Proceedings of the National Academy of Sciences of the United States of America
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No more than approximately 30% of hereditary breast cancer has been accounted for by mutations in known genes. Most of these genes, such as BRCA1, BRCA2, TP53, CHEK2, ATM, and FANCJ/BRIP1, function in DNA repair, raising the possibility that germ line mutations in other genes that contribute to this process also predispose to breast cancer. Given its close relationship with BRCA2, PALB2 was sequenced in affected probands from 68 BRCA1/BRCA2-negative breast cancer families of Ashkenazi Jewish, French Canadian, or mixed ethnic descent. ⋯ Moreover, comparative genomic hybridization analysis showed major similarities to that of BRCA2 tumors but with some notable differences, especially loss of 18q, a change that was previously unknown in BRCA2 tumors and less common in sporadic breast cancer. This study supports recent observations that PALB2 mutations are present, albeit not frequently, in breast cancer families. The apparently high penetrance noted in this study suggests that at least some PALB2 mutations are associated with a substantially increased risk for the disease.
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Proc. Natl. Acad. Sci. U.S.A. · Apr 2007
Comparative StudySimultaneous amino acid substitutions at antigenic sites drive influenza A hemagglutinin evolution.
The HA1 domain of HA, the major antigenic protein of influenza A viruses, contains all of the antigenic sites of HA and is under continual immune-driven selection. To resolve controversies on whether only a few or many residue sites of HA1 have undergone positive selection, whether positive selection at HA1 is continual or punctuated, and whether antigenic change is punctuated, we introduce an approach to analyze 2,248 HA1 sequences collected from 1968 to 2005. ⋯ Strikingly, 88 of the 95 substitutions occurred in groups, and multiple mutations at antigenic sites sped up the fixation process. Our results suggest that positive selection has been ongoing most of the time, not sporadic, and that multiple mutations at antigenic sites cumulatively enhance antigenic drift, indicating that antigenic change is less punctuated than recently proposed.