Daelemans, Caroline Sophie Frédérique; (2013) High-throughput analysis of candidate imprinted genes and allele-specific expression. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

In diploid human organisms, the ~20,000 genes are usually functional as two active copies or alleles. Exceptionally, some genes have only one active allele while the other is silenced. Two different groups of genes fall into this minor category; the genes that exhibit random monoallelic expression (e.g. odorant receptor genes and genes coding for immunoglobulins), and those genes exhibiting monoallelic expression in a parent-of-origin specific manner, named imprinted genes. At the outset of this study in October 2006, 56 genes in humans were known to be imprinted and 98 in mice, but the total number of imprinted genes in either species was unknown. I have used high-throughput allele-specific PCR assays to screen human term placental tissue samples for new imprinted genes. Hundreds of genes were tested either because they were predicted to be imprinted or because they were candidates for which the imprinted status was simply unknown in human term placenta. My results suggested that we are reaching saturation in the number of human placentally imprinted genes. I show that ZNF331 is imprinted in human placenta and is part of a primate lineagespecific imprinted locus showing differential methylation. My data also highlights that parental allelic specific expression is a continuum, from imprinted monoallelic expression to partial imprinting (i.e., one parental allele is slightly more (or less) expressed than the other). This continuum suggests a requirement to sequence the transcriptome of every human tissue at each different developmental stage exhaustively to assess genes for parent-of-origin specific expression and to clearly define what imprinting means. Most importantly whether ‘partial’ imprinting has functional significance or is just a part of the dynamic flux of gene expression. Specifically, my results call for thorough investigation of the ZNF331 locus in human development, physiology and parent-of-origin specific diseases.

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