Beyond microsatellite instability : intrinsic disorder as a potential link between protein short tandem repeats and cancer

Short tandem repeats (STRs) are abundant in genomic sequences and are known for comparatively high mutation rates; STRs therefore are thought to be a potent source of genetic diversity. In protein-coding sequences STRs primarily encode disorder-promoting amino acids and are often located in intrinsically disordered regions (IDRs). STRs are frequently studied in the scope of microsatellite instability (MSI) in cancer, with little focus on the connection between protein STRs and IDRs. We believe, however, that this relationship should be explicitly included when ascertaining STR functionality in cancer. Here we explore this notion using all canonical human proteins from SwissProt, wherein we detected 3,699 STRs. Over 80% of these consisted completely of disorder promoting amino acids. 62.1% of amino acids in STR sequences were predicted to also be in an IDR, compared to 14.2% for non-repeat sequences. Over-representation analysis showed STR-containing proteins to be primarily located in the nucleus where they perform protein- and nucleotide-binding functions and regulate gene expression. They were also enriched in cancer-related signaling pathways. Furthermore, we found enrichments of STR-containing proteins among those correlated with patient survival for cancers derived from eight different anatomical sites. Intriguingly, several of these cancer types are not known to have a MSI-high (MSI-H) phenotype, suggesting that protein STRs play a role in cancer pathology in non MSI-H settings. Their intrinsic link with IDRs could therefore be an attractive topic of future research to further explore the role of STRs and IDRs in cancer. We speculate that our observations may be linked to the known dosage-sensitivity of disordered proteins, which could hint at a concentration-dependent gain-of-function mechanism in cancer for proteins containing STRs and IDRs

Mutation and selection processes regulating short tandem repeats give rise to genetic and phenotypic diversity across species

Short tandem repeats (STRs) are units of 1-6 bp that repeat in a tandem fashion in DNA. Along with single nucleotide polymorphisms and large structural variations, they are among the major genomic variants underlying genetic, and likely phenotypic, divergence. STRs experience mutation rates that are orders of magnitude higher than other well-studied genotypic variants. Frequent copy number changes result in a wide range of alleles, and provide unique opportunities for modulating complex phenotypes through variation in repeat length. While classical studies have identified key roles of individual STR loci, the advent of improved sequencing technology, high-quality genome assemblies for diverse species, and bioinformatics methods for genome-wide STR analysis now enable more systematic study of STR variation across wide evolutionary ranges. In this review, we explore mutation and selection processes that affect STR copy number evolution, and how these processes give rise to varying STR patterns both within and across species. Finally, we review recent examples of functional and adaptive changes linked to STRs

Genomes reveal marked differences in the adaptive evolution between orangutan species

Integrating demography and adaptive evolution is pivotal to understanding the evolutionary history and conservation of great apes. However, little is known about the adaptive evolution of our closest relatives, in particular if and to what extent adaptions to environmental differences have occurred. Here, we used whole-genome sequencing data from critically endangered orangutans from North Sumatra (Pongo abelii) and Borneo (P. pygmaeus) to investigate adaptive responses of each species to environmental differences during the Pleistocene

Morphometric, Behavioral, and Genomic Evidence for a New Orangutan Species

Six extant species of non-human great apes are currently recognized: Sumatran and Bornean orangutans, eastern and western gorillas, and chimpanzees and bonobos [1]. However, large gaps remain in our knowledge of fine-scale variation in hominoid morphology, behavior, and genetics, and aspects of great ape taxonomy remain in flux. This is particularly true for orangutans (genus: Pongo), the only Asian great apes and phylogenetically our most distant relatives among extant hominids [1]. Designation of Bornean and Sumatran orangutans, P. pygmaeus (Linnaeus 1760) and P. abelii (Lesson 1827), as distinct species occurred in 2001 [1, 2]. Here, we show that an isolated population from Batang Toru, at the southernmost range limit of extant Sumatran orangutans south of Lake Toba, is distinct from other northern Sumatran and Bornean populations. By comparing cranio-mandibular and dental characters of an orangutan killed in a human-animal conflict to those of 33 adult male orangutans of a similar developmental stage, we found consistent differences between the Batang Toru individual and other extant Ponginae. Our analyses of 37 orangutan genomes provided a second line of evidence. Model-based approaches revealed that the deepest split in the evolutionary history of extant orangutans occurred ∼3.38 mya between the Batang Toru population and those to the north of Lake Toba, whereas both currently recognized species separated much later, about 674 kya. Our combined analyses support a new classification of orangutans into three extant species. The new species, Pongo tapanuliensis, encompasses the Batang Toru population, of which fewer than 800 individuals survive

Regulatory Architecture of the Neuronal Cacng2/Tarpγ2 Gene Promoter: Multiple Repressive Domains, a Polymorphic Regulatory Short Tandem Repeat, and Bidirectional Organization with Co-regulated lncRNAs

CACNG2 (TARPγ2, Stargazin) is a multi-functional regulator of excitatory neurotransmission and has been implicated in the pathological processes of several brain diseases. Cacng2 function is dependent upon expression level, but currently, little is known about the molecular mechanisms that control expression of this gene. To address this deficit and investigate disease-related gene variants, we have cloned and characterized the rat Cacng2 promoter and have defined three major features: (i) multiple repressive domains that include an array of RE-1 silencing transcription factor (REST) elements, and a calcium regulatory element-binding factor (CaRF) element, (ii) a (poly-GA) short tandem repeat (STR), and (iii) bidirectional organization with expressed lncRNAs. Functional activity of the promoter was demonstrated in transfected neuronal cell lines (HT22 and PC12), but although selective removal of REST and CaRF domains was shown to enhance promoter-driven transcription, the enhanced Cacng2 promoter constructs were still about fivefold weaker than a comparable rat Synapsin-1 promoter sequence. Direct evidence of REST activity at the Cacng2 promoter was obtained through co-transfection with an established dominant-negative REST (DNR) construct. Investigation of the GA-repeat STR revealed polymorphism across both animal strains and species, and size variation was also observed in absence epilepsy disease model cohorts (Genetic Absence Epilepsy Rats, Strasbourg [GAERS] and non-epileptic control [NEC] rats). These data provide evidence of a genotype (STR)-phenotype correlation that may be unique with respect to proximal gene regulatory sequence in the demonstrated absence of other promoter, or 3′ UTR variants in GAERS rats. However, although transcriptional regulatory activity of the STR was demonstrated in further transfection studies, we did not find a GAERS vs. NEC difference, indicating that this specific STR length variation may only be relevant in the context of other (Cacna1h and Kcnk9) gene variants in this disease model. Additional studies revealed further (bidirectional) complexity at the Cacng2 promoter, and we identified novel, co-regulated, antisense rat lncRNAs that are paired with Cacng2 mRNA. These studies have provided novel insights into the organization of a synaptic protein gene promoter, describing multiple repressive and modulatory domains that can mediate diverse regulatory inputs

Fazla Kilolu ve Obez Adölesanlarda Motivasyonel Görüşme Tekniğinin Kullanımı

Obezite tüm dünyayı etkileyen ve yetişkinlerde olduğu kadar son zamanlarda adölesan ve çocukluk çağındaki bireyleride etkileyen bulaşıcı olmayan kronik bir hastalıktır. Obezitenin oluşumunda bireylerin sağlık davranışları büyük biretkendir. Obezite tedavisini tek boyutta ele almak doğru bir yaklaşım olmayıp aynı zamanda davranış değişikliği ve kiloyönetimini de kapsamalıdır. Kilo yönetimi ve davranış değişikliği için kullanılan birçok mevcut yöntem olup bunlardanbiri de motivasyonel görüşmedir. Motivasyonel görüşme danışan merkezli olup içsel görüyü ve aynı zamanda özetkililiği de arttıran bir terapötik girişimdir. Motivasyonel görüşme farklı alanlarda kullanılmakla birlikte özellikle kiloverme, kilo kontrolü ve yönetimi, kronik hastalıklarda tedaviye uyum, sigara bırakma tedavisi ve maddenin kötüyekullanımı gibi davranış değişiminin yapılması gereken konularda kullanılmaktadır. Motivasyonel görüşmenin obez veyafazla kilolu adölesanlar üstünde davranış değişiminde etkili olduğu ve istendik yönde olumlu sağlık davranışlarınıngeliştirildiğini gösteren araştırmalar mevcuttur. Ancak motivasyonel görüşmenin klinik etkinliğini ortaya koymak vekanıt düzeyini yükseltmek için konu ile ilgili daha fazla çalışmaya gereksinim bulunmaktadır. Bu derlemenin amacıfazla kilolu ve obez adölesanlarda motivasyonel görüşme tekniği kullanımının bireyler üstündeki etkilerini ortayakoymaktır

A survey of tandem repeat instabilities and associated gene expression changes in 35 colorectal cancers

BACKGROUND: Colorectal cancer is a major contributor to cancer morbidity and mortality. Tandem repeat instability and its effect on cancer phenotypes remain so far poorly studied on a genome-wide scale. RESULTS: Here we analyze the genomes of 35 colorectal tumors and their matched normal (healthy) tissues for two types of tandem repeat instability, de-novo repeat gain or loss and repeat copy number variation. Specifically, we study for the first time genome-wide repeat instability in the promoters and exons of 18,439 genes, and examine the association of repeat instability with genome-scale gene expression levels. We find that tumors with a microsatellite instable (MSI) phenotype are enriched in genes with repeat instability, and that tumor genomes have significantly more genes with repeat instability compared to healthy tissues. Genes in tumor genomes with repeat instability in their promoters are significantly less expressed and show slightly higher levels of methylation. Genes in well-studied cancer-associated signaling pathways also contain significantly more unstable repeats in tumor genomes. Genes with such unstable repeats in the tumor-suppressor p53 pathway have lower expression levels, whereas genes with repeat instability in the MAPK and Wnt signaling pathways are expressed at higher levels, consistent with the oncogenic role they play in cancer. CONCLUSIONS: Our results suggest that repeat instability in gene promoters and associated differential gene expression may play an important role in colorectal tumors, which is a first step towards the development of more effective molecular diagnostic approaches centered on repeat instability

Lepral ı hastaların yaşam kalitesinin d eğerlendirilmesi

Objective: Determine to quality of life leather and genitals diseases unit of registered leprosy patients residing in the province of Izmir and affecting the socio-demographic characteristics. Method: Between January 2014 and January 2013 as a descriptive research was conducted with 59 patients with leprosy that registered in The Skin and Genital Diseases Dispensary in Izmir. Data was collected by questionnaire and SF-36 quality of life questionnaires and was analyzed through. The SPSS 21.0 software package. The frequency and distribution on data are given. Average, Mann-Whitney U test andKruskall Walls was used for the evaluation of the data. Results: The mean SF-36 physical functioning score (23.4 ± 6.9) was higher in the leprosy patients participating in the study, while the emotional role strength was lower (1.4 ± 1.4). It was determined that characteristics such as age, marital status, damage status, damage area and educational status affect the quality of life in patients with leprosy. Conclusion: This study has shown that Lebron patients need support from emotional aspects. In order to increase the quality of life of Lepra patients, nurses may be recommended to support these patients in the emotional direction