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The comparison of related genomes has emerged as a powerful lens for genome interpretation. Here we report the sequencing and comparative analysis of 29 eutherian genomes. We confirm that at least 5.5% of the human genome has undergone purifying selection, and locate constrained elements covering ∼4.2% of the genome. We use evolutionary signatures and comparisons with experimental data sets to suggest candidate functions for ∼60% of constrained bases. These elements reveal a small number of new coding exons, candidate stop codon readthrough events and over 10,000 regions of overlapping synonymous constraint within protein-coding exons. We find 220 candidate RNA structural families, and nearly a million elements overlapping potential promoter, enhancer and insulator regions. We report specific amino acid residues that have undergone positive selection, 280,000 non-coding elements exapted from mobile elements and more than 1,000 primate- and human-accelerated elements. Overlap with disease-associated variants indicates that our findings will be relevant for studies of human biology, health and disease.

Transcription factors (TF) play an essential role in the cell as locus- and condition-specific recruiters of transcriptional machinery or chromatin-modifying complexes. However, predicting the in vivo profile of TF occupancy along the genome, which depends on complex interactions with other chromatin-associated proteins, from the DNA sequence remains a major challenge. Through careful reanalysis of ChIP-chip data for 138 TFs obtained in rich media, we were able to classify the upstream promoter regions of S. cerevisiae into 15 distinct chromatin types. One of these encompasses 5% of all promoters and is unique in that it is highly occupied by (essentially) all TFs expressed in rich media. These "hotspots" of TF occupancy are strongly nucleosome-depleted and preferentially targeted by chromatin-remodeling complexes and the origin-of-replication complex (ORC). They are also the only chromatin type enriched for predicted Rap1p and Pdr1p binding sites, which we found to work cooperatively with AAA/TTT motifs, known to affect local DNA structure, to reduce nucleosome occupancy. Taken together, our results reveal and characterize a new type of local chromatin structure in yeast., Comment: This paper has been withdrawn by the author due to a crucial error in the text

Association studies provide genome-wide information about the genetic basis of complex disease, but medical research has focused primarily on protein-coding variants, owing to the difficulty of interpreting noncoding mutations. This picture has changed with advances in the systematic annotation of functional noncoding elements. Evolutionary conservation, functional genomics, chromatin state, sequence motifs and molecular quantitative trait loci all provide complementary information about the function of noncoding sequences. These functional maps can help with prioritizing variants on risk haplotypes, filtering mutations encountered in the clinic and performing systems-level analyses to reveal processes underlying disease associations. Advances in predictive modeling can enable data-set integration to reveal pathways shared across loci and alleles, and richer regulatory models can guide the search for epistatic interactions. Lastly, new massively parallel reporter experiments can systematically validate regulatory predictions. Ultimately, advances in regulatory and systems genomics can help unleash the value of whole-genome sequencing for personalized genomic risk assessment, diagnosis and treatment., National Institutes of Health (U.S.) (Grant R01HG004037), National Institutes of Health (U.S.) (Grant RC1HG005334), National Science Foundation (U.S.) (CAREER Grant 0644282)