V)

building an Ig requires 2 of 3 families of genes on 3 different chromosomes - Irreversible recombination of germline genes during prenatal development

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14
Q

Ig gene organisation

A

V = variable

J - junction

C = constant

D = diversity with heavy chain, as well as V, J and C

For either light or heavy only use 1 type of exon

Spliced at random to make different type of globulin

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15
Q

κ gene family

regions present

A

C REGION

1 C (constant) region

V REGION

250 V regions (2 exons - L codes for a leader region and V for most of variable region

several J exons

J exons are located between V and C regions

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16
Q

λ gene family

A

C REGION

4 C region genes, 1 for each subtype of λ chain

V REGION

30 V regions

J (joining) regions, in between Cs

the L, V, J and C exons are separated by introns

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17
Q

arrangement of κ and λ light chain genes in germ line of undifferentiated cells

A
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18
Q

4 steps in making a κ light chain

A
  1. somatic DNA recombination
  2. transcription of pre-mRNA
  3. RNA splicing
  4. translation into protein
    5.
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19
Q
  1. somatic DNA recombination
A

occurs in B cell precursors (somatic DNA recombination)

V and J are joined together to encode the variable domain of the Ig light chain

any 1 V and any 1 J can join (intervening introns and exons excised)

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20
Q
  1. transcription of pre-mRNA and 3. RNA splicing
A
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21
Q
  1. translation into protein
A

translation into protein

light chain protein transport to ER, carried out by leader sequence

removal of leader sequence (L)

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22
Q

a light chain rearrangement of the exons

A
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23
Q

making a heavy chain - what is needed

when is heavy chain made

A

germ line

9 C genes

> 1 for each class M (μ), D (δ), G 1-4 (γ1-γ4), E (ε), A 1-2 (α1-α2)

H gene for hinge region

V gene (L and V)

J gene

D genes (D for diversity)

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24
Q

heavy chain gene family

A
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25
Q

heavy chain DNA rearrangement

A
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26
Q

making a heavy chain - alternative ways of processing of the same pre-mRNA

A
  1. LVDJ spliced to be contiguous with Cmu
  2. LVDJ spliced to be contiguous with Cdelta

expression of IgM heavy chain or IgD heavy chain

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27
Q

heavy chain transcription and translation

A

Goes to ER and leader sequence is cleaved off

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28
Q

how is DNA rearrangement co-ordinated

A

recombination signal sequences

non-coding DNA sequences that are found directly adjacent to the points at which recombination takes place (VDJ)

function as signals for the recombination process that rearranges the gene segments

located 3’ side of each V segment, 5’ side of each J segment and both sides of D segments

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29
Q

recombination of signal sequences (RSS)

A

nonmer

heptamer

1 (12 bp) or 2 (23 bp) turn signals

Rag-1 and Rag-2 - Cleave out introns and exons in between

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30
Q

how does rearrangement occur

kappa, lambda and heavy chains

A

ONLY between a 1 and 2 turn signal - 12/23 rule

κ light chains

a 1 turn signal downstream (3’) of V

a 2 turn signal upstream (5’) of J

so κ V and J can join, but V won’t join to another V

λ light chains

a 2 turn signal downstream (3’) of V

a 1 turn signal upstream (5’) of J

so λ V and J can join, but V won’t join to another V

heavy chains - 2-1-1-2

a 2 turn signal downstream (3’) of the V gene

1 turn signals on each side of the D exon

a 2 turn signal upstream (5’) of the J exon

only 2 to 1 and 1 to 2 recombination is permitted

V cannot recombine directly to J

31
Q

recombination - removal of itrons

A

catalysed by Rag-1 and Rag-2 (also involved with TCRs)

mutations in the genes for these proteins results in severe combined immunodeficiency disease (SCID) as the recombination mechanisms are also involved in generation of TCRs

32
Q

terminal transferase - diversity

A

randomly inserts nucleotides at the junction between D and J

further diversity in this hypervariable region - junctional diversity

result = 107 - 108 idiotypes of Ig

33
Q

order of Ig gene expression

A

Heavy chain expressed first

Recombination - in frame - go on to form heavy chain - pre b cell (either maternal or paternal)

B cell is diploid - only 1 allele expressed so whatever allele makes a heavy chain first is going to be expressed

34
Q

how is the mature B cell formed

A
35
Q

somatic hypermutation

enzyme involved

mutation rate

A

a process of affinity maturation of the V segments which occurs in the subset of B cells that can bind to a specific foreign antigen post-stimulation

involves activation-induced deaminase (AID)

mutation rate increase to 103 per bp per generation

some Igs have high affinity binding and B cells with these Igs are selected and proliferate extensively

result = population of mature plasma cells secreting highly specific Ig

36
Q

Ig gene expression - irreversible somatic genetic change

A

excision of introns and somatic hypermutation constitutes irreversible somatic genetic change

considerable element of random recombination and mutation

Fred and George - almost certainly end up with a different repertoire of their 1010 - 1011 idiotypes of Ig

similarly different TCR idiotypes and olfactory receptors

37
Q

things to remember

A
38
Q

learning outcomes

A
39
Q

Copy Number Variants

A

for most of maternal chr 1 the sequence in both monozygotic twins are identical

for CNV loci the number of copies at a given locus on maternal chr 1 may differ between the 2 twins

in a twin with a duplication of the CNV on mat chr 1 the 2nd/duplicate copy (paralogous sequence) may differ slightly from the original copy

40
Q

importance of CNVs in MZ twins

A

if twin A develops complex disease and twin B does not - regions of the genome with CNV can be investigated further

changes in CNV may identify whether a missing gene, or multiple copies of a gene, are implicated in disease onset

pathogenic CNVs are particularly enriched for genes involved in development

link to dosage sensitivity and neurodevelopmental disorders

41
Q

haploinsufficiency

A

bi-allelic expression is usual - from both maternal and paternal

some genes normal physiological function requires full gene dose - 2 functional alleles

individual with only 1 functional allele is haploinsufficient

may be because of:

heterozygous with 1 functional and 1 non-functional (null) allele

OR hemizyogus (del) - allele deleted on 1 chr

e.g. CNV microdeletion syndrome - Smith-Magennis syndrome (SMS) - haploinsufficiency of RAI1. microdel 17p11.2

42
Q

genetic determination triangle

A
43
Q

inheritance of genes vs characters

A

genes - mendelian

characters (phenotype) - never entirely Mendelian

environmental influence

genetic interactions

chance (stochastic) events

* Penetrance and Expressivity

44
Q

multifactorial traits/disorders

A

traits/disorders showing familial clustering, but no recognised Mendelian inheritance pattern

determined by the additive effects of many genes at different loci (polygenic), combined with effects of environmental factors

e.g. height, T2DM, hypertension, CV disease, schizophrenia, Alzheimer’s disease

45
Q

mendelian vs complex traits

A
46
Q

polygenic theory

A

a useful framework for considering the inheritance patterns of traits/disorders that rely on the interaction of a large number of genetic factors, each of which make a small contribution to overall phenotype

47
Q

2 main concepts of polygenic theory

A

HERITABILITY

estimates how much of differences between populations are down to their genes

THRESHOLDS

explains how dichotomous characters can be polygenic

48
Q

heritability

A

proportion of total phenotypic variance that is attributable to genetic variance in a population

how much of differences between people in a group are down to genetic differences between them, and how much is down to differences in their environments

nature (genes) vs nurture (environment)

heritability is not about individuals - relates to populations

49
Q

heritability compares

what does a heritability of 0.5 mean

A

compares incidence in relatives of affected individual vs incidence in general population

heritability of 0.5 does not mean that a trait is 50% caused by genetic factors - it means that 50% of variability in the trait in a population is due to genetic differences among people

e.g. heritability of religion is 0

intelligence is somewhere between 0 and 1

50
Q

Phenylketonuria (PKU)

gene

symptoms

A

caused by mutations in the PAH gene - phenylalanine hydroxylase

mutations prevent conversion of the AA phenylalanine to other compounds

builds up toxic levels, affecting nerve cells - brain damage

51
Q

what is the heritability (proportion of total phenotypic variance that is attributable to genetic variance in a population) of PKU in Ireland

A

as we screen for PKU now, heritability of PKU is close to 0 - diet adjusted

52
Q

concordance

A

co twin also affected

higher rate with monozygotic twins

53
Q

discordance

A

co twin unaffected

higher rate in fraternal (dizygotic) twins - share 50% of genes - siblings

54
Q

family studies - evidence for genetic involvement in complex diseases

A

weaker evidence as family environment is shared and so could be responsible for the effect

55
Q

adoption studies - evidence for genetic involvement in complex diseases

A

stronger evidence than family studies as separates the effects of genes and family environment

56
Q

adopted twin studies - evidence for genetic involvement in complex diseases

A

rare, but very strong evidence as genetics are matched and family environment is different

57
Q

threshold theory

what does it explain

A

explains how dichotomous characters can be polygenic

susceptibility to a disease is a continuous character that depends on combined effect of many genes

if your susceptibility exceeds a threshold you will manifest the disease - all or nothing

relatives will therefore be more likely to also manifest the disease, than the general population

explains why complex diseases tend to run in families

58
Q
A

Julie

Already have 2 children with cleft palate - threshold is low - a lot of susceptibility genes

59
Q

multifactorial inheritance

recurrence risk rules

A

polygenic threshold characters run in families

parents with several affected children have more high risk alleles than parents with one affected

RECURRENCE RISK RULES

the more seriously affected, the higher the risk for siblings

the more affected children you have, the higher risk of recurrence

the closer the relative to the index case, the higher the risk of recurrence

60
Q

gender biased polygenic inheritance

e.g.

symptoms

A

hypertonic pyloric stenosis

projectile vomiting and failure to thrive

5x more common in males

must be higher threshold for girls than boys

61
Q

offspring of affected males vs offspring of affected females - who is more likely to manifest hypertrophic pyloric stenosis

A

offspring of affected females

As females have higher threshold, she must have a lot of susceptibility genes for this disorder so more likely to pass on gene

62
Q

the Carter effect

A

higher recurrence risk if the index case is of the less commonly affected sex

e.g. HPS - Male - lower threshold

Most likely to have it - a male child of an affected female

63
Q

how do we finds genes involved in complex disorders

A

linkage analyses - microsatellites

association

candidate gene testing - gene you think might be involved - haplotyping

genome-wide association studies (GWAS)

64
Q

linkage analysis

A

relationship between loci not alleles

specifically genetic phenomenon

linkage analysis looks at physical chunks of the genome of related individuals with the phenotype and associates them with given traits

PRINCIPLE

if we find a common genetic marker (e.g. microsatellite, SNP) we assume that the gene that causes the disease is somewhere in the same area

65
Q

genetic association - phenomenon

goal

method

A

purely statistical phenomenon and not specifically genetic

GOAL = identify 1 or more allels within a population that co-occur with a particular phenotypic trait more often than would be expected by chance

METHOD = gather some people with a disease (cases) and some people without a disease (controls) in a population and look to see what alleles are present more in cases than controls

association is not causation - may be on same haplotype, or by chance present in higher frequency in subgroup with the disease - Gene involved - but molecular investigation must prove it

66
Q

linkage analysis vs association

A
67
Q

candidate gene testing

A

targets can be informed by:

knowledge of the disease apthology (functional cloning) - quicker, but need prior knowledge to make an educated guess

linkage and association testing (positional cloning)

68
Q

GWAS

A

scans all genes in genome

no prior knowledge needed

high resolution SNP chips used

WGS also used

69
Q

cases of diabetes

A
70
Q

DM

A

HYPERGLYCAEMIA

> 7mmol/L fasting

> 11 mmol/L non fasting

TYPE 1 = sudden onset in youth related to autoimmune pancreatitis

TYPE 2 = gradual onset in middle/later years associated with obesity and inactivity (diabetes epidemic)

71
Q

MODY

A

mature onset diabetes of the young

autosomal dominant pattern of inheritance

not associated with obesity or sedentary lifestyle

7 different single gene defects identified

72
Q

mitochondrial T2D

A

severe single gene defects

some associated with deafness

73
Q

T2DM - evidence for genetic factors

A

ethnic differences

family and twin studies - 2.4x risk for families

15-25% of first degree relatives develop impaired glucose tolerance or T2D

> 30 genes with susceptibility alleles (linkage/GWAS studies)

74
Q

things to remember

A

GGE (33 decks)

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