Proteins with homopolymeric repeat tracts are very common in the human proteome. Intriguingly, some but not all repeat tracts show length variation in the Population and, in a few, the expansion of repeat tract beyond the normal length is associated with neurodegenerative and developmental disorders. In this study we have addressed questions Such as why some amino acid residues are favored in longer repeat tracts and why repeat tracts show terminal bias. Using cell biological assays for repeat tracts fused to green fluorescent protein we show here that homopolymeric repeats that are beyond their naturally occurring length in the proteome are cytotoxic in nature, This toxicity is further modulated by the length of the peptide that bears the repeat and the spatial location of the repeat within the peptide. Thus, the cellular toxicity appears to be one of the selective processes that regulate the evolution Of homopolymeric repeats in the proteome. (C) 2009 Elsevier Inc. All rights reserved.