Abstract for presentation at 11th International Congress of Human Genetics

Male mutation bias in the age of genomics: Who should be in the driver’s seat?

  • Kateryna Makova, Penn State University, United States
  • James Taylor, Penn State University, United States
  • Svitlana Tyekucheva, Penn State University, United States
  • Erika Kvikstad, Penn State University, United States
  • Yogeshwar Kelkar, Penn State University, United States
  • Paula Goetting-Minesky, Penn State University, United States
  • Michael Zody, Broad Institute, United States
  • Francesca Chiaromonte, Penn State University, United States

    • Male bias is a higher mutation rate in mammalian males than in mammalian females thought to result from the greater number of germline cell divisions in males. If errors in DNA replication cause most mutations, then the magnitude of male bias should reflect the relative excess of male vs. female germline cell divisions. Substitution rates averaged among all sites in a sequence and compared between mammalian sex chromosomes were shown to be indeed higher in males than in females. Here we employ genome-wide comparisons between human and chimpanzee as well as between mouse and rat to investigate mutation mechanism of individual classes of nucleotide substitutions and of insertions and deletions. Our analysis of CpG transitions that occurred between human and chimpanzee indicated only a weak male bias, suggesting that such mutations are largely replication-independent. In contrast, a strong male bias was observed in a study of small insertions and deletions occurring between mouse and rat. Thus, these mutations result from DNA replication errors. We speculate about the power of the whole-genome analysis to resolve the recent controversy surrounding the magnitude of male mutation bias in humans and to explain regional variation in mutation rates within human genome. Recent findings on male bias at microsatellite mutations and large indels are also discussed. The research presented here has been considered one of the main findings of the Chimpanzee Sequencing and Analysis Consortium. It has applications for the origin of human genetic diseases and genetic counseling.

    - Chimpanzee Sequencing and Analysis Consortium (K. D. Makova – member). 2005. Initial sequence of the chimpanzee genome and comparison with the human genome. Nature.
    - Taylor, J., S. Tyekucheva, M. Zody, F. Chiaromonte, and K. D. Makova. 2006. Strong and weak male mutation bias at different sites in the primate genomes: Insights from the human-chimpanzee comparison. Molecular Biology and Evolution.

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