Integrative systematic review meta-analysis and bioinformatics identifies MicroRNA-21 and its target genes as biomarkers for colorectal adenocarcinoma

BACKGROUND: Advanced colorectal has poor survival and are difficult to treat. Therefore, there is an urgent need for biomarkers to diagnose this cancer at earlier manageable stages. Micro-RNAs (miRNAs) are amongst the most significant biomarkers that have shown promise in improving management and early detection of different types of cancers. However, since MiRNAs are non-coding, the main limitation of using them as biomarkers is that they do not have associated phenotype and therefore difficult to validate using other techniques. This makes it difficult to understand the mechanism of miRNA is disease initiation and progression, therefore any methodology that can provide semantics to miRNA expression would enhance the understanding of the role of miRNA in disease. METHODS: Here we report an integrative meta-analysis and bioinformatics methodology that showed microRNA21 and its associated target mRNA to be the most significant predictive biomarkers for colorectal adenoma and adenocarcinoma. After drawing key inferences by meta-analysis, the authors then developed a bioinformatics method to identify mir-21 gene targeting in a specific tissue using two different bioinformatics approaches; absolute GSEA (Gene Set Enrichment Analysis) and LIMMA (Linear Models for MicroArray data) to identify differentially expressed genes of miRNA-21. RESULTS: Results from GSEA intersection with mir-21 gene targets was a subset of longer gene list that was obtained from the GEO2R intersect. In our study, both of longer GEO2R gene target list and the more focused GSEA list established the fact that mir-21 target numerous functional pathways that are mostly interconnected. Our three steps bioinformatics approach identified ABCB1, HPGD, BCL2, TIAM1, TLR3, and PDCD4 as common targets for mir-21 in both of adenoma as well as adenocarcinoma suggesting they are biomarkers for early CRC. CONCLUSIONS: The approach in this study proposed combining the big data from the scientific literature together with novel bioinformatics to bring about a methodology that can be used to first identify which microRNAs are involved in a specific disease, and then to identify a panel of biomarkers derived from the microRNAs target genes, and from these target genes the functional significance of these microRNAs can be inferred providing better clinical value for the surgeon

The earliest settlers' antiquity and evolutionary history of Indian populations: evidence from M2 mtDNA lineage

BACKGROUND: The "out of Africa" model postulating single "southern route" dispersal posits arrival of "Anatomically Modern Human" to Indian subcontinent around 66–70 thousand years before present (kyBP). However the contributions and legacy of these earliest settlers in contemporary Indian populations, owing to the complex past population dynamics and later migrations has been an issue of controversy. The high frequency of mitochondrial lineage "M2" consistent with its greater age and distribution suggests that it may represent the phylogenetic signature of earliest settlers. Accordingly, we attempted to re-evaluate the impact and contribution of earliest settlers in shaping the genetic diversity and structure of contemporary Indian populations; using our newly sequenced 72 and 4 published complete mitochondrial genomes of this lineage. RESULTS: The M2 lineage, harbouring two deep rooting subclades M2a and M2b encompasses approximately one tenth of the mtDNA pool of studied tribes. The phylogeographic spread and diversity indices of M2 and its subclades among the tribes of different geographic regions and linguistic phyla were investigated in detail. Further the reconstructed demographic history of M2 lineage as a surrogate of earliest settlers' component revealed that the demographic events with pronounced regional variations had played pivotal role in shaping the complex net of populations phylogenetic relationship in Indian subcontinent. CONCLUSION: Our results suggest that tribes of southern and eastern region along with Dravidian and Austro-Asiatic speakers of central India are the modern representatives of earliest settlers of subcontinent. The Last Glacial Maximum aridity and post LGM population growth mechanised some sort of homogeneity and redistribution of earliest settlers' component in India. The demic diffusion of agriculture and associated technologies around 3 kyBP, which might have marginalized hunter-gatherer, is coincidental with the decline of earliest settlers' population during this period

The earliest settlers' antiquity and evolutionary history of Indian populations: evidence from M2 mtDNA lineage

Abstract Background The "out of Africa" model postulating single "southern route" dispersal posits arrival of "Anatomically Modern Human" to Indian subcontinent around 66–70 thousand years before present (kyBP). However the contributions and legacy of these earliest settlers in contemporary Indian populations, owing to the complex past population dynamics and later migrations has been an issue of controversy. The high frequency of mitochondrial lineage "M2" consistent with its greater age and distribution suggests that it may represent the phylogenetic signature of earliest settlers. Accordingly, we attempted to re-evaluate the impact and contribution of earliest settlers in shaping the genetic diversity and structure of contemporary Indian populations; using our newly sequenced 72 and 4 published complete mitochondrial genomes of this lineage. Results The M2 lineage, harbouring two deep rooting subclades M2a and M2b encompasses approximately one tenth of the mtDNA pool of studied tribes. The phylogeographic spread and diversity indices of M2 and its subclades among the tribes of different geographic regions and linguistic phyla were investigated in detail. Further the reconstructed demographic history of M2 lineage as a surrogate of earliest settlers' component revealed that the demographic events with pronounced regional variations had played pivotal role in shaping the complex net of populations phylogenetic relationship in Indian subcontinent. Conclusion Our results suggest that tribes of southern and eastern region along with Dravidian and Austro-Asiatic speakers of central India are the modern representatives of earliest settlers of subcontinent. The Last Glacial Maximum aridity and post LGM population growth mechanised some sort of homogeneity and redistribution of earliest settlers' component in India. The demic diffusion of agriculture and associated technologies around 3 kyBP, which might have marginalized hunter-gatherer, is coincidental with the decline of earliest settlers' population during this period.</p

The earliest settlers' antiquity and evolutionary history of Indian populations: evidence from M2 mtDNA lineage-1

PD) limits. Panel 'A'- The Bayesian skyline plot (= 10) for India total, derived from complete mtDNA sequences (= 76). Panel 'B'- The Bayesian skyline plot (= 10) for India total, derived from coding region (577–16023) mtDNA sequences (= 76). The time estimates (yBP) were calculated as per []. For comparison, the cold and arid period around the Last Glacial Maximum are also indicated on panel A & B. Panel 'C to F' shows Bayesian skyline plots (= 10) derived from complete mtDNA sequences of eastern (n = 11), central (n = 29), southern (n = 14) and western (n = 22) regions of India respectively.<p><b>Copyright information:</b></p><p>Taken from "The earliest settlers' antiquity and evolutionary history of Indian populations: evidence from M2 mtDNA lineage"</p><p>http://www.biomedcentral.com/1471-2148/8/230</p><p>BMC Evolutionary Biology 2008;8():230-230.</p><p>Published online 11 Aug 2008</p><p>PMCID:PMC2528015.</p><p></p

The earliest settlers' antiquity and evolutionary history of Indian populations: evidence from M2 mtDNA lineage-2

Ur additional complete mtDNA sequence of M2 lineage (labeled as R102, T3, T11 and T27) are acquired from published sources [] has been used for tree reconstruction. Suffixes A, C, G, and T indicate transversions, "d" signifies a deletion and a plus sign (+) an insertion; recurrent mutations are underlined. The prefix "@" indicates back mutation. The coalescent estimates were calculated as per [] and [] presented as bold and Italic respectively.<p><b>Copyright information:</b></p><p>Taken from "The earliest settlers' antiquity and evolutionary history of Indian populations: evidence from M2 mtDNA lineage"</p><p>http://www.biomedcentral.com/1471-2148/8/230</p><p>BMC Evolutionary Biology 2008;8():230-230.</p><p>Published online 11 Aug 2008</p><p>PMCID:PMC2528015.</p><p></p

The earliest settlers' antiquity and evolutionary history of Indian populations: evidence from M2 mtDNA lineage-0

Ur additional complete mtDNA sequence of M2 lineage (labeled as R102, T3, T11 and T27) are acquired from published sources [] has been used for tree reconstruction. Suffixes A, C, G, and T indicate transversions, "d" signifies a deletion and a plus sign (+) an insertion; recurrent mutations are underlined. The prefix "@" indicates back mutation. The coalescent estimates were calculated as per [] and [] presented as bold and Italic respectively.<p><b>Copyright information:</b></p><p>Taken from "The earliest settlers' antiquity and evolutionary history of Indian populations: evidence from M2 mtDNA lineage"</p><p>http://www.biomedcentral.com/1471-2148/8/230</p><p>BMC Evolutionary Biology 2008;8():230-230.</p><p>Published online 11 Aug 2008</p><p>PMCID:PMC2528015.</p><p></p