32 Questions
What percentage of human disease states and traits result from a combination of genetic and environmental factors?
Most disease states and traits
What is the defining feature of monogenic diseases?
They are caused by mutations in a single gene
What is the purpose of identifying disease-causing genes?
To understand the molecular basis of the disease
What is the expected inheritance pattern of monogenic diseases in pedigrees?
Autosomal dominant or recessive
How many human phenotypes are described in 'Mendelian Inheritance in Man'?
8000
What is the approximate number of human phenotypes with a known molecular basis?
2000
What is the primary goal of molecular confirmation of clinical diagnosis?
To accurately diagnose a patient's condition
What is the current approach to disease gene discovery?
Contemporary DNA sequencing
What is the key feature of monogenic disease mutations?
They are both necessary and sufficient to produce the clinical phenotype
What is the key characteristic of autosomal dominant inheritance?
Mutations in one copy of the gene is necessary to cause the disease
What is the process during meiosis where two chromosomes of a homologous pair exchange segments?
Recombination
What is the term used to describe the phenomenon where DNA regions that are located in close proximity are more likely to be co-inherited?
Linkage
What is the purpose of identifying multigenerational affected pedigree?
To identify the location of a disease gene
What is the key characteristic of X-linked recessive inheritance?
Mutations in one copy of the gene are necessary to cause the disease in males
What is the purpose of linkage analysis?
To map the location of a disease gene
What is the key characteristic of autosomal recessive inheritance?
Mutations in both copies of a gene are necessary to cause the disease
What is the purpose of measuring variation to evaluate linkage?
To measure the frequency of recombination between two locations
What is the purpose of positional cloning?
To identify the location of a disease gene
What is the significance of observing the inheritance of the mutation three times with allele B1 and once with allele B3?
The mutation locus is nearly linked to the locus B
What is the purpose of using the LOD score in linkage analysis?
To detect the presence of linkage between the disease locus and a genomic region
What is the minimum number of multialelic loci required for linkage analysis?
400
What is the implication of a LOD score >3?
There is linkage between the disease locus and the genomic region
What is the significance of cosegregation with variant locus C?
The mutation locus is linked to the locus C
What is the purpose of using ~5000 biallelic loci in linkage analysis?
To enable systematic evaluation of cosegregation of genomic regions with the disease locus
What is the result of observing the inheritance of the mutation with allele C1 every time the disease is transmitted?
The mutation locus is linked to the locus C
What is the advantage of using the linkage approach?
It enables systematic evaluation of cosegregation of genomic regions with the disease locus
What is the purpose of considering a series of variable loci across the genome?
To see if they are linked to the mutation locus
What do we observe when considering the cosegregation of the mutation with the variant locus A?
The mutation is sometimes linked to locus A
What can be inferred from the observation of inheritance of the mutation with allele A2?
The mutation is not linked to locus A
What does the lack of linkage between the mutation locus and locus A indicate?
The mutation is located far from locus A
What is the significance of observing twice where we cannot be sure if the mutation has been inherited with A1 or A2?
The inheritance pattern is ambiguous
How does the consideration of cosegregation with variant locus A help in mapping genes?
By identifying the inheritance pattern of the mutation
Study Notes
Genetic Linkage and Disease Gene Mapping
- Genetic linkage is used to assess segregation of genomic regions using ~400 multialelic loci or ~5000 biallelic loci.
- This approach enables systematic evaluation of cosegregation of genomic regions with the disease locus.
- A statistical test, known as the LOD score, is used to detect the presence of linkage.
Linkage and Gene Mapping
- Linkage is observed when two loci are close together on a chromosome and tend to be inherited together.
- The frequency of recombination between two loci depends on their distance.
- DNA regions that are located in close proximity are more likely to be co-inherited than DNA regions originating from further apart.
Inheritance Patterns
- Autosomal Dominant Inheritance: mutations in one copy of the gene are necessary to cause the disease; transmission is vertical; equal number of affected males to females; male to male transmission is observed.
- Autosomal Recessive Inheritance: mutations in both copies of a gene are necessary to cause the disease; both parents are carriers, generally clinically normal; equal number of affected males and females; consanguinity may be present.
- X-linked Recessive: mutations in one copy of a gene are necessary to cause the disease in males, females would need mutations in both copies of the gene.
Measuring Variation to Evaluate Linkage
- Same scenario but with genotypes: A1A2, A3A4, B1B2, B3B4, C1C2, C3C4.
Positional Cloning
- Identification of multigenerational affected pedigree
- Systematic evaluation of inheritance patterns across the genome
- Mutational search within genomic regions cosegregating with the disease
The Discovery of Human Disease Genes
- An appreciation of the genetic contribution to disease
- An understanding of inheritance patterns in Monogenic disease
- An insight into evaluating segregation of genomic regions
- How this segregation can be used to map disease genes with linkage
- How to find the disease-causing mutation once a genomic region is mapped
Assess the segregation of genomic regions and detect the presence of linkage using statistical tests, in the context of disease gene mapping.
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