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I read in the book "Why we get sick." by Nesse and Williams that:

Steady detective work and fabulous luck have enabled geneticists to pinpoint the Huntington's gene on the short arm of chromosome 4.

I want to know what was the "detective" work and the fabulous luck - the whole story of the discovery of the location of the gene.

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A Google search for "Huntingtons disease gene discovery" yielded this page at the Nature Education Scitable website. The following citations are provided regarding the molecular basis of HD:

Huntingtin (HTT) was the first disease-associated gene to be molecularly mapped to a human chromosome (Gusella et al., 1983)2. Ten years later, scientists identified the DNA sequence and determined the precise nature of the HD-associated mutation in HTT (MacDonald et al., 1993).

Gusella et al. used restriction fragment length polymorphism (RFLP) analysis to locate a RFLP marker linked to Huntington's disease on chromosome 4. From the introduction of their paper:

We have now identified an anonymous DNA fragment from human chromosome 4 that detects two different RFLPs in a HindIII digest of human genomic DNA. This polymorphic DNA marker shows close genetic linkage to the Huntington's disease gene in two separate families, although a different haplotype of the marker segregates with the Huntington's disease gene in each family. We infer that the Huntington's disease locus resides on human chromosome 4.

Further details given in the paper might justify the description given in the question. "Fabolous luck" could refer to the discovery or availability of suitable families and pedigrees for the genetic studies. The "steady detective work" would be the genetic mapping and fieldwork required to establish the link. The following quotes describe some of the efforts spent on the project:

The success of any genetic linkage project depends in large part on the quality of family material available for study. We initially invested considerable effort in identifying a useful family from the National Research Roster for Huntington's Disease Patients and Families at Indiana University. An American family of reasonable size was selected and blood samples were obtained (...). Subsequently, a substantially larger Huntington's disease family was located. This pedigree stem from a unique community of interrelated Huntington's disease gene carriers living along the shores of Lake Maracaibo, Venezuela. (...)For the past three years an expedition has spent one month annually in Venezuela collecting pedigree information, tissue samples, and clinical data. (...) In Venezuela, many family members were examined for three consectuvie years. Permanent lymphoblastoid cell lines were again established for each individual to act as a permanent source of genomic DNA. In both families each individual was examined by at least one neurologist experienced and knowledgable about Huntington's disease.

The Scitable page also summarizes the approach and results described in the paper. For the RFLP analysis, several DNA probes were tried, of which one, "G8", resulted in a HD-linked pattern:

James F. Gusella and colleagues carried out a study to determine whether they could identify a DNA probe that would show an HD-associated restriction fragment length polymorphism (RFLP) when used in Southern blot analyses of chromosomal DNA digested with the restriction enzyme HindIII (palindromic recognition sequence 5'-AAGCTT-3'). The team identified one probe out of 12 tested, called G8, that showed a specific RFLP pattern associated with HD in two large families with a history of the disease (Gusella et al., 1983). Using the G8 probe, they next identified two HindIII sites (called H1 and H2) that were palindromic within this chromosomal region. DNA fragments at these sites vary in length among different HD lineages. Because researchers used two large pedigrees in these experiments, they were able to obtain statistical support for their discovery (Figure 3).

However, at the time the origin of the G8 probe DNA in the human genome was not known, so human-mouse somatic cell hybrids were made to identify where the G8 probe DNA belonged. This showed that the G8 probe corresponded to chromosome 4, and indicated that the HD gene would be found there:

Researchers found that the G8 DNA probe hybridized only to Southern blots using chromosomal DNA from human-mouse somatic cell hybrid lines that contained human chromosome 4. Therefore, researchers determined that the G8 DNA probe is located on human chromosome 4, and they concluded that the HD gene is located on chromosome 4 near the region corresponding to the G8 DNA probe (Figure 5; Gusella et al., 1983).

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It was fascinating because Huntington himself described what we now call genetics before the field existed. Then to locate the gene scientists used essentially trial and error. They took enzymes that cut different parts of the DNA and looked at which of these were inherited. If it were inherited then there would be cuts made, otherwise not. Then they matched it up to who had the disease. Of course with 46 chromosomes there were thousands and thousands of places to check but they somehow luckily managed to find it on their twelfth try!

The full story can be found here:

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