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MIMS > Genetics in Human and Animal Medicine > Flashcards

Genetics in Human and Animal Medicine Flashcards

1
Q

what is a karyotype?

A

the set of chromosomes found in a particular species

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2
Q

what is a diploid karyotype?

A

having 2 copies of each chromosomes

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3
Q

what are the 2 types of chromosomes?

A

autosomes and sex chromosomes

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4
Q

what are autosomes?

A

chromosomes which are diploid in all individuals of a species regardless of sex

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5
Q

what are sex chromosomes?

A

chromosomes which confer sexual traits and are different between males and females

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6
Q

which are the heterogametic sex in mammals?

A

males

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7
Q

what is the heterogametic sex?

A

the sex with 2 different types of sex chromosomes

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8
Q

how many chromosomes do humans have?

A

22 pairs of autosomes, 1 pair of sex chromosome

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9
Q

how many chromosomes do dogs have?

A

38 pairs of autosomes and 1 set of sex chromosomes

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10
Q

what are centromeres the site of?

A

spindle attachment during mitosis and constriction between the 2 sister chromatids in G2 cells

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11
Q

what are sister chromatids?

A

the 2 replicated chromosomes present in G2 of the cell cycle

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12
Q

what is a chromosomal arm?

A

the region from the centromere to the end of the telomere

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13
Q

which is the p-arm?

A

the shorter of the 2 chromosome arms

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14
Q

which is the q-arm?

A

the longer of the 2 chromosome arms

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15
Q

what percentage of the genome is non-coding?

A

98%

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16
Q

what does non-coding mean?

A

doesn’t encode protein-coding gene exons

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17
Q

what is the reference genome?

A

a completely sequenced genome isolate that is used for reference for genetic studies

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18
Q

how many chromosomes and chromatids will a human cell in G1 have?

A

46 chromosomes, 46 chromatids

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19
Q

how many chromosomes and chromatids will a human cell in G2 have?

A

46 chromosomes and 92 chromatids

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20
Q

what is a locus?

A

a position in a genome

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21
Q

what are alleles?

A

variant sequences at a particular locus

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22
Q

when are 2 loci considered linked/under linkage disequilibrium?

A

if they are frequently inherited together

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23
Q

what are the 5 classes of genome variation?

A

SNVs, indels, structural variants, transposable element insertions, cytogenetic variation

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24
Q

what are SNVs?

A

single nucleotide variations

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25
Q

what are indels?

A

small insertions and deletions

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26
Q

what are SNVs also known as?

A

point mutations or substitutions

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27
Q

when are SNVs termed SNPs?

A

if they occur in the germline and are variable within individuals in a population

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28
Q

what are SNPs?

A

single nucleotide polymorphisms

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29
Q

what are the 6 types of SNV?

A

2 transitions and 4 transversions

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30
Q

what do transitions involve?

A

only purines/pyrimidines respectively

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31
Q

what do transversions involve?

A

purines -> pyrimidines or vice versa

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32
Q

what 3 cellular DNA repair pathways repair the majority of incipient SNVs?

A

NER, BER, MMR

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33
Q

what is NER?

A

nucleotide excision repair

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34
Q

what is BER?

A

base excision repair

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35
Q

what is MMR?

A

mismatch repair

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36
Q

what does NER primarily repair?

A

helix distorting damage

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37
Q

what does BER primarily repair?

A

small, non-helix-distorting lesions

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38
Q

what does MMR repair?

A

base-base mismatches

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39
Q

what can SNVs be caused by?

A

exogenous or endogenous mutational processes

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40
Q

what are exogenous mutational processes?

A

those that involve exposure to exogenous agents

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41
Q

what are endogenous mutational processes?

A

processes that derive from mutational activities that naturally operate within the cell

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42
Q

what mutation is present in 60% of human malignant melanomas?

A

BRAF V600E

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43
Q

what does the BRAF V600E mutation cause?

A

activation of the cell cycle without growth factor binding to RTK

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44
Q

SNV mutation in what gene causes phenylketonuria?

A

PAH, the gene encoding phenylalanine hydroxylase

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45
Q

what causes xeroderma pigmentosum?

A

mutations, often SNVs, in components of the NER pathway causing extreme sensitivity to UV light and accumulation of SNVs in sun-exposed cells

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46
Q

where does polymerase slippage often occur?

A

at simple repeat tracts called microsatellite/STRs

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47
Q

what does polymerase slippage cause?

A

indels

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48
Q

what are STRs?

A

short tandem repeats

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49
Q

what are microsatellite length alleles?

A

alleles present at simple repeat tracts characterised by different lengths of repeat tract loci

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50
Q

what is the causative mutation in trinucleotide expansion diseases?

A

simple repeat indels

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51
Q

what sort of disease is Huntington’s?

A

trinucleotide expansion disease

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52
Q

do all indels occur at repeat regions?

A

no

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53
Q

what do structural variants in DNA often involve?

A

dsDNA breakage repaired by HR or NHEJ

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54
Q

what are structural variants in DNA?

A

large scale genomic rearrangements that lead to juxtaposition of DNA that wasn’t previously connected

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55
Q

what are the 2 types of structural variants?

A

interchromosomal or intrachromosomal

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56
Q

what is involved in inter-chromosomal structural variants?

A

2 chromosomes

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57
Q

what is involved in intrachromosomal structural variants?

A

different parts of the same chromosome

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58
Q

what are balanced structural variants?

A

ones that don’t lead to an overall gain or loss of DNA from the cell

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59
Q

what are unbalanced structural variants?

A

ones that introduce additional DNA or cause DNA to be lost from the cell leading to copy number variants

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60
Q

what is the Philadelphia chromosome?

A

a translocation between human chromosomes 9 and 22, type of balanced structural variant

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61
Q

what disease is the Philadelphia chromosome frequently observed in?

A

chronic myeloid leukaemia

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62
Q

what are transposable element insertions?

A

virus-like sequences that copy themselves and transpose around the genome

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63
Q

what genes do autonomous transposable elements encode?

A

genes required for transposition such as reverse transcriptase

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64
Q

what type of transposable element are LINE elements?

A

autonomous

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65
Q

what do non-autonomous transposable elements use to support transposition?

A

transposition proteins encoded by autonomous elements

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66
Q

what type of transposable element are SINE elements?

A

non-autonomous

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67
Q

what is the merle phenotypes an example of?

A

a transposable element insertion

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68
Q

what is the function of transposable elements in the genome?

A

no function, they are parasitic elements

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69
Q

what is involved in cytogenetic variation?

A

the gain or loss of 1 or more entire chromosomes leading to aneuploidy

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70
Q

what does whole genome duplication lead to?

A

tetraploid cells and additional aneuploidy

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71
Q

what does whole genome duplication frequently occur in, and via what process?

A

cancer cells, via endoreduplication

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72
Q

how does the spindle assembly checkpoint prevent aneuploidy?

A

prevents progression through mitosis if chromosomes aren’t correctly attached to spindle apparatus

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73
Q

how is genome variation detected?

A

by whole genome sequencing

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74
Q

how can copy number variants be identified by whole genome sequencing?

A

by identifying differences in the number of reads mapping to the reference genome

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75
Q

what are the 2 cell types the body is composed of?

A

germline cells and somatic cells

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76
Q

what are germline cells?

A

gametes (sperm and egg cells) or their precursors

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77
Q

what are somatic cells?

A

the cells of the body that cannot contribute to the next generation

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78
Q

what is germline variation?

A

genetic variation that occurs in the germline and is inherited

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79
Q

what is the germline lineage?

A

the lineage of cells that contributes to the production of gametes

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80
Q

what does the germline lineage begin with?

A

the fertilised egg

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81
Q

how many cell divisions occur before the specification of primordial germ cells?

A

10

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82
Q

what are primordial germ cells (PGCs)?

A

embryonic cells committed to the germline lineage

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83
Q

what leads to formation of a germline mosaic?

A

if a variant occurs in the 10 cell divisions prior to PGC specification

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84
Q

what is a germline mosaic?

A

when a subset of somatic and germline cells contain a variant

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85
Q

where do the primordial germ cells migrate to?

A

the developing gonads (testes/ovaries)

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86
Q

what happens to germ cells in the male at puberty?

A

cell division recommences

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87
Q

how many times per year do male spermatogonial stem cells (SSCs) divide per year in humans?

A

23

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88
Q

how many more divisions do committed sperm cells undergo to become mature?

A

4

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89
Q

what happens in the female at puberty?

A

menstrual cycles commence and 1 oocyte completes maturation and is ovulated each month

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90
Q

how many divisions will the germline cells of adult women have undergone?

A

30

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91
Q

how many divisions will the germline cells of a 30 yr old adult man have undergone, assuming he entered puberty at 15 yrs?

A

383

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92
Q

which is more vulnerable to acquiring variants, the male or female germline?

A

the male as it undergoes more division

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93
Q

how many germline SNVs are introduced via the male germline?

A

70-80%

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94
Q

what is the number of de novo germline SNVs dependent on?

A

the father’s age at conception

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95
Q

what germline are most cytogenetic variants introduced via?

A

the female germline

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96
Q

what does the number of cytogenetic abnormalities appear to be due to?

A

segregation errors

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97
Q

what percentage of gametes derived from the SSC will a variant be present in if a de novo germline variant occurs in the SSC?

A

50%

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98
Q

how many de novo variants will each sperm have?

A

50-100

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99
Q

how much DNA is shared between identical twins?

A

100%

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100
Q

how much DNA is shared between full siblings?

A

50%

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101
Q

how much DNA is shared between grandparent + grandchild?

A

25%

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102
Q

how much DNA is shared between aunt/uncle and niece/nephew?

A

25%

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103
Q

how much DNA is shared between first cousins?

A

12.5%

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104
Q

how many positions do the genomes of 2 unrelated individuals differ at?

A

around 3 million

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105
Q

what are common variants shared between?

A

populations

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106
Q

what are rare variants unique to?

A

families or individuals

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107
Q

what is genetic drift?

A

the change in the frequency of alleles in a population due to chance

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108
Q

when is genetic drift particularly important?

A

when populations are small and chance fluctuations can have a large effect

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109
Q

when do genetic bottlenecks occur?

A

when a population is drastically reduced in size

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110
Q

when do founder effects occur?

A

when a small number of individuals leave a population and found a new colony

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111
Q

what has caused the high frequency of some disease alleles in breed dogs?

A

genetic bottleneck and then genetic drift

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112
Q

what is an example of founder effects?

A

the Amish population

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113
Q

what is natural selection?

A

a change in allele frequencies due to a change in fitness

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114
Q

what 2 types of variants can impact the cell?

A

coding and non-coding/copy number

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115
Q

what do coding variants lead to?

A

a change in the amino acid composition of the protein product

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116
Q

what do non-coding variants/copy number variants lead to?

A

changes in the amount of protein product produced

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117
Q

what variant types can coding variants cause?

A

missense, nonsense, in-frame insertion or deletion, frameshift, splicing, gene truncation via rearrangement, fusion gene

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118
Q

what happens in a missense variant?

A

causes a single amino acid to be switched from 1 to another via an SNV variant

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119
Q

what happens in a nonsense variant?

A

causes the introduction of a premature stop codon via an SNV variant

120
Q

what happens in an in-frame insertion or deletion?

A

indel variant of 3bp or multiple of 3bp causes insertion or deletion of 1 or more amino acids

121
Q

what happens in a frameshift variant?

A

indel or other type of insertion/deletion variant inserts or deletes a number of bases that isn’t a multiple of 3 - changes reading frame, leads to premature termination of protein

122
Q

what happens in a splicing variant?

A

causes a change to splice donor or splice acceptor site which causes abnormal splicing such as exon skipping

123
Q

what happens in a gene truncation variant via rearrangement?

A

structural variant leads to gene truncation

124
Q

what happens in a fusion gene variant?

A

structural variant brings 2 genes together, they splice together to forma a novel in-frame fusion gene

125
Q

what are examples of non-coding variants?

A

variants in promoters, enhancers, 5’ or 3’ UTRs, non-coding RNAs such as miRNAs, copy number variants, cytogenetic variants

126
Q

what do dominantly acting variants do?

A

generate a phenotype when present in at least 1 copy in the cell regardless of the number of additional chromosomal copies

127
Q

what do recessive variants do?

A

generate a phenotype only when the variant is carried by all chromosomal copies present within the cell

128
Q

what is co-dominance?

A

where the impact of both alleles is visible in the heterozygous phenotype

129
Q

what is positive selection?

A

selection acting on a phenotype to increase allele frequency in a population

130
Q

what types of fitness advantage are there?

A

adaptive, selfish, artificial

131
Q

what is an adaptive fitness advantage?

A

one that enhances individual’s adaptation to environment

132
Q

what is a selfish fitness advantage?

A

one at the level of the cell rather than the level of the individual

133
Q

what is artificial fitness advantage?

A

one caused by human intervention (like dog breeding)

134
Q

what does negative selection do?

A

acts on a phenotype to reduce allele frequencies in populations

135
Q

what is balancing selection?

A

an interaction between positive and negative selection which acts to maintain several alleles in population

135
Q

what can most diseases be broadly categorised into?

A

single mutation, complex genetic, infectious, cancer

136
Q

what are single mutation diseases?

A

diseases that arise due to a single mutation

137
Q

what are complex genetic diseases?

A

diseases that don’t have a single genetic cause

138
Q

what do infectious diseases develop due to?

A

exposure to an infectious agent

139
Q

what does compound heterozygosity involve?

A

2 mutations in the same gene

140
Q

what are de novo mutation diseases?

A

diseases that occur due to inheritance of a newly-arising germline variant

141
Q

what are de novo mutation diseases that are passed on to offspring known as?

A

autosomal dominant/sex-linked/mitochondrial inherited diseases

142
Q

what are many miscarriages likely due to?

A

de novo mutations that are incompatible with embryonic development

143
Q

when do autosomal dominant diseases with severe phenotypes in humans tend to onset?

A

in adulthood as otherwise wouldn’t be inherited

144
Q

what are examples of autosomal dominant diseases in humans?

A

Huntington’s disease and polycystic kidney disease

145
Q

what are compound heterozygotes of autosomal recessive inherited diseases?

A

affected individuals that inherit 2 different faulty copies of the same gene (each carries distinct disease allele at different locus)

146
Q

what are recessive lethal alleles?

A

alleles that are incompatible with fetal development in the homozygous state

147
Q

which individuals are at a significantly higher risk of autosomal recessive disease?

A

those with a family history of consanguinity

148
Q

what is reduced penetrance?

A

when different individuals harbour the same disease genotype and only some individuals develop the disease

149
Q

what can cause reduced penetrance?

A

accumulation of somatic mutations, mosaicism, variable copy number of disease haplotype, epigenetic and environmental factors

150
Q

what is variable disease severity/expressivity?

A

when individuals with the same disease develop less severe symptoms

151
Q

what is an example of variable disease severity in dogs?

A

double merle phenotype

152
Q

what causes the double merle phenotype of dogs?

A

inheriting 2 copies of a SINE element insertion in the SILV gene

153
Q

what does gene therapy involve?

A

delivery of normal copies of genes directly to target cells in individuals affected with genetic diseases

154
Q

what are the gene copies normally packaged into in gene therapy?

A

non-integrating viruses

155
Q

what is mosaicism used to refer to in the context of disease?

A

the situation when a de novo disease mutation arises during embryonic development

156
Q

what is a germline mosaic individual?

A

when a de novo mutation disease is present in a subset of germline cells and a subset of somatic cells

157
Q

what does transmission frequency depend on in germline mosaic individuals?

A

the proportion of germline cells which carry the mutation

158
Q

what is a clone?

A

a set of cells with a common origin (common ancestor)

159
Q

somatic evolution of cancer?

A

occurs when a somatic cell of the body acquires a set of somatic mutations that cause that cell to acquire a selective advantage relative to other somatic cells

160
Q

what sort of evolution is cancer an example of?

A

selfish evolution

161
Q

what is the role of somatic cells from an evolutionary perspective?

A

to nourish and optimise the germline in order to maximise genetic contribution to the next generation

162
Q

why is the evolution of cancer usually self-destructive?

A

the continued growth and survival of the cancer is not compatible with continued survival of the host upon which the cancer relies for nutrients and support

163
Q

what are neoplasms?

A

all abnormal clonal cell growths in the body

164
Q

when are neoplasms known as benign tumours?

A

if they remain localised, respect tissue boundaries and don’t have potential to invade host tissues

165
Q

when does a neoplasm become malignant tumours?

A

when it disrupts tissue boundaries and invades host tissues or has the potential to

166
Q

what is cancer?

A

a malignant clone of cells which arises when a somatic cell follows a programme of selfish positive selection maximising the fitness of the cell instead of the cell body

167
Q

how many somatic mutations do somatic cells get per cell division?

A

2-10

168
Q

what are neutral somatic mutations known as?

A

passenger mutations

169
Q

what are passenger mutations?

A

somatic mutations with no effect on the cell

170
Q

what are driver mutations?

A

somatic mutations that confer the cell with phenotypes that confer a selective advantage in terms of proliferation and survival

171
Q

what phenotypes do selfish positive selection act on?

A

phenotypes that confer a growth or survival advantage to the cell

172
Q

how are somatic mutations in cancers discovered?

A

by whole genome sequencing- any genetic variant not found in normal DNA is considered somatic mutation

173
Q

how many somatic mutations do most human cancers have?

A

between 1000 and 30000

174
Q

how are driver mutations in cancers discovered?

A

by searching for the same mutation occurring in independent cancers from different patients

175
Q

what is the most common driver mutation in BRAF V600E?

A

an SNV which causes a missense mutation

176
Q

how many driver mutations do most cancers have?

A

between 1 and 10

177
Q

how many cancer genes are known in humans?

A

743

178
Q

what is a cancer gene?

A

a gene known to harbour driver mutations in human cancer

179
Q

what are oncogenes?

A

dominantly acting cancer genes where mutation of 1 copy is sufficient to trigger the selective advantage

180
Q

what are 2 examples of oncogenes?

A

KRAS and BRAF

181
Q

what is BCR-ABL1?

A

a dominantly-acting fusion gene created by the Philadelphia chromosome mutation

182
Q

what mutation creates BCR-ABL1?

A

Philadelphia chromosome mutation

183
Q

what is MYC?

A

a dominantly acting cancer gene

184
Q

what are double minutes?

A

tiny circular DNA elements created by unbalanced structural variants

185
Q

what can double minutes lead to?

A

massive copy number amplifications

186
Q

what are tumour-suppressor genes?

A

recessively-acting cancer genes where both copies must be lost in order for selective advantage to be gained

187
Q

what are 2 examples of tumour-suppressor genes?

A

CDKN2A and PTEN

188
Q

what is CDKN2A also known as?

A

p16/ARRF

189
Q

what is TP53?

A

a (usually) recessively acting cancer gene

190
Q

what is PTEN?

A

a recessively acting cancer gene

191
Q

what cancers are the most common in humans?

A

carcinomas

192
Q

what cancers are relatively common in dogs and rare in humans?

A

sarcomas

193
Q

what cells are carcinomas derived from?

A

epithelial

194
Q

what tissues are sarcomas derived from?

A

connective tissue

195
Q

how can cancer therapies lead to therapy resistant cancers?

A

therapy imposes a selective pressure on cancers- if resistance mutations are present these will be strongly positively selected

196
Q

what is an example of a therapy resistance mechanism in ovarian cancer?

A

the reversion of BRAC1/2 mutations to wild-type in PARP inhibitor resistant ovarian cancer

197
Q

what are transmissible cancers?

A

cancers that survive beyond the deaths of their original hosts by transmission of living cancer cells between hosts

198
Q

how many known transmissible cancers are there?

A

14

199
Q

what is chimerism?

A

the presence of cells derived from 2 different individuals (2 separated fertilised eggs) in the same body

200
Q

what is a tetragametic chimera?

A

when fraternal twin embryos fuse in utero forming a single embryo

201
Q

what are blood chimeras?

A

a pair of fraternal twins who exchange blood cells in utero

202
Q

what % of fraternal twins have blood chimerism?

A

10%

203
Q

which sex chromosome is smaller?

A

Y

204
Q

what are the regions at the tips of the Y chromosome that are homologous with the X chromosomes?

A

the pseudoautosomal regions (PAR)

205
Q

what allow the X and Y chromosomes to pair and recombine during meiosis in the male?

A

the PARs on the tips of the Y

206
Q

what are many of the genes on the Y chromosome involved in?

A

spermatogenesis

207
Q

what is the distal half of the long arm on the Y chromosome like?

A

made up of highly repetitive DNA and is heterochromatic

208
Q

what is the region of the Y chromosome involved in sex determination?

A

the SRY gene

209
Q

what does the SRY gene encode?

A

a transcription factor that activates a testis-forming pathway early in development

210
Q

what is the embryonic gonad described as before the SRY pathway is triggered?

A

indifferent- meaning it is capable of developing into either a testis or ovary

211
Q

what is dosage compensation between the mammalian sexes achieved by?

A

inactivating one of the 2 X chromosomes in females

212
Q

how many X linked recessive traits are known in humans to date?

A

515

213
Q

what % of daughters of females affected with an X-linked dominant disorder will be affected?

A

50%

214
Q

what is the important difference between the pedigree of an X-linked dominant trait and an autosomal dominant condition?

A

lack of father to son transmission for X linked dominant trait

215
Q

is X inactivation always the maternal chromosome?

A

no, random which is inactivated

216
Q

which specific genes are included in the genes that escape X inactivation?

A

the PAR genes

217
Q

what gene does X inactivation require the expression of?

A

the non-coding RNA gene Xist

218
Q

what does Xist expression initiate?

A

a hierarchy of epigenetic events that lead to progressively stronger silencing of the inactive X

219
Q

what are the repressive histone modifications found along the length of the inactive X?

A

H3K27me3 and H3K9me3

220
Q

what are epigenetic modifications?

A

chemical marks on DNA and post-translational modifications to chromatin-associated histone proteins

221
Q

what dinucleotides does DNA methylation occur on in mammalian cells

A

CG dinucleotides

222
Q

why is DNA methylation symmetrical on the 2 DNA strands in mammals?

A

it occurs on CG dinucleotides

223
Q

what maintains DNA methylation during DNA replication?

A

the maintenance methyltransferase Dnmt I

224
Q

how is DNA methylation acquired anew?

A

by de novo DNA methyltransferases

225
Q

what does deamination of unmethylated cytosine convert it to?

A

uracil

226
Q

what does the cytosine->urine conversion cause cell to do?

A

recognition as alien in DNA, repair back to cytosine by cell

227
Q

what is produced when 5’-methylcytosine is deaminated?

A

thymine

228
Q

what happens if the methylcytosine -> thymine shift is not corrected?

A

the change becomes a permanent mutation of C to T, CPG dinucleotide lost

229
Q

what % of CpG dints are methylated in somatic cells of mammalian genomes?

A

75%

230
Q

what % of their expected frequency do CpG dints occur at?

A

21%

231
Q

what is the exception to CpG depletion in mammals?

A

CpG islands which are generally hypomethylated so have retained CpG content

232
Q

what does loss of the heterochromatic marks H3K9me3 and H3K9me2 result in?

A

inability of chromosomes to segregate properly

233
Q

what are the 3 essential processes in cells that epigenetic modifications regulate?

A

chromosome architecture, silencing of repetitive transposable elements, somatically heritable changes in gene expression

234
Q

what is an example of 2 epigenetic modifications that are incompatible with the presence of each other?

A

H3K27me3 and H3K27Ac

235
Q

what is an example of 2 epigenetic modifications that go hand in hand?

A

DNA methylation and H3K9me3

236
Q

what suggests that DNA methylation can sometimes be a consequence of gene repression not a cause?

A

sometimes acquired at repressed promotors long after gene has been repressed

237
Q

is epigenetic information generally inherited from 1 generation to the next?

A

no

238
Q

when is DNA methylation erased from the germline?

A

epigenetic marks are erased early in PGC development

239
Q

what does PGC stand for?

A

primordial germ cell

240
Q

when does establishment of new epigenetic marks occur in the male germline?

A

on prospermatogonia during foetal development

241
Q

when does establishment of new epigenetic marks occur in the female germline?

A

after birth during the growing oocyte phase

242
Q

when does the second phase of genome-wide epigenetic erasure and re-establishment occur?

A

immediately after fertilisation

243
Q

what mechanisms remove epigenetic marks immediately after fertilisation?

A

active (enzymatic) and passive (dilution during DNA replication)

244
Q

what are genomic imprints?

A

DNA methylation marks that are established in different places in the male and female germlines and are resistant to the 2nd wave of epigenetic reprogramming immediately after fertilisation

245
Q

how many genes have been identified that are expressed solely from 1 of the 2 parental chromosome homologues?

A

around 200

246
Q

which allele expresses and represses the IGF2 gene in developing embryos?

A

the paternally inherited chromosome homologue expresses, the maternally inherited one represses

247
Q

what regulates the monoallelic expression of an imprinted gene?

A

DNA methylation that differs on the 2 parental chromosomes

248
Q

what is the imprinting control region?

A

a differentially methylated region (DMR) located at the promoter of an imprinted transcript or in the vicinity of an imprinted locus

249
Q

when are ICRs established?

A

in the germline

250
Q

how are imprinted genes often arranged?

A

in clusters, with a single ICR regulating the monoallelic expression of all imprinted genes in the cluster

251
Q

what do imprinting disorders in humans arise from?

A

mis-expression of imprinted genes

252
Q

what can cause imprinting disorders in humans?

A

uniparental disomy, or epimutation

253
Q

what does epimutation cause in the ICR?

A

it to lose its appropriate differential methylation status and hence normal imprinting perturbed

254
Q

why is evidence as to whether the environment talks to the genome (via epigenome) hard to ascertain?

A
  1. it’s hard to rule out genetic effects 2. it’s hard to determine whether an observed epigenetic change associated with an environmental influence is causal or a secondary consequence of the phenotype
255
Q

what does undernourishment of the embryo in utero lead to in mice?

A

developmental delay, smaller pups and adult onset diseases, effects also seen in F2 generation

256
Q

what is the Dutch Hunger winter an example of?

A

how in utero nutritional compromise during a defined developmental window can lead to adult onset disease in offspring

257
Q

how long is the mitochondrial genome?

A

16.5kb

258
Q

characteristics of the mitochondrial genome?

A

16.5kb long, circular, each mitochondrion has several copies (2-10), 27 genes, no introns

259
Q

how many genes does the mitochondrial genome contain?

A

27

260
Q

how much of the mitochondrial genome makes a functional gene product?

A

all but 1kb of it

261
Q

what does the mtDNA encode?

A

some of the components needed for mitochondrial protein synthesis on mitochondrial ribosomes

262
Q

what does the endosymbiont theory propose?

A

the 2 genomes (mitochondrial and nuclear) originated when a type of aerobic prokaryotic cell was endocytosed by an anaerobic eukaryotic precursor

263
Q

how are mitochondria inherited?

A

matrilineally

264
Q

why do sperm mitochondria not contribute any mtDNA to the embryo?

A

they are degraded upon fertilisation

265
Q

what is homoplasmy (mtDNA)?

A

every mtDNA is the same

266
Q

what is heteroplasmy (mtDNA)?

A

can be a mixed population of normal and mutant mtDNAs

267
Q

what is the threshold level for most pathogenic mtDNA mutations?

A

60-80%

268
Q

why can level of heteroplasmy change over time?

A

due to the random way mtDNAs are replicated and segregated

269
Q

characteristics of mtDNA replication?

A

stochastic (random), not directly linked to cell cycle

270
Q

how many mitochondria do egg cells contain?

A

more than 100000

271
Q

where do mitochondrial disorders show the greatest impact?

A

in tissues of high energy requirements- muscle and brain

272
Q

when did the UK government make mitochondrial therapy legal?

A

Feb 2015

273
Q

what is MRT?

A

mitochondrial replacement therapy

274
Q

when is the nuclear genome transferred in metaphase II spindle transfer MRT?

A

before fertilisation of the egg

275
Q

when is the nuclear genome transferred in pronuclear transfer MRT?

A

after fertilisation of the egg

276
Q

what does MRT require?

A

preimplantation genetic diagnosis and in vitro fertilisation

277
Q

what is a polymorphism?

A

an allele with a frequency <1%

278
Q

what is a haplotype?

A

a group of alleles inherited from a single parent on the same chromosome homologue

279
Q

what does the Hardy-Weinberg law provide?

A

a mathematical relationship between allele and genotype frequencies

280
Q

what is the hardy weinberg law?

A

p + q = 1, p2 + 2pq + q2= 1

281
Q

what are the requirements for the hardy-weinberg law to be applicable

A

no mutation, random mating, no gene flow, infinite population size, no selection

282
Q

example of an allele that doesn’t obey Hardy-Weinberg predictions?

A

sickle cell anaemia allele HbS provides comparative resisitance to malaria

283
Q

which genome variants are more likely to be neutral, those in introns or exons?

A

introns

284
Q

what do genetic linkage studies do?

A

follow the inheritance of a trait in an affected family (pedigree) and look for co-segregation of the phenotype with alleles of polymorphic genetic loci from across the genome

285
Q

what are identical twins?

A

monozygotic

286
Q

what are non-identical twins?

A

dizygotic

287
Q

what are concordant twins?

A

twins that both show a trait

288
Q

when are twins discordant?

A

if only 1 shows a trait

289
Q

for which is the concordance rate higher, monozygotic or dizygotic twins?

A

monozygotic twins

290
Q

what does the concordance rate in monozygotic twins range from?

A

6-100%

291
Q

how can twin studies be used to obtain an idea of the contribution of genetics to a disease?

A

comparing ratio of concordance between monozygotic and dizygotic twins

292
Q

what is a GWAS?

A

a genome wide association study

293
Q

what is a genome wide association study?

A

the approach of scanning the genome for regions contributing to complex phenotypes

294
Q

what happens in a GWAS screen?

A

a large number of individuals with the trait/disorder of interest are genotyped alongside a large set of neutral control individuals from the same population

295
Q

how is GWAS data presented?

A

in the form of Manhattan plots where the x axis shows the chromosomal location of each SNP, each dot represents an SNP, y axis shows statistical significance of association of each SNP with the particular trait

296
Q

what is the OMIM database?

A

online mendelian inheritance in man database, has info on all known monogenic disorders on over 15000 genes

MIMS (15 decks)

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