Dataset Information

Compendious survey of protein tandem repeats in inbred mouse strains.

ABSTRACT: Short tandem repeats (STRs) play a crucial role in genetic diseases. However, classic disease models such as inbred mice lack such genome wide data in public domain. The examination of STR alleles present in the protein coding regions (are known as protein tandem repeats or PTR) can provide additional functional layer of phenotype regulars. Motivated with this, we analysed the whole genome sequencing data from 71 different mouse strains and identified STR alleles present within the coding regions of 562 genes. Taking advantage of recently formulated protein models, we also showed that the presence of these alleles within protein 3-dimensional space, could impact the protein folding. Overall, we identified novel alleles from a large number of mouse strains and demonstrated that these alleles are of interest considering protein structure integrity and functionality within the mouse genomes. We conclude that PTR alleles have potential to influence protein functions through impacting protein structural folding and integrity.

SUBMITTER: Arslan A

PROVIDER: S-EPMC9354378 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Compendious survey of protein tandem repeats in inbred mouse strains.

Arslan Ahmed A

BMC genomic data 20220805 1

Short tandem repeats (STRs) play a crucial role in genetic diseases. However, classic disease models such as inbred mice lack such genome wide data in public domain. The examination of STR alleles present in the protein coding regions (are known as protein tandem repeats or PTR) can provide additional functional layer of phenotype regulars. Motivated with this, we analysed the whole genome sequencing data from 71 different mouse strains and identified STR alleles present within the coding region ...[more]

PMID: 35931961

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Project description:C57BL/6J (B6) and DBA/2J (D2) inbred mouse strains are highly variable genetically and differ in a large number of behavioral traits related to striatal function, including depression, anxiety, stress response, and response to drugs of abuse. The genetic basis of these phenotypic differences are, however, unknown. Here, we present a comparison of the striatal proteome between B6 and D2 and relate differences at the protein level to strain differences at the mRNA level. We also leverage a recombinant inbred BXD population derived from B6 and D2 strains to investigate the role of genetic variation on the regulation of mRNA and protein levels. Finally, we test the hypothesis that differential protein expression contributes to differential behavioral responses between the B6 and D2 strain. We detected the expression of over 2,500 proteins in membrane-enriched protein fractions from B6 and D2 striatum. Of these, 160 proteins demonstrated significant differential expression between B6 and D2 strains at a 10% false discovery level, including COMT, GABRA2, and cannabinoid receptor 1 (CNR1)-key proteins involved in synaptic transmission and behavioral response. Similar to previous reports, there was little overlap between protein and transcript levels (25%). However, the overlap was greater (51%) for proteins demonstrating genetic regulation of cognate gene expression. We also found that striatal proteins with significantly higher or lower relative expression in B6 and D2 were enriched for dopaminergic and glutamatergic synapses and processes involved in synaptic plasticity [e.g., long-term potentiation (LTP) and long-term depression (LTD)]. Finally, we validated higher expression of CNR1 in B6 striatum and demonstrated greater sensitivity of this strain to the locomotor inhibiting effects of the CNR1 agonist, Δ9-tetrahydrocannabinol (THC). Our study is the first comparison of differences in striatal proteins between the B6 and D2 strains and suggests that alterations in the striatal proteome may underlie strain differences in related behaviors, such as drug response. Furthermore, we propose that genetic variants that impact transcript levels are more likely to also exhibit differential expression at the protein level.

Project description:BackgroundTandem repetition of structural motifs in proteins is frequently observed across all forms of life. Topology of repeating unit and its frequency of occurrence are associated to a wide range of structural and functional roles in diverse proteins, and defects in repeat proteins have been associated with a number of diseases. It is thus desirable to accurately identify specific repeat type and its copy number. Weak evolutionary constraints on repeat units and insertions/deletions between them make their identification difficult at the sequence level and structure based approaches are desired. The proposed graph spectral approach is based on protein structure represented as a graph for detecting one of the most frequently observed structural repeats, Ankyrin repeat.ResultsIt has been shown in a large number of studies that 3-dimensional topology of a protein structure is well captured by a graph, making it possible to analyze a complex protein structure as a mathematical entity. In this study we show that eigen spectra profile of a protein structure graph exhibits a unique repetitive profile for contiguous repeating units enabling the detection of the repeat region and the repeat type. The proposed approach uses a non-redundant set of 58 Ankyrin proteins to define rules for the detection of Ankyrin repeat motifs. It is evaluated on a set of 370 proteins comprising 125 known Ankyrin proteins and remaining non-solenoid proteins and the prediction compared with UniProt annotation, sequence-based approach, RADAR, and structure-based approach, ConSole. To show the efficacy of the approach, we analyzed the complete PDB structural database and identified 641 previously unrecognized Ankyrin repeat proteins. We observe a unique eigen spectra profile for different repeat types and show that the method can be easily extended to detect other repeat types. It is implemented as a web server, AnkPred. It is freely available at 'bioinf.iiit.ac.in/AnkPred'.ConclusionsAnkPred provides an elegant and computationally efficient graph-based approach for detecting Ankyrin structural repeats in proteins. By analyzing the eigen spectra of the protein structure graph and secondary structure information, characteristic features of a known repeat family are identified. This method is especially useful in correctly identifying new members of a repeat family.

Dataset Information

Compendious survey of protein tandem repeats in inbred mouse strains.

Publications

Compendious survey of protein tandem repeats in inbred mouse strains.

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