Skip Navigation


Human Molecular Genetics Advance Access originally published online on September 22, 2004
Human Molecular Genetics 2004 13(22):2737-2751; doi:10.1093/hmg/ddh301
This Article
Right arrow Full Text Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Supplementary Material
Right arrow All Versions of this Article:
13/22/2737    most recent
ddh301v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (25)
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Pavlicek, A.
Right arrow Articles by Larionov, V.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Pavlicek, A.
Right arrow Articles by Larionov, V.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Human Molecular Genetics, Vol. 13, No. 22 © Oxford University Press 2004; all rights reserved

Evolution of the tumor suppressor BRCA1 locus in primates: implications for cancer predisposition

Adam Pavlicek1,{dagger}, Vladimir N. Noskov2,{dagger}, Natalay Kouprina2, J. Carl Barrett2, Jerzy Jurka1 and Vladimir Larionov2,*

1Genetic Information Research Institute, Mountain View, CA, USA and 2Laboratory of Biosystems and Cancer, National Cancer Institute, Bethesda, MD, USA

Received June 7, 2004; Revised September 1, 2004; Accepted September 14, 2004

Germ-line mutations in the BRCA1 gene predispose affected individuals to breast and ovarian cancer syndromes. In an attempt to systematically analyze a broader spectrum of genetic changes ranging from frequent exon deletions and duplications to amino acid replacements and protein truncations, we isolated and characterized full size BRCA1 homologues from a representative group of non-human primates. Our analysis represents the first comprehensive sequence comparison of primate BRCA1 loci and corresponding proteins. The comparison revealed an unusually high proportion of indels in non-coding DNA. The major force driving evolutionary changes in non-coding BRCA1 sequences was Alu-mediated rearrangements, including Alu transpositions and Alu-associated deletions, indicating that structural instability of this locus may be intrinsic in anthropoids. Analysis of the non-synonymous/synonymous ratio in coding portions of the gene revealed the presence of both conserved and rapidly evolving regions in the BRCA1 protein. Previously, a rapidly evolving region with evidence of positive evolutionary selection in human and chimpanzee had been identified only in exon 11. Here, we show that most of the internal BRCA1 sequence is variable between primates and evolved under positive selection. In contrast, the terminal regions of BRCA1, which encode the RING finger and BRCT domains, experienced negative selection, which left them almost identical between the compared primates. Distribution of the reported missense mutations, but not frameshift and nonsense mutations, is positively correlated with BRCA1 protein conservation. Finally, on the basis of protein sequence conservation, we identified missense changes that are likely to compromise BRCA1 function.

* To whom correspondence should be addressed. Tel: +1 3014967941; Fax: +1 3014802772; Email: larionov{at}mail.nih.gov


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 Mol Biol EvolHome page
Y. Zhao and R. J. Epstein
Programmed Genetic Instability: A Tumor-Permissive Mechanism for Maintaining the Evolvability of Higher Species through Methylation-Dependent Mutation of DNA Repair Genes in the Male Germ Line
Mol. Biol. Evol., August 1, 2008; 25(8): 1737 - 1749.
[Abstract] [Full Text] [PDF]

Home page
 CarcinogenesisHome page
C. E. Wood, T. C. Register, and J.M. Cline
Soy isoflavonoid effects on endogenous estrogen metabolism in postmenopausal female monkeys
Carcinogenesis, April 1, 2007; 28(4): 801 - 808.
[Abstract] [Full Text] [PDF]

Home page
 Biol. Reprod.Home page
C. E. Wood, S. E. Appt, T. B. Clarkson, A. A. Franke, C. J. Lees, D. R. Doerge, and J. M. Cline
Effects of High-Dose Soy Isoflavones and Equol on Reproductive Tissues in Female Cynomolgus Monkeys
Biol Reprod, September 1, 2006; 75(3): 477 - 486.
[Abstract] [Full Text] [PDF]

Home page
 Vet PatholHome page
C. E. Wood, A. L. Usborne, M. F. Starost, R. P. Tarara, L. R. Hill, L. M. Wilkinson, K. R. Geisinger, E. A. Feiste, and J. M. Cline
Hyperplastic and neoplastic lesions of the mammary gland in macaques.
Vet. Pathol., July 1, 2006; 43(4): 471 - 483.
[Abstract] [Full Text] [PDF]

Home page
 Mol Biol EvolHome page
A. J. Gentles, O. Kohany, and J. Jurka
Evolutionary Diversity and Potential Recombinogenic Role of Integration Targets of Non-LTR Retrotransposons
Mol. Biol. Evol., October 1, 2005; 22(10): 1983 - 1991.
[Abstract] [Full Text] [PDF]


Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.