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Thesis of Thomas Brüls

2001 may

"Large scale genome mapping applied to the construction of a human chromosome 14 physical map and to a transcriptional map of the mouse genome. "
  Thomas Brüls(mail)

This thesis is subdivided into three parts.

The first part introduces key concepts of genome mapping along with the principal analytical methods associated with them. Genome mapping techniques differ from each other by the nature of the observations, which constitute the raw data, and by the analytical requirements to build maps starting with them. The objective of this introduction is also to make apparent numerous aspects that are common to the different genome mapping approaches, both at the conceptual and analytical levels.

Meiotic linkage and radiation hybrid mapping are among the most powerful techniques to build continuous maps across large genomic intervals, but are also the most demanding from the analytical point of view. These approaches rely on random processes to separate markers (X ray induced chromosomal breakages or meiotic recombinations), and hence require probabilistic analyses of marker co-segregation frequencies in order to infer marker orders and inter-marker distances.

These kind of maps form the core of a transcriptional map of the mouse genome that was built at Genoscope. A high resolution radiation hybrid map of human chromosome 14 framed the sequencing effort for this chromosome.

The techniques of mapping by marker content and by restriction enzyme fingerprints are more related to each other and enable the construction of physical maps in the form of overlapping genomic cloned fragments. Both of these approaches were used to assist the human chromosome 14 sequencing effort.

In the implementation of large scale sequencing projects, the mapping approaches mentioned above were traditionaly executed in a phase preliminary to the sequencing phase itself. An alternative approach, dubbed STC for Sequence Tagged Connectors, relies on the construction and use of clone end sequence libraries to carry out the mapping and sequencing steps in parallel. Such an approach was used to speed up the sequencing of human chromosome 14, and will be described afterwards.

The second part of this thesis reports results of our mapping efforts on human chromosome 14 and on the mouse genome, as well as the result of a conceptualization of the data and data processing steps associated with different mapping techniques in order to allow their integration.

The latter result has been incorporated in the form of a mapping module into Genoscope’s Laboratory Information Management System (LIMS).

The strategy used to map human chromosome 14 combined the STC approach with a high resolution radiation hybrid map. The transcriptional map of the mouse genome was based on radiation hybrid data and also made use of a previously built meiotic linkage map.

The last part of this thesis aims to discuss some limitations associated with the different mapping methods and some of the problems inherent to the integration of data from different maps. We will put the results obtained into perspective with the initial goals, and will conclude by making some considerations about the future of mapping projects in the context of the finished human genome sequence and the launch of genome projects for an increasing number of organisms.

Last update on 20 April 2009

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