Conversely, conserved elements lacking activity show increased human diversity, suggesting that some recently became nonfunctional. We find statistically robust evidence that (1) scrambling, removing, or disrupting the predicted activator motifs abolishes enhancer function, while silent or motif-improving changes maintain enhancer activity; (2) evolutionary conservation, nucleosome exclusion, binding of other factors, and strength of the motif match are all associated with wild-type enhancer activity; (3) scrambling repressor motifs leads to aberrant reporter expression in cell lines where the enhancers are usually not active. Massachusetts Institute of Technology. Analysis of the CUG leucine-to-serine genetic-code change reveals that 99% of ancestral CUG codons were erased and new ones arose elsewhere. Software Engineer Jingwei Zhang. We use evolutionary signatures and comparisons with experimental data sets to suggest candidate functions for 60% of constrained bases. Characterizing the intermediate phenotypes, such as gene expression, that mediate genetic effects on complex diseases is a fundamental problem in human genetics. We annotate 30,247 genetic variants associated with 534 traits, recognize principal and partner tissues underlying each trait, infer trait-tissue, tissue-tissue and trait-trait relationships, and partition multifactorial traits into their tissue-specific contributing factors. We identify network neighborhoods composed of topologically-specific genes that are central for cell-type influence but not for global interactome connectivity. While duplication-loss (DL) reconciliation leads to a unique maximum-parsimony solution, duplication-transfer-loss (DTL) reconciliation yields a multitude of optimal solutions, making it difficult to infer the true evolutionary history of the gene family. We define 51 distinct chromatin states, including promoter-associated, transcription-associated, active intergenic, large-scale repressed and repeat-associated states. Overall, the project provides new insights into the organization and regulation of our genes and genome, and is an expansive resource of functional annotations for biomedical research. Long intergenic noncoding RNAs (lincRNAs) play diverse regulatory roles in human development and disease, but little is known about their evolutionary history and constraint. We seek to understand the mechanistic basis of human disease, using a combination of computational and experimental techniques. The human genome encodes the blueprint of life, but the function of the vast majority of its nearly three billion bases is unknown. “Obesity has traditionally been seen as the result of an imbalance between the amount of food we eat and how much we exercise, but this view ignores the contribution of genetics to each individual’s metabolism,” says senior author Manolis Kellis, a professor of computer science and a member of MIT’s Computer Science and Artificial Intelligence Laboratory (CSAIL) and of the Broad Institute. The algorithm is the first for this problem with provable guarantees. The most widely appreciated role of DNA is to encode protein, yet the exact portion of the human genome that is translated remains to be ascertained. Our results suggest that gene-regulatory properties previously observed for individual factors are general principles of metazoan regulation that are remarkably well-preserved despite extensive functional divergence of individual network connections. We examined epigenomic data, allelic activity, motif conservation, regulator expression, and gene coexpression patterns, with the aim of dissecting the regulatory circuitry and mechanistic basis of the association between the FTO region and obesity. Chromatin variability shows genetic inheritance in trios, correlates with genetic variation and population divergence, and is associated with disruptions of transcription factor binding motifs. Previously our analysis of conserved protein coding signatures that extend beyond annotated stop codons predicted stop codon readthrough of several mammalian genes, all of which have been validated experimentally. Dna fragments in a 67 amino-acid-long C-terminal extension that generates a VDR proteoform named.! Extraction with self-transcribing episomal reporters ( ATAC-STARR-seq ) usage signatures can also be detected the state... 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