Finding cis-regulatory elements using comparative genomics: Some lessons from ENCODE data

Abstract

Identification of functional genomic regions using interspecies comparison will be most effective when the full span of relationships between genomic function and evolutionary constraint are utilized. We find that sets of putative transcriptional regulatory sequences, defined by ENCODE experimental data, have a wide span of evolutionary histories, ranging from stringent constraint shown by deep phylogenetic comparisons to recent selection on lineage-specific elements. This diversity of evolutionary histories can be captured, at least in part, by the suite of available comparative genomics tools, especially after correction for regional differences in the neutral substitution rate. Putative transcriptional regulatory regions show alignability in different clades, and the genes associated with them are enriched for distinct functions. Some of the putative regulatory regions show evidence for recent selection, including a primate-specific, distal promoter that may play a novel role in regulation.

Novel non-TCR chromosome translocations t(3;11)(q25;p13) and t(X;11)(q25;p13) activating LMO2 by juxtaposition with MBNL1 and STAG2

“…The overall median time to engraftment was 10 (3-23) weeks (adults 10 (5-23) weeks/pediatric 9 (3-19) weeks). Fresh samples engrafted in 96.3% of the cases with an overall median delay of 8 (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) weeks (adult 8 (5-20) weeks/pediatric 7 (3-16) weeks) whereas frozen samples showed a median time to…”

“…Although this is the first report indicting STAG2 in a leukemic translocation, the cis-regulatory potential of its 5 0 -region is known. 6 Real-time quantitative-PCR analysis of 26 T-ALL cell lines (Figure 3a) showed LMO2 upregulation correlated with genomic rearrangement, which occurred in 5 of the top 10 (50%) expressers, but not in the remaining 16 (t-test: Po0.001). Our data also hint that the degree of LMO2 upregulation may be rearrangement-class dependent, TCR-/NRE-deletion cells trumping t(3;11)/t(X;11).…”

Qualifying the relationship between sequence conservation and molecular function

“…With respect to other classes of functional sequence, recent estimates suggest that 70% of the nucleotides evolving under purifying selection in mammalian genomes are not within exons of protein-coding genes ("noncoding") and, except for the extreme constraint seen on some critical proteins (e.g., histones), the range of selection coefficients affecting these positions appears similar to that for protein-coding DNA (Mouse Genome Sequencing Consortium 2002; Rat Genome Sequencing Project Consortium 2004; King et al 2007). Furthermore, analysis of the regulatory function and biochemical specificity of individual transcription-factor binding sites also supports the presence of a quantitative spectrum of selective strength in noncoding functional sequences.…”

“…Indeed, it has been shown that many regulatory elements in the human genome are restricted to particular clades and are likely to play important, but clade-specific roles (King et al 2007); sequences involved in the articulation of digits in the developing mammalian limb bud are unlikely to be systematically captured in a human-fish comparison, for example. Even for those elements present in the common ancestral genome, changes in genomic or biological context that alter the strength of selection are likely to be major contributors to a loss of sensitivity in the detection of constraint.…”

DeepFinder: An integration of feature-based and deep learning approach for DNA motif discovery

“…To speed up the alignment of genomes, heuristic techniques such as anchoring [6], threaded blockset [10] or greedy search [11] have been employed. Although comparative genomic methods enabled identification of conserved motifs, these methods missed many functional motifs that are not conserved [12]. The second group of methods uses a database of annotated motif profiles to detect associated sites in input datasets [13][14][15][16].…”