Abstract: The invention relates to a method for obtaining a set of reference samples and/or a set of reference parameters for the diagnosis of fetal aneuploidy from a maternal biological sample, containing cell-free DNA, said method comprising:—extracting cell-free DNA from a set of biological samples obtained from euploid pregnant women carrying a euploid fetus;—after the extraction step, analyzing the size distribution of the DNA molecules within each sample and selecting a set of samples based on the size distribution of the DNA molecules within said samples;—performing a massively parallel sequencing of DNA of each size-selected sample;—mapping the obtained sequences to the human genome for each sample;—calculating a set of reference parameters, wherein each reference parameter is indicative of the number of unique exact sequences mapped to a chromosome or chromosomal region of interest for each sample;—obtaining a set of reference samples and/or a set of reference parameters.

Abstract: The invention provides methods for determining genome-wide sequence variations associated with a phenotype of a species in a hypothesis-free manner. In the methods of the invention, a set of restriction fragments for each of a sub-population of individuals having the phenotype are generated by digesting nucleic acids from the individual using one or more different restriction enzymes. A set of restriction sequence tags for the individual is then determined from the set of restriction fragments. The restriction sequence tags for the sub-population of organisms are compared and grouped into one or more groups, each of which comprising restriction sequence tags that comprise homologous sequences. The obtained one or more groups of restriction sequence tags identify the sequence variations associated with the phenotype. The methods of the invention can be used for, e.g., analysis of large numbers of sequence variants in many patient samples to identify subtle genetic risk factors.

Abstract: The invention provides methods for determining genome-wide sequence variations associated with a phenotype of a species in a hypothesis-free manner. In the methods of the invention, a set of restriction fragments for each of a sub-population of individuals having the phenotype are generated by digesting nucleic acids from the individual using one or more different restriction enzymes. A set of restriction sequence tags for the individual is then determined from the set of restriction fragments. The restriction sequence tags for the sub-population of organisms are compared and grouped into one or more groups, each of which comprising restriction sequence tags that comprise homologous sequences. The obtained one or more groups of restriction sequence tags identify the sequence variations associated with the phenotype. The methods of the invention can be used for, e.g., analysis of large numbers of sequence variants in many patient samples to identify subtle genetic risk factors.