Abstract
The main objectives of the PhD study are to identify and characterise chromosomal
rearrangements within evolutionarily conserved regulatory landscapes around genes
involved in the regulation of transcription and/or development (trans-dev genes). A
frequent feature of trans-dev genes is that they are associated with gene-poor or -empty
regions, enriched for evolutionarily conserved non-coding elements (CNEs). Some of these
CNEs have been shown to function as tissue-specific enhancers and the combined effect of
these enhancers (and possibly also other cis-regulatory elements) is believed to determine
the complex spatio-temporal expression of the associated trans-dev gene. Rare
chromosomal breakpoints that disrupt the integrity of these regulatory landscapes may be
used as a tool, not only to make genotype-phenotype associations, but also to link the
associated phenotype with the position and tissue specificity of the individual CNEs.
In this PhD study I have studied several chromosomal rearrangements with
breakpoints in the vicinity of trans-dev genes. This included chromosomal rearrangements
compatible with known phenotype-genotype associations (Rieger syndrome-PITX2,
Mowat-Wilson syndrome-ZEB2 and mental retardation-AUTS2), where the breakpoints in
all cases mutated the known disease-causing protein-coding genes. In two rearrangements
with breakpoints within putative regulatory landscapes of genes where human phenotypes
are unknown (HMX2/HMX3 and FOXP1), the functional characterization of CNEs in a
zebrafish assay supported the hypothesis that the disruption of the putative regulatory
landscapes was responsible for the phenotypes due to long-range position effects.
rearrangements within evolutionarily conserved regulatory landscapes around genes
involved in the regulation of transcription and/or development (trans-dev genes). A
frequent feature of trans-dev genes is that they are associated with gene-poor or -empty
regions, enriched for evolutionarily conserved non-coding elements (CNEs). Some of these
CNEs have been shown to function as tissue-specific enhancers and the combined effect of
these enhancers (and possibly also other cis-regulatory elements) is believed to determine
the complex spatio-temporal expression of the associated trans-dev gene. Rare
chromosomal breakpoints that disrupt the integrity of these regulatory landscapes may be
used as a tool, not only to make genotype-phenotype associations, but also to link the
associated phenotype with the position and tissue specificity of the individual CNEs.
In this PhD study I have studied several chromosomal rearrangements with
breakpoints in the vicinity of trans-dev genes. This included chromosomal rearrangements
compatible with known phenotype-genotype associations (Rieger syndrome-PITX2,
Mowat-Wilson syndrome-ZEB2 and mental retardation-AUTS2), where the breakpoints in
all cases mutated the known disease-causing protein-coding genes. In two rearrangements
with breakpoints within putative regulatory landscapes of genes where human phenotypes
are unknown (HMX2/HMX3 and FOXP1), the functional characterization of CNEs in a
zebrafish assay supported the hypothesis that the disruption of the putative regulatory
landscapes was responsible for the phenotypes due to long-range position effects.
| Original language | English |
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| Publication status | Published - 2008 |
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