Reading homework for Huntington’s disease due by Monday
Today's focus:
Big picture on gene linkage and positional cloning
Upcoming classes:
Friday: Start Chapter 5 - gene mapping in eukaryotes
Independent Assortment vs Linkage of Genes
Unlinked genes:
Feature: Independently assort because they are located on different chromosomes.
Linked genes:
Feature: Close together on a single chromosome; therefore, they do NOT independently assort.
Referenced Image: BioNinja
Importance of Discussing Huntington’s Disease
Overview: Understanding gene mapping's significance for studying human diseases, such as Huntington's disease.
Significance of positional cloning in gene mapping highlighted.
Reminder: The discussions on gene mapping in Drosophila laid the framework for human gene mapping.
Huntington's Disease Overview
Definition and Characteristics
Huntington disease (HD):
Type of disorder: Autosomal dominant disorder.
Effects:
Influences the development, structure, and function of the brain.
Symptoms include:
Behavioral abnormalities (e.g., uncontrolled movements known as chorea)
Cognitive decline
Psychiatric disturbances
Prevalence: Affects approximately 1 in 10,000 individuals.
Onset of symptoms: Typically occurs between ages 30 and 50.
Prognosis: Death usually occurs within 10 years from symptom onset.
The Search for the Huntington Gene
Initial Steps in Gene Mapping
In 1979:
A U.S. Congressional Commission funded a working group dedicated to gathering blood samples and pedigree information from families impacted by Huntington's disease.
Key Locations:
Notable clustering of cases near Lake Maracaibo, Venezuela.
Duration: The project spanned 22 years, involving samples from about 18,000 individuals, both affected and unaffected.
Processing Blood Samples
Aim: To map the Huntington disease-causing mutation to identify the gene and determine its function.
Method: Utilization of Restriction Fragment Length Polymorphisms (RFLP) markers.
Definition: RFLP markers are polymorphisms that result in variations in DNA sequence within the population.
Relevance: If a polymorphism alters a restriction enzyme site and is located close enough to the disease mutation, they are considered linked.
Examining Inheritance Patterns Using RFLP
Methodology: By analyzing DNA fragment patterns through gel electrophoresis, genotypes of both parents and offspring concerning the disease can be determined.
Source: Images referenced from https://dbgap.ncbi.nlm.nih.gov/projects/genome/probe/doc/TechRFLP.shtml
Historical Context of RFLP usage (1980-1993)
In the 1980s:
Approximately 150 RFLPs were distributed across the genome and used with pedigree data to detect linkage between RFLP and the gene of interest.
Significance: This technique allowed mapping of a disease gene without prior knowledge of the gene, its product, or function—referred to as reverse genetics or positional cloning.
Definition: Haplotype - a grouping of genomic variants or polymorphisms that are inherited together, providing valuable data in genetic studies.
Discovery of the HD-causing Gene (1983)
Haplotype C was linked with Huntington’s disease in all studied cases, indicated by the co-inheritance with the G8 marker/D4S10.
Significance: This finding suggested that the RFLP marker and the mutant allele of Huntington's disease share the same chromosome.
Research narrowed the gene's location to a few million base pairs at the tip of chromosome 4’s short arm.
Conclusion of the Search (1993)
Duration: Over 10 years were required to successfully positionally clone the gene responsible for Huntington's disease.
Historical Context: This effort marked one of the first instances of a human disease-causing gene being positionally cloned.
Discovery: The mutation responsible for Huntington's disease was identified as the HTT gene, initially referred to as the HD gene.
Key Feature: The gene involves CAG repeats that contribute to the disease.
Result: The protein produced by the HTT gene is termed huntingtin.
Functionality of the HTT Gene and Implications of Mutations
Primary Role of HTT gene: Encodes a critical protein known as huntingtin.
Function: Involved in vesicle transport at neuronal synapses.
Consequences: Leads to progressive accumulation of misfolded proteins and protein aggregates, resulting in disrupted cellular functions, neurodegeneration, and cell death.
Gene Linkage: Foundation for Gene Mapping
Importance: Understanding gene linkage was critical for the positional cloning before the advent of the Human Genome Project, which provided vital DNA sequence information.
Next Topic: Exploration of gene linkage and gene mapping through studies conducted on Drosophila, setting the groundwork for modern positional cloning, also known as reverse genetics.
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