Population genetics of human copy number variations: models and simulation of their evolution along and across the genomes

ABSTRACT

Population genetic models play a significant role in human genetic research, since they promise to provide a better understanding of both evolution of normal variations of the genomes as well as development of disease promoting genomic segments. In this paper, we propose and computationally simulate a model of evolution for unique and segmentally duplicated regions of human genome, which manifest in genome-wide Variations in Copy Number. Copy Number Variations (CNVs) are known for their possible association with genomic diseases and predisposition to various health conditions, and yet, the underlying population genetic models, needed for association studies, have remained largely undeveloped. Additionally, Segmentally Duplicated (SD) regions of the human genome are of a specific interest, since they exhibit a complex behavior of copy number changes and are specifically known for catalyzing pathogenic and unstable genomic rearrangements. Our main contribution is in suggesting mechanisms for evolution of Copy Number changes in regions of segmental duplication of the human genome, which is essential for association studies involving CNV markers and estimation of parameters of stochastic diffusion that determine asymptotic behavior of such evolutionary processes.

REFERENCES

• 1: Sharp AJ, Locke DP, McGrath SD, et al, "Segmental duplications and copy-number variation in the human genome," Am J Hum Genet, 77(1): 78--88, July 2005.
• 2: Locke DP, Sharp AJ, et al, "Linkage disequilibrium and heritability of copy-number polymorphisms within duplicated regions of the human genome," Am J Hum Genet., 79(2): 275--290, August 2006.
• 3: Redon R, et al "Global variation in copy number in the human genome," Nature, 444(23): 444--454, Nov 2006.
• 4: Moran, PAP, The Statistical Processes of Evolutionary Theory. Clarendon Press, Oxford, 1962.
• 5: www.cs.nyu.edu/~antonina/paper.htm

INDEX TERMS

Primary Classification:
  J. Computer Applications
  J.3 LIFE AND MEDICAL SCIENCES
      Subjects: Biology and genetics

Additional Classification:
  F. Theory of Computation
  F.2 ANALYSIS OF ALGORITHMS AND PROBLEM COMPLEXITY
      F.2.2 Nonnumerical Algorithms and Problems

  I. Computing Methodologies
  I.5 PATTERN RECOGNITION
      I.5.2 Design Methodology
  I.6 SIMULATION AND MODELING
      I.6.5 Model Development

General Terms:
Algorithms, Design, Theory

Keywords:
copy number variations (CNV), population genetics, segmental duplications (SD) & coalescent process