Trinucleotide repeats in human genome and exome

Kozlowski, Piotr; Mezer, Mateusz de; Krzyżosiak, Włodzimierz J.

doi:10.1093/nar/gkq127

Cited by 121 publications

(157 citation statements)

References 79 publications

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“…Finally, how do the various triplet repeats differ in their susceptibility to cellular ribonucleases? A survey of triplet repeats, which are present in about 4% of human mRNAs, revealed that some of these repeats are highly prevalent, whereas others are either rare or absent (61). CNG repeats, associated with human neurological diseases, are among the most frequent repeat types and have attracted the highest interest to date.…”

Section: Discussionmentioning

confidence: 99%

“…These five repeated motifs constitute 77% of the 1,030 total repeat tracts composed of six or more uninterrupted repeats found in 878 human mRNAs. At the other end of the frequency scale are the CGU, CUA, UAG, CAU, CUU, CGA, and UGG repeats (61).…”

Section: Discussionmentioning

confidence: 99%

“…In annotated human exons, which account for less than 3% of the genomic sequence, there are as many as 1,030 TNR tracts (61). Some AT-rich TNR types, such as CTT, AAC, and AAT, are particularly underrepresented in exons, whereas GC-rich repeats (CGG, CAG, and CCG) are highly overrepresented, implying that these sequences have a functional significance.…”

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confidence: 99%

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Structural Diversity of Triplet Repeat RNAs

Sobczak

Michlewski

Mezer

et al. 2010

Journal of Biological Chemistry

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116

153

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Tandem repeats of various trinucleotide motifs are present in the human transcriptome, but the functions of these regular sequences, which likely depend on the structures they form, are still poorly understood. To gain new insight into the structural and functional properties of triplet repeats in RNA, we have performed a biochemical structural analysis of the complete set of triplet repeat transcripts, each composed of a single sequence repeated 17 times. We show that these transcripts fall into four structural classes. The repeated CAA, UUG, AAG, CUU, CCU, CCA, and UAA motifs did not form any higher order structure under any analyzed conditions. The CAU, CUA, UUA, AUG, and UAG repeats are ordered according to their increasing tendency to form semistable hairpins. The repeated CGA, CGU, and all CNG motifs form fairly stable hairpins, whereas AGG and UGG repeats fold into stable G-quadruplexes. The triplet repeats that formed the most stable structures were characterized further by biophysical methods. UV-monitored structure melting revealed that CGG and CCG repeats form, respectively, the most and least stable hairpins of all CNG repeats. Circular dichroism spectra showed that the AGG and UGG repeat quadruplexes are formed by parallel RNA strands. Furthermore, we demonstrated that the different susceptibility of various triplet repeat transcripts to serum nucleases can be explained by the sequence and structural features of the tested RNAs. The results of this study provide a comprehensive structural foundation for the functional analysis of triplet repeats in transcripts.Trinucleotide repeats (TNRs) 4 belong to a family of microsatellite sequences also known as short tandem repeats or simple sequence repeats. TNRs are present in both prokaryotic and eukaryotic genomes and, similar to other microsatellites, show high mutation rates resulting in frequent length variability. Polymorphic TNRs are better tolerated than dinucleotide and tetranucleotide repeats in translated sequences because their length variation does not change the open reading frame.A recent survey of the human genome reference sequence showed that it harbors more than 32,000 tracts of uninterrupted TNR sequences composed of six or more repeated units. In annotated human exons, which account for less than 3% of the genomic sequence, there are as many as 1,030 TNR tracts (61). Some AT-rich TNR types, such as CTT, AAC, and AAT, are particularly underrepresented in exons, whereas GC-rich repeats (CGG, CAG, and CCG) are highly overrepresented, implying that these sequences have a functional significance. The AT-rich and GC-rich TNRs tend to localize preferentially in the 3Ј-UTR and 5Ј-UTR, respectively (1). About 60% of exonic TNRs are localized in the open reading frame. These coding repeats are primarily translated to the poly-Gln, polyAla, poly-Glu, and poly-Leu tracts. However, the amino acid coding property of TNRs is not the only feature for which these sequences are selected in exons. The other properties of TNR sequences that manifest thems...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Structural Diversity of Triplet Repeat RNAs

Sobczak

Michlewski

Mezer

et al. 2010

Journal of Biological Chemistry

Self Cite

116

153

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“…At least 30 Drosophila proteins possess polyQ tracts of 20 residues or longer, which are conserved in other drosophilid species. In the human proteome, there are several prevalent homo-amino acid tracts, whereby polyQ tracts are the most frequent homo-amino acid tracts encoded by repeats of a single codon (CAG) (Kozlowski et al , 2010 ). Screening of the Saccharomyces cerevisiae protein database ( www.yeastgenome.org ) revealed that polyQ tracts are the most common homopolymeric amino acid tracts of eight amino acids length or longer.…”

Section: Introductionmentioning

confidence: 99%

Polyglutamine tracts as modulators of transcriptional activation from yeast to mammals

Atanesyan¹,

Günther

Dichtl

et al. 2012

Biological Chemistry

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Microsatellite repeats are genetically unstable and subject to expansion and shrinkage. A subset of them, triplet repeats, can occur within the coding region and specify homomeric tracts of amino acids. Polyglutamine (polyQ) tracts are enriched in eukaryotic regulatory proteins, notably transcription factors, and we had shown before that they can contribute to transcriptional activation in mammalian cells. Here we generalize this fi nding by also including evolutionarily divergent organisms, namely, Drosophila and baker ' s yeast. In all three systems, Gal4-based model transcription factors were more active if they harbored a polyQ tract, and the activity depended on the length of the tract. By contrast, a polyserine tract was inactive. PolyQs acted from either an internal or a C-terminal position, thus ruling out a merely structural ' linker ' effect. Finally, a two-hybrid assay in mammalian cells showed that polyQ tracts can interact with each other, supporting the concept that a polyQ-containing transcription factor can recruit other factors with polyQ tracts or glutamine-rich activation domains. The widespread occurrence of polyQ repeats in regu latory proteins suggests a benefi cial role; in addition to the contribution to transcriptional activity, their genetic instability might help a species to adapt to changing environmental conditions in a potentially reversible manner.

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“…Therefore, they should be reconsidered in the future genetic association. 16,76 PRESENT Single nucleotide polymorphisms The completion of the Human Genome Project is a major scientific development in human genomics and biomedical sciences. The reference DNA sequence has provided the basis for studying genetic variations in the human genome among individuals in populations.…”

Section: Tandem Repeatsmentioning

confidence: 99%

The discovery of human genetic variations and their use as disease markers: past, present and future

Loy

Salim

et al. 2010

J Hum Genet

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The field of human genetic variations has progressed rapidly over the past few years. It has added much information and deepened our knowledge and understanding of the diversity of genetic variations in the human genome. This significant progress has been driven mainly by the developments of microarray and next generation sequencing technologies. The array-based methods have been widely used for large-scale copy number variation (CNV) detection in the human genome. The arrival of next generation sequencing technologies, which enabled the completion of several whole genome resequencing studies, has also resulted in a massive discovery of genetic variations. These studies have identified several hundred thousand short indels and a total of thousands of CNVs and other structural variations in the human genome. The discovery of these 'newer' types of genetic variations, indels, CNVs and copy neutral variations (inversions and translocations) has also widened the scope of genetic markers in human genetic and disease gene mapping studies. The aim of this review article is to summarize the latest developments in the discovery of human genetic variations and address the issue of inadequate coverage of genetic variations in the current genome-wide association studies, which mainly focuses on common SNPs. Finally, we also discuss the future directions in the field and their impacts on next generation genome-wide association studies.

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Trinucleotide repeats in human genome and exome

Cited by 121 publications

References 79 publications

Structural Diversity of Triplet Repeat RNAs

Structural Diversity of Triplet Repeat RNAs

Polyglutamine tracts as modulators of transcriptional activation from yeast to mammals

The discovery of human genetic variations and their use as disease markers: past, present and future

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