15 February 2011 00:00 hrs.
Identifying Novel Microdeletions and Imprinted Genes in the Human Genome.

Andrew Sharp, PhD Associate Professor, Mount Sinai School of Medicine, New York, USA


Dr. L. Peart-Vissers, department of Human Genetics, RUNMC, Nijmegen

15-02-2011 00:00:00Europe/AmsterdamIdentifying Novel Microdeletions and Imprinted Genes in the Human Genome.

Remarks / more information:

Andrew-SharpRecurrent microdeletion/duplication syndromes are often catalyzed by aberrant recombination between large flanking repeats. Over the past five years, by focusing on genomic regions that are predicted to have an architecture to recurrent rearrangement my research has identified seven novel microdeletion/duplication syndromes that collectively account for ~2% of mental retardation cases, in addition to a variety of other neuro-psychiatric syndromes. I will describe the rationale behind these studies, and using the example of deletions of 15q13 review more detailed observations of this region that give insights into mechanisms of rearrangement and genome evolution. I will also discuss recent studies investigating genetic susceptibilities to microdeletions, including the possible role of PRDM9, a protein that is a major determinant of the location of meiotic recombination in humans. I am also interested in identifying imprinted genes in the human genome, and I will discuss two different approaches that my lab is using. First, as many imprinted genes are associated with differential epigenetic marks on the two parental chromosomes, by profiling DNA methylation in patients with uniparental disomy for specific chromosomes we are able to successfully identify known and novel differentially methylated regions associated with imprinted genes. Second, I will discuss a novel methodology we are developing that utilizes a modification of the classical genome-wide association study approach, correlating SNP genotypes with gene expression levels. By analyzing mother/father/child trios, laws of Mendelian inheritance allow parental origin to be assigned to SNPs in each child, and the two parental genotypes can then be independently correlated with gene expression levels. SNPs that show differential association with gene expression levels when inherited maternally versus paternally represent candidate loci that exert imprinted regulatory effects on gene expression. Such hypothesis-driven approaches to the study of the human genome represent powerful methods for identifying variation associated with human phenotypes.

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