BRCA1 in the primary literature
Once the idea of a predisposing gene for early-onset breast cancer was put forward, scientists searched for the location and identity of such an allele in the human genome. Here I will describe the article published in 1994 reporting the sequence of the BRCA1 gene. Since this discovery the amount of research devoted to the study of this gene has only increased, with over 6,000 articles published to date using BRCA1 as a keyword.
A Strong Candidate for the Breast and Ovarian Cancer Susceptibility Gene BRCA1
Science, Vol. 266, No. 5182, 1994
by Miki, Y. et al. [1]
The authors set the stage for BRCA1 by first discussing the evidence for a gene being involved in hereditary cases of breast and ovarian cancer. They noted that the gene likely encodes a tumor suppressor gene based on observations made in patterns of inheritance in familial cases. The scientists sequenced the BRCA1 gene by cloning the cDNA and amplifying pieces of it for sequencing. By finding the sequence of overlapping fragments of the cDNA, the authors pieced together the coding sequence of the gene. The length of the protein reported in this article is the same as can be found today in databases, which indicates something of the reliability of their data. The authors also identified a zinc finger domain, which is known to bind to DNA. They proposed that this may indicate a role for BRCA1 as a transcription factor. Comparison of the human gene to homologous gene from other closely related species indicated the conserved nature of the gene.
Not only did the authors sequence the "wild-type" coding sequence of the gene, but they also examined eight variants of the gene sequence that are associated with familial cases of breast and ovarian cancer. Linkage analysis was used to further determine that this gene was indeed the one initially theorized to be responsible for the familial cases. The sequences were mostly truncations of the wild-type sequences, but all varied in how much of the wild-type protein sequence was still encoded. One of the variants, however, did not appear to have any truncation of the protein, but upon analysis of the expression of the two gene copies, one gene was found to be consistently turned-off, indicating that there may be a mutation affecting transcriptional activation of the gene.
Overall, I was quite satisfied with the amount of information the authors presented in this paper. Sequencing the gene alone was a big step forward at the time, but the authors also presented cross-species data and several mutation variants with linkage analysis associated with them. For the time this research was conducted, the methods used were appropriate. Today there are many faster analyses that could be used to make the discovery of a gene linked to a disease much faster.
| miki_1994.pdf | |
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[1] Miki, Y., Swensen, J., Shattuck-Eidens, D., Futreal, P.A., Harshman, K., Tavtigian, S., Liu, Q., Cochran, C., Bennett, L.M.,
Ding, W., Bell, R., Rosenthal, J., Hussey, C., Tran, T., McClure, M., Frye, C., Hattier, T., Phelps, R., Haugen-Strano, A.,
Katcher, H., Yakumo, K., Gholami, Z., Shaffer, D., Stone, S., Bayer, S., Wray, C., Bogden, R., Dayananth, P., Ward, J.,
Tonin, P., Narod, S., Bristow, P.K., Norris, F.H., Helvering, L., Morrison, P., Rosteck, P., Lai, M., Barrett, J.C., Lewis, C.,
Neuhausen, S., Cannon-Albright, L., Goldgar, D., Wiseman, R., Kamb, A., and Skolnick, M.H. (1994). A stong candidate
for the breast and ovarian cancer susceptibility gene BRCA1. Science, 266(5182), 66-71.
doi:10.1126/science.7545954.
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Genetics 677 Assignment, Spring 2009
University of Wisconsin-Madison
