Provided are methods of determining differences between nucleic acids in a
test sample and a reference sample. In certain embodiments the methods
are used for detecting and mapping chromosomal or genetic abnormalities
associated with various diseases or with predisposition to various
diseases, or to detecting the phenomena of large scale copy number
variants. In particular, provided are advanced methods of performing
array-based comparative hybridization that allow reproducibility between
samples and enhanced sensitivity by using the same detectable label for
both test sample and reference sample nucleic acids. Invention methods
are useful for the detection or diagnosis of particular disease
conditions such as cancer, and detecting predisposition to cancer based
on detection of chromosomal or genetic abnormalities and gene expression
level. Invention methods are also useful for the detection or diagnosis
of hereditary genetic disorders or predisposition thereto, especially in
prenatal samples. Moreover, invention methods are also useful for the
detection or diagnosis of de novo genetic aberrations associated with
post-natal developmental abnormalities.