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Cellular and Molecular pathology > 2. Genetics and disease 1 > Flashcards

2. Genetics and disease 1 Flashcards

1. Discuss the major types of human genetic diseases and their patterns of inheritance. 2. Outline the methods used to clone genes responsible for inherited human diseases. 3. describe the cloning of genes for selected inheritance diseases and how this explains the pathogenesis of these diseases. 4. discuss the practical applications of genetic studies for diagnosis and treatment.

1
Q

what are some germline defeats?

A
  1. chromosomal defects
  2. mitochondrial disorders
  3. Monogenic disorders
  4. polygenic disorders
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2
Q

what are some somatic defects?

A
  1. Cancers
  2. Mosaics
  3. Chimeras
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3
Q

what cells do germline defects effect?

A

germline cells before fertilisation

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4
Q

what cells do somatic defects effect?

A

any cell after fertilisation

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5
Q

what are the most common genetic disorders?

A

somatic diseases especially cancer

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6
Q

how common are germline disorders?

A

not uncommon generally about 1 in 20 people

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7
Q

what do we mean when we refer to genotype?

A
  1. the genetic make up of the organism including nuclear and mitochondrial DNA
  2. it reflects the DNA sequence of the genome
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8
Q

what do we mean when we refer to phenotype?

A
  1. the physical characteristics of the organism
  2. these can be observed, detected or measured
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9
Q

how is most genetic material organised?

A

into chromosomes

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10
Q

how many chromosomes do humans have?

A

23 diploid pairs = 46 individual chromosomes

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11
Q

what is classical or forwards genetics?

A

identifying the underlying genetic cause of a given phenotype using techniques such as genome-wide association studies
- work from the disease phenotype back to the genetic cause

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12
Q

what is reverse genetics?

A

finding the function of a known gene.
done by altering gene expression using knock-out, knock-down or over expression as well as mutagenesis

look for the end phenotype and disease

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13
Q

what is positional cloning?

A

Identifying a gene based on chromosomal location

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14
Q

what was positional cloning before the genome project?

A
  1. identify a chromosomal abnormality
  2. generate genetic and physical maps
  3. breakdown into contigs
  4. find the candidate genes
  5. mutation detection
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15
Q

what was positional cloning after the genome project?

A

whole genome mapping was a lot easier and chromosomal contigs
then genome sequencing to find the candidate gene
then mutation detection

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16
Q

what is linkage analysis?

A
  1. aims to identify genetic loci that are inherited together more often then by chance
  2. mainly use polymorphic markers that are known and can be tested
  3. co-inherited polymorphic markers can give a specific loci from which we can look for candidate genes
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17
Q

what is linkage analysis good for?

A

identifying traits that are strongly influence by a single gene
monogenic disorders

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18
Q

what are genome wide association studies good for identifying?

A

more complex traits caused by polygenic disorders

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19
Q

what is the principle behind linkage analysis?

A

the closer 2 genes physically on the chromosome the more likely they are to be inherited together

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20
Q

what are the 2 genes used in linkage analysis?

A

the candidate gene for the disease in question
the polymorphic marker that is tagged and identifiable

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21
Q

how is mapping done using linkage analysis?

A

markers 1 million bp apart have 1% recombination frequency = 1 centimorgan
measure linkage using the LOD score
LOD>3 indicates linkage

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22
Q

what are some common polymorphic markers?

A
  1. Restriction fragment length polymorphisms
  2. variable number tandem repeats (mini satellites)
  3. microsatellites
  4. single nucleotide polymorphisms
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23
Q

what are Restriction fragment length polymorphisms?

A

single point mutations that cause the addition or loss of a restriction site
commonly used

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24
Q

what are variable number tandem repeats (mini satellites)?

A

repeats of 20-30bp with a varying number of repeats
when run on a gel a large band indicated lots of repeats

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25
Q

what are micro satellites?

A

Di, Tri and tetra nucleotide repeats
often linked with certain diseases

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26
Q

what are single nucleotide polymorphisms?

A

single base changes that occur around every 300 bases
each SNP has a 1% frequency in the population

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27
Q

gene mapping: pre-genome project

A
  1. develop regional genetic maps but you have to start in kind of the right area
  2. use markers to select genomic clones
  3. produce a contig which is a complete clone map of a region
  4. search for genes
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28
Q

what methods were used to search for genes pre-genome project?

A

CpG islands
Zoo blots
northern blots
cDNA library screening
Exon trapping
cDNA selection

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29
Q

gene mapping: post-genome project

A
  1. genetic and physical maps are readily available
  2. thousands of mapped genes and exressed sequenced tags are available
  3. gene predicted from the genomic sequence
  4. allows rapid identication of candidate genes
  5. often called the positional candidate approach
30
Q

what is a genetic map?

A

the relative distances between genes based on recombination frequencies of markers
measures in centiMorgans
basically shows the likelihood of being inherited together

31
Q

what is a physical map?

A

the distance based on the number of base pairs
measured in base pairs
used to track genes and diseases

32
Q

what are expressed sequence tags?

A

a snapshot of mRNA in the cell at one time
screen onto the genome

33
Q

why is finding a candidate gene important?

A

it is then easier to find the causative gene using experimentantion to then prove the hypothesis

34
Q

how have genome maps improved over the years?

A
  • started pretty basic
  • then annotated maps with all indentified genes and information about them
  • then the databases grow as more people do research and discover things
35
Q

what happens once you have found the gene responsible for the disease?

A

the gene needs to be examined for mutations to figure out what went wrong

36
Q

how can mutations in disease genes be identified ?

A

mutation screening using single strand conformational polymorphism which looks at different shapes produced by polymorphisms
OR
direct sequencing to see the difference in the sequence

37
Q

what were the achievements of the human genome project?

A
  1. produce a high resolution genetic map
  2. TAC physical clone map
  3. 95% complete in Jan 2003
  4. 2012 ENCODE papers published
    it has been refined and corrected ever since
38
Q

what are the advantages of illumina sequencing?

A

high through put
very accurate

39
Q

what are the disadvantages of illumina sequencing?

A

it is not good at reading repeats

40
Q

what are the advantages of nanopore sequencing?

A

it doesnt involve synthesis as it uses an electrical signal
great for reading long sequences

41
Q

what are the disadvantages of nanopore sequencing?

A

it is error prone so you have to do it a few times and compare

42
Q

what are numerical chromosomal defects?

A

a change in the overall number of chromosomes
extra haploid number = euploidy
extra single chromosome = aneuploidy

43
Q

what are structural chromosomal defects?

A

rearrangements
deletions
translocations

44
Q

chromosome nomenclature

A

top arm = p arm
bottom arm = q arm
separated by the centromere

45
Q

what is cytogenetic analysis?

A
  1. take a blood sample
  2. contrifuge the blood
  3. treat with hypotonic solution to get rid of RBC
  4. Fixing
  5. staining for banding
  6. microscope analysis
46
Q

karyotype analysis

A

line up chromosomes based on size with chr1 as the biggest
REMEMBER
- some chromosomes don’t have p arms

47
Q

what is fluorescence in situ hybridisation (FISH)?

A

staining to pick up on deletions or additions or translocation
used in cancer to see when there are more copies of a gene then there should be

48
Q

what does Euploidy cause?

A

death due to multiple sets of extra chromosomes
it does exist in some adults cells like cancer but its after development

49
Q

what is aneuploidy - monosomy?

A

lethal
except XO - turners syndrome

50
Q

why is XO the only viable monosomy?

A

due to the X chromosome being mostly silenced to balance out the Y chromosome

51
Q

what are some viable trisomy?

A

Trisomy 21 = down syndrome
Trisomy 18 = edwards syndrome
Trisomy 13 = pate syndrome
sex chromosome Trisomy - XXY/XXX

52
Q

what makes a viable Trisomy?

A

when it is an extra chromosome of one that has fewer genes on it in the first place

53
Q

what is usually the cause of Euploidy - triploidy?

A

defective diploid sperm or 2 sperm entering the ovum

54
Q

what is a less common cause of Euploidy - triploidy?

A

a diploid ovum
or
Non-expulsion of polar body

55
Q

how does trisomy 21 occur?

A

Non-disjunction in female meiosis and the risk increases with maternal age

4 meiosis products
2 eggs = normal 2 copies of chr21
1 egg = 1 chr21 which is not viable
1 egg = 3 chr21 is viable as chr21 is small

56
Q

when is aneuploidy not viable?

A

when it is in a gene dense chromosome like chr1/2

57
Q

how common is autosomal trisomy?

A

trisomy 21 = 1/700 live births
trisomy 18 = 1/5000 live births (1/2500 all births including still births)
trisomy 13 = 1/5000 live births

58
Q

how common is sex chromosome aneuploidy?

A

XO females (turner’s) = 1/2500 live births
XXY (kleinfelter) = 1/1000 live male births

59
Q

how can non 13/18/21 trisomies be viable?

A

when not all cells are effected and are mosaics or partial trisomies

60
Q

what are chromosomal structural abnormalities?

A

robertsonian translocation is when one chromosome attaches to another

reciprocal translocation is when 2 chromosomes randomly exchange DNA
survival depeands on what genes were exchanged

61
Q

what happens when you inherit balanced chromosomal translocations?

A

often has no effect but can produce offspring with unbalanced chromosomal complement that results in partial trisomy or monosomy

62
Q

what other kinds of other structural abnormalities are there?

A

deletions like cry-du-chat syndrome
inversions
ring chromosomes

63
Q

what is uniparental disomy (UPD)?

A

when a person receives 2 copies of a chromosome or part of a chromosome from one parent and no copy from the other parent

64
Q

what effects can uniparental disomy have?

A

often has no phenotypic effects but when a parent has a heterozygous mutation for a recessive disorder the child can end up showing the phenotype
or if they are imprinted genes

65
Q

what happens in maternal heterodisomy?

A

both maternal chromosomes are different the mutation is disguised

66
Q

what happens in maternal isodisomy?

A

both maternal chromosomes are identical so the recessive mutation effects the phenotype

67
Q

how can uniparental disomy arise?

A

a trisomy gamete corrects itself but the remaining 2 chromosomes are from the same parent

68
Q

what are some uniparental disomy disorders?

A

recessive disorders like cystic fibrosis with UPD 7
imprinted genes with duplication or loss
- maternal or paternal UPD 15
- Prader-willi syndrome maternal UPD 15
- angelman syndrome paternal UPD 15

69
Q

what is mitochondrial DNA?

A

circular DNA with around 37 genes all for the function of the mitochondria
inherited maternally

70
Q

what tissues do mitochondrial disorders effect?

A

tissues with high energy demands

71
Q

Homoplasmic vs Heteroplasmic

A

homoplasmic = identical DNA
hetertoplasmic = mutation in only some mitochondria

72
Q

what are some examples of mitochondrial disorders?

A

Leber hereditary optic neuropathy = mutation in NADH dehydrogenase
leigh syndrome = mutation in ATP synthase
Pearson syndrome = deletion of mitochondrial DNA = bone marrow failure

Cellular and Molecular pathology (25 decks)

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