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Genes Evo & Dev Y1 > Genes L14 Notes > Flashcards

Genes L14 Notes Flashcards

1
Q

Describe the characteristics of Mendelian Diseases in Humans

A 
•	Mendelian Diseases in Humans:
-	3 x 109 base pairs -> haploid genome
-	20,000 protein-coding genes
-	Mendelian / monogenic disease
	1% affected -> birth
	5% affected
	40% paediatric hospital referral -> Mendelian diseases
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2
Q

What are the benefits of identification of disease genes?

A 
•	Benefits of identifying disease gene?
-	Genetic testing:
Whole pop / high risk pop
Eg. Newborn blood spot test -> sickle-cell, hypothyroidism, inherited metabolic diseases. 
-	Development of new therapies:
Eg. Drugs, gene therapy
-	Provide insights into causes of other types of the disease
Eg. Alzheimers
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3
Q

Describe the 3 steps in location of disease

A

Location of disease:
• Pedigree Analysis:
- Investigate disease occurrence -> families
 Determine mutation type
• Linkage Analysis:
- Search -> evidence -> genetic linkage between disease gene & markers
 Map disease gene
• Positional cloning:
- Select designated genes in region of chromosome
 Search -> disease-associated mutations -> each gene selected.

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4
Q

Name the three stages in location of disease?

A
  • Pedigree Analysis:
  • Linkage Analysis:
  • Positional cloning:
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5
Q

Describe the function of pedigree analysis

A

• Pedigree Analysis:
- Investigate disease occurrence -> families
 Determine mutation type

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6
Q

Describe the function of linkage analysis

A

• Linkage Analysis:
- Search -> evidence -> genetic linkage between disease gene & markers
 Map disease gene

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7
Q

Describe the function of Positional cloning

A

• Positional cloning:
- Select designated genes in region of chromosome
 Search -> disease-associated mutations -> each gene selected.

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8
Q

Describe the characteristics of autosomal recessiveness in Mendelian inheritance

A
  • Autosomal recessive:
     Phenotype can skip generations
     Both parents -> carriers -> pass trait to offspring.
     Equally affects both genders.
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9
Q

Describe the characteristics of autosomal dominance in Mendelian inheritance

A
  • Autosomal dominant:
     Phenotype -> every generation
     Equally affects both genders
     Homozygous mutant -> sometimes lethal.
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10
Q

Describe the characteristics of x-linked recessiveness in Mendelian inheritance, including examples of types of transmission using crosses

A
  • X-linked recessive:
     More males affected
    -> males with one mutant allele -> hemizygous.
     Types of transmission:
    1. Transmission -> Female heterozygous carrier
     Half -> sons affected
     Half -> daughters carriers.

> > XAXa x XAY
> XAXA ; XAY ; XAXa ; XaY

  1. Transmission -> Hemizygous affected male
     No sons affected / carriers
     All daughters -> carriers

 XAXA x XaY
XAXa ; XAXY ; XAXa ; XAY

  1. Transmission -> Affected female:
     All sons -> affected
     All daughters -> carriers.

 XaXa x XAY
XAXa ; XaY ; XAXa ; XaY

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11
Q

Describe the characteristics of x-linked recessiveness in Mendelian inheritance & the consequences of different types of transmission

A 
	More males affected 
-> males with one mutant allele -> hemizygous. 
	Types of transmission:
1.	Transmission -> Female heterozygous carrier 
	Half -> sons affected
	Half -> daughters carriers. 
2.	Transmission -> Hemizygous affected male
	No sons affected / carriers
	All daughters -> carriers
3.	Transmission -> Affected female:
	All sons -> affected
	All daughters -> carriers.
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12
Q

Describe the characteristics of x-linked dominance in Mendelian inheritance, including the consequences of different types

A
  • X-linked domiant:
     Affected male parents
    » All daughters affected
    » No sons affected / carriers
             >> XdXd       x        XDY
             XDXd ; XdY ; XDXd ; XdY

 Affected heterozygote females
» Half -> sons affected
» Half -> daughters affected.

> > XDXd x XdY
XDXd ; XDY ; XdXd ; XdY

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13
Q

What is the result of an x-linked recessive mendelian inheritance in which transmission occurs from female heterozygous carrier?

A

Transmission -> Female heterozygous carrier
 Half -> sons affected
 Half -> daughters carriers

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14
Q

Describe the problems affecting pedigree analysis

A

Problems affecting pedigree analysis:
• Incomplete penetrance / Variable expressivity
 Not all carrying disease allele express phenotype.
• Delayed onset
Eg. Huntington’s, familial breast cancer.
 Even though dominant genetic disease, phenotype only expressed later in life ->
after reproduction -> already potentially passed to offspring.
• Genetic Heterogenity
- Mutations -> different genes -> produce same disease
Eg. 3 genes -> familial early-onset Alzheimers
- Can solve this by observing genetically homogenous populations
Eg. Icelanders & Mormons
• Non-paternity / misattributed paternity

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15
Q

Explain why there are difficulties using linkage analysis to study disease genes. State what method is used as an alternative solution.

A

• Difficulties using linkage analysis to study disease genes as requires at least 2 genetic disease genes present in a family at any one time.
 Solved by DNA markers.

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16
Q

Describe the requirements of DNA Markers

A 
•	DNA Markers:
-	Requirements:
	Polymorphic:
>> 2 or more alleles -> significant proportion of population
>> Easy to assay 
   -> Easy to distinguish alleles.
17
Q

Name the types of DNA markers commonly used

A

Short Tandem Repeats (STRs)

Single Nucleotide Polymorphisms (SNPs)

18
Q

What are STRs/ Short tandem repeats?

A

 Short Tandem Repeats (STRs)
Microsatellite repeats
Tandem repeats -> Short, non coding sequences (2-4 nucleotides)
Eg. GAGAGA / TTATTATTATTA
Longer repeats (>10 nucleotides) -> minisatellite repeats.

19
Q

Describe how STRs can be used in forensic analysis

A

 Forensic Analysis -> STRs
Polymerase Chain Reaction (PCR)
&raquo_space; Amplifies 10 STRs & Gender DNA marker
>Separated -> electrophoresis -> DNA profile.
Forensic uses -> DNA profiles:
&raquo_space; Each individual excl. identical twins -> unique DNA profile
&raquo_space; Individuals placed at scene -> analysis -> hair, blood, saliva / semen
samples.
&raquo_space; DNA profiles of crime -> compared -> suspect / database profiles
&raquo_space; Close matches -> indicate close relatives.

20
Q

What is a Single Nucleotide Polymorphism?

A

 Single Nucleotide Polymorphisms (SNPs)
Non-coding DNA
Most common type found -> Human genome
Abundant & easy to identify -> gene chip technology

1 Nucleotide difference per 1000 nucleotides -> Any 2 individuals.

21
Q

Describe the HapMap project

A

HapMap Project:
&raquo_space; Gene chip technology -> identification -> common SNPs -> across
ethnic groups.
SNP genotyping -> GeneChip
&raquo_space; Each individual -> pedigree
-> 0.5-1 mill SNPs genotyped
-> Each SNP tested -> linakge w/ disease phenotype -> using genetic
model.
-> Identifies several SNPs in region -> genome where disease must be
located.

22
Q

Describe what is occurring in this family inheritance of the homozygous female offspring in terms of x-linked inheritance

{} -> Family/siblings [] - Reproduction
- Generation 1:
[ XAY x { XAXB ] + XAY }
Generation 2:
{ XAY + XBY + [ XAXA } x XBY ]
Generation 3:
{ XAXB x XAXB XAY }

A
  • Pedigree Analysis -> X-linked SNP -> 2 alleles -> family w/ Haemophillia A
     Allele A -> Always associated -> haemophilia -> hemizygous males
    »Evidence -> linkage to disease in family.
    »Allele A not causing disease -> a disease allele linked to this haemophilia
    allele on chromosome is.
     Female (Generation 2) -> Homozygous AA -> not affected
    » 2nd allele -> father (Generation 1)
    ->Family didn’t suffer with Haemophillia A
    »Haemophillia allele not actually causing disease
     Disease allele linked to haemophilia allele on mother’s side of family is.
    -»Therefore homozygous female -> not affected -> only one of the
    haemophillia alleles inhertited -> linkage with disease allele ->
    haemophilia allele from father’s family not linked to disease allele.
    -> So heterozygous for disease allele.
23
Q

What is a haplotype?

A

• Haplotype:

 Particular combination of SNPs -> small chromosomal region.

24
Q

Describe how the haplotype of individuals are determined.

A
  • 6,000 bp -> 20 of which are SNPs.
    Each individual -> one of 4 possible haplotypes
    -> 1 haplotype -> same differences in nucleotide seq. to other haplotypes.
    Therefore identification of Haplotype can be done using tag SNPs rather than assessing all differences in SNP bases.
    &raquo_space;For example -> at particular nucleotide base -> A/G tag
    -> if A nucleotide -> Haplotype 1/2/4/
    At 2nd tag -> T/C ->
    -> if C nucleotide -> Haplotype 2/4
    At 3rd tag -> C/G ->
    -> if C nucleotide -> Haplotype 4
    Therefore identifying haplotype.
    »Genotyping 3 tags of 20 sufficient to identify haplotype.
25
Q

Describe a factor affecting linkage of a disease allele & SNPs regarding location on the chromosome. Explain the consequences of these possible factors that may occur.

A
  • The closer a mutation occurs to a particular SNP on the chromosome, the higher the linkage illustrated by that SNP to the disease in future generations / the higher the no. of future generations with SNPs associated to the disease.
  • The further away an SNP is located from the original mutation on the chromosome, less likely association will still be present as the no. of future generations/pedigrees incr.
    Eg. Muatation closest -> SNP1 & furthest -> SNP3.
    -» SNP3 -> least linkage with disease
    -» SNP2 -> linkage in some pedigrees.
    -» SNP1 -> linkage -> all pedigrees.
26
Q

What is positional cloning

A

• Positional Cloning:
 Identifies candidate genes -> inspection -> specific region -> human genome
sequence .
 Sequences -> Candidate genes -> affected & unaffected observed.
 Location within genome of SNPs -> disease linkage known.

27
Q

Describe Disease Gene Discovery using Next Generation Sequencing (NGS)

A

• Disease Gene Discovery -> Next Generation Sequencing (NGS):
- Sequencing -> Whole genomes (WGS) & whole exomes (WES) -> unaffected & affected pedigree individuals.
- Identification -> rare variants
-» shared only by affected individuals.
- Identification -> potential causative variants in candidate genes
- Investigation -> functional consequences -> potentially causative variants.
 Highly effective -> identification -> de novo mutations -> parent-child trios.

28
Q

Symbols in pedigree analysis?
Male ; Female ; Affected & Non-affected ; Deceased ; Heterozygous ; Twins ; Monozygotic twins ; Consanguineous relationships / mating between individuals.

A

• Symbols in pedigree analysis:

  • Circle -> Female
  • Square -> Male
  • Coloured -> Affected
  • Half-coloured -> Heterozygous carrier
  • Diagonal line through shape -> Deceased
  • 2 individuals -> same generation -> joined by = -> Mating between relatives (Consanguineous)
  • 2 individuals -> same generation -> joined by ^
  • 2 individuals -> same generation -> joined by triangle -> monozygotic twins

Genes Evo & Dev Y1 (23 decks)

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