Communicated by Georgia Chenevix-Trench
Article first published online: 17 MAR 2005
© 2005 Wiley-Liss, Inc.
Volume 25, Issue 4, pages 396–409, April 2005
How to Cite
Sivakumaran, T. A., Shen, P., Wall, D. P., Do, B. H., Kucheria, K. and Oefner, P. J. (2005), Conservation of the RB1 gene in human and primates. Hum. Mutat., 25: 396–409. doi: 10.1002/humu.20154
The Supplementary Material referred to in this article can be accessed at http://www.interscience.wiley.com/jpages/1059-7794/suppmat.
- Issue published online: 17 MAR 2005
- Article first published online: 17 MAR 2005
- Manuscript Accepted: 13 DEC 2004
- Manuscript Received: 25 MAY 2004
- International Union Against Cancer (UICC)
- International Cancer Technology Transfer Fellowship
- National Institutes of Health. Grant Number: GM28428
- nucleotide diversity;
- HKA test;
- maximum likelihood ratio
Mutations in the RB1 gene are associated with retinoblastoma, which has served as an important model for understanding hereditary predisposition to cancer. Despite the great scrutiny that RB1 has enjoyed as the prototypical tumor suppressor gene, it has never been the object of a comprehensive survey of sequence variation in diverse human populations and primates. Therefore, we analyzed the coding (2,787 bp) and adjacent intronic and untranslated (7,313 bp) sequences of RB1 in 137 individuals from a wide range of ethnicities, including 19 Asian Indian hereditary retinoblastoma cases, and five primate species. Aside from nine apparently disease-associated mutations, 52 variants were identified. They included six singleton, coding variants that comprised five amino acid replacements and one silent site. Nucleotide diversity of the coding region (π=0.0763±1.35 × 10−4) was 52 times lower than that of the noncoding regions (π=3.93±5.26 × 10−4), indicative of significant sequence conservation. The occurrence of purifying selection was corroborated by phylogeny-based maximum likelihood analysis of the RB1 sequences of human and five primates, which yielded an estimated ratio of replacement to silent substitutions (ω) of 0.095 across all lineages. RB1 displayed extensive linkage disequilibrium over 174 kb, and only four unique recombination events, two in Africa and one each in Europe and Southwest Asia, were observed. Using a parsimony approach, 15 haplotypes could be inferred. Ten were found in Africa, though only 12.4% of the 274 chromosomes screened were of African origin. In non-Africans, a single haplotype accounted for from 63 to 84% of all chromosomes, most likely the consequence of natural selection and a significant bottleneck in effective population size during the colonization of the non-African continents. Hum Mutat 25:396–409, 2005. © 2005 Wiley-Liss, Inc.