Genomic Diversity in the Human Brain: The Functional Role of Expandable DNA Repeats

Although genetic variation can potentially occur anywhere in the genome, certain genomic regions are particularly susceptible to genetic changes. These regions are called hotspots of genomic instability, and are frequently underlied by repeated DNA sequences.

One class of hotspots of genomic instability particularly relevant to brain function consists of expandable DNA repeats. These are tandem DNA repeats, most often trinucleotide repeats (TNRs) such as (CGG)n, (CAG)n, (GAA)n, which have an intrinsic propensity to increase in length during germline transmission. TNR expansions cause more than 30 neuro-psychiatric disorders, including Huntington’s disease, Fragile X syndrome and Friedriech’s ataxia (Mirkin 2007A).

A surprising characteristic of human disorders caused by TNRs is that they affect primarily the brain (Mirkin 2007), although the mutation is present in all tissues, suggesting that the human brain is particularly vulnerable to this type of genetic variation. Somatic TNR expansions have been documented in the human brain at some of the TNR disease loci (Telenius et al. 1994; McMurray 2010). However, the human genome contains over 30,000 TNRs (Kozlowski et al. 2010) and whether somatic TNR expansions occur in the brain on a genome-wide scale is currently unknown.

This project aims to identify somatic TNR instability events in the normal human brain and assess their effect on gene expression.

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