Genes L14 Notes Flashcards
Describe the characteristics of Mendelian Diseases in Humans
• 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
What are the benefits of identification of disease genes?
• 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
Describe the 3 steps in location of disease
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.
Name the three stages in location of disease?
- Pedigree Analysis:
- Linkage Analysis:
- Positional cloning:
Describe the function of pedigree analysis
• Pedigree Analysis:
- Investigate disease occurrence -> families
Determine mutation type
Describe the function of linkage analysis
• Linkage Analysis:
- Search -> evidence -> genetic linkage between disease gene & markers
Map disease gene
Describe the function of Positional cloning
• Positional cloning:
- Select designated genes in region of chromosome
Search -> disease-associated mutations -> each gene selected.
Describe the characteristics of autosomal recessiveness in Mendelian inheritance
- Autosomal recessive:
Phenotype can skip generations
Both parents -> carriers -> pass trait to offspring.
Equally affects both genders.
Describe the characteristics of autosomal dominance in Mendelian inheritance
- Autosomal dominant:
Phenotype -> every generation
Equally affects both genders
Homozygous mutant -> sometimes lethal.
Describe the characteristics of x-linked recessiveness in Mendelian inheritance, including examples of types of transmission using crosses
- 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
- Transmission -> Hemizygous affected male
No sons affected / carriers
All daughters -> carriers
XAXA x XaY
XAXa ; XAXY ; XAXa ; XAY
- Transmission -> Affected female:
All sons -> affected
All daughters -> carriers.
XaXa x XAY
XAXa ; XaY ; XAXa ; XaY
Describe the characteristics of x-linked recessiveness in Mendelian inheritance & the consequences of different types of transmission
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.
Describe the characteristics of x-linked dominance in Mendelian inheritance, including the consequences of different types
- 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
What is the result of an x-linked recessive mendelian inheritance in which transmission occurs from female heterozygous carrier?
Transmission -> Female heterozygous carrier
Half -> sons affected
Half -> daughters carriers
Describe the problems affecting pedigree analysis
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
Explain why there are difficulties using linkage analysis to study disease genes. State what method is used as an alternative solution.
• 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.
Describe the requirements of DNA Markers
• DNA Markers: - Requirements: Polymorphic: >> 2 or more alleles -> significant proportion of population >> Easy to assay -> Easy to distinguish alleles.
Name the types of DNA markers commonly used
Short Tandem Repeats (STRs)
Single Nucleotide Polymorphisms (SNPs)
What are STRs/ Short tandem repeats?
Short Tandem Repeats (STRs)
Microsatellite repeats
Tandem repeats -> Short, non coding sequences (2-4 nucleotides)
Eg. GAGAGA / TTATTATTATTA
Longer repeats (>10 nucleotides) -> minisatellite repeats.
Describe how STRs can be used in forensic analysis
Forensic Analysis -> STRs
Polymerase Chain Reaction (PCR)
»_space; Amplifies 10 STRs & Gender DNA marker
>Separated -> electrophoresis -> DNA profile.
Forensic uses -> DNA profiles:
»_space; Each individual excl. identical twins -> unique DNA profile
»_space; Individuals placed at scene -> analysis -> hair, blood, saliva / semen
samples.
»_space; DNA profiles of crime -> compared -> suspect / database profiles
»_space; Close matches -> indicate close relatives.
What is a Single Nucleotide Polymorphism?
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.
Describe the HapMap project
HapMap Project:
»_space; Gene chip technology -> identification -> common SNPs -> across
ethnic groups.
SNP genotyping -> GeneChip
»_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.
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 }
- 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.
What is a haplotype?
• Haplotype:
Particular combination of SNPs -> small chromosomal region.
Describe how the haplotype of individuals are determined.
- 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.
»_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.
