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Nucleic Acids Research, 2001, Vol. 29, No. 21 4405-4413
© 2001 Oxford University Press

Hypermutability at a poly(A/T) tract in the human germline

Andrea L. Bacon, Malcolm G. Dunlop and Susan M. Farrington*

University of Edinburgh Department of Oncology and MRC Human Genetics Unit, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK

Poly(A/T) tracts are abundant simple sequence repeats (SSRs) within the human genome. They constitute part of the coding sequence of a variety of genes, encoding polylysine stretches that are important for protein function. Assessment of poly(A/T) tract stability is also used to identify microsatellite unstable colorectal cancers, which are characteristic of tumours defective in DNA mismatch repair. Despite their importance, little is known about the stability of poly(A/T) SSRs in the human germline. We have determined the stability of a paradigm poly(A/T) tract, BAT-40, by study of population allele frequencies, mutation frequency in families and mutation frequency in sperm DNA. We show that the locus is polymorphic, with a level of heterozygosity of 59.7%. Germline mutation was observed in 13 of 187 germline transmissions (7.0%) in 10 families suggesting BAT-40 is unstable in the germline. Further evidence for germline instability at BAT-40 was provided by small pool PCR analysis of matched blood and sperm DNA templates, revealing a significantly elevated frequency of mutation in the germline (P < 0.001). These findings provide insight into poly(A/T) tract stability in the germline. They also have relevance to the study of gene expression and to determination of microsatellite instability in tumours.

* To whom correspondence should be addressed at: Colon Cancer Genetics Group, MRC Human Genetics Unit, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK. Tel: +44 131 467 8422; Fax: +44 131 343 2620; Email: susan.farrington{at}hgu.mrc.ac.uk


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