* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download Ultraconserved Elements in the Human Genome
Ridge (biology) wikipedia , lookup
Pathogenomics wikipedia , lookup
Gene expression profiling wikipedia , lookup
History of genetic engineering wikipedia , lookup
Therapeutic gene modulation wikipedia , lookup
Polyadenylation wikipedia , lookup
Human genome wikipedia , lookup
Metagenomics wikipedia , lookup
Nucleic acid analogue wikipedia , lookup
RNA interference wikipedia , lookup
Minimal genome wikipedia , lookup
Transposable element wikipedia , lookup
Genome evolution wikipedia , lookup
Long non-coding RNA wikipedia , lookup
Microevolution wikipedia , lookup
Deoxyribozyme wikipedia , lookup
Epigenetics of human development wikipedia , lookup
Non-coding DNA wikipedia , lookup
Nucleic acid tertiary structure wikipedia , lookup
RNA silencing wikipedia , lookup
Helitron (biology) wikipedia , lookup
Epitranscriptome wikipedia , lookup
History of RNA biology wikipedia , lookup
Non-coding RNA wikipedia , lookup
Primary transcript wikipedia , lookup
Short interspersed nuclear elements (SINEs) wikipedia , lookup
Ultraconserved Elements in the Human Genome Gill Bejerano, Michael Pheasant, Igor Makunin, Stuart Stephen, W. James Kent, John S. Mattick, David Haussler Science Vol.304 28 May 2004 Presented By Victor Jensen Overview • • • • • • Definition of an ultraconserved element Diversity of the elements Where are the elements Possible function Origins Summary Definition of an Ultraconserved Element • Segment of DNA with 100% sequence identity across species (mouse, rat & human) • Orthologous location • At least 200 bp • Not rRNA What they found • Total of 481 sequences • Up to 779 bp • >5000 if you look at sequences >100bp Diversity Across Species 500 400 300 324 Dog Chicken 29 Mouse Rat Human 100 0 477 Fugu 200 481 481 481 438 67% 95% 99.20% 100% Diversity Within Species • Ultraconserved elements have a total of 106,767 bases • Only 6 bases have confirmed SNPs (dbSNP) • Expect 119 based on neutral evolution 6 observed 119 expected SNPs 106,767 bases Diversity Within Species • With only 6 SNPs within these elements they show very low diversity • This represents 20 times lower SNP density and rate of change compared to the rest of the genome •Very similar in chimpanzees, 38 SNPs found where 716 are expected There Must be Selection • Random chance for one of these elements to occur is less than 10-22 • This is more conservation than most (if not all) proteins • Evidence for very strong selection So, why are these so important and where are they located?? Location of Elements • Elements are everywhere!! Location of Elements 300 250 200 Non-Exonic, 256 150 100 Exonic, 111 50 Possibly Exonic, 114 0 Elements Non-Exonic elements • Found in clusters • 140 are >10 kb away from a gene (88 are >100kb away) • Others lie in introns • Areas around elements are enriched for developmental genes and transcription factors Exonic • Randomly distributed • Enriched for RNA processing proteins • Shows some correlation with RNA recognition motif often associated with alternative splicing Location of Elements Exonic, or Type 1 Nonexonic, or Type 2 •Overview of GO term abundance vs. expected Groups of Elements • Some elements are paralogous • Significant divergence between paralogs • Surrounding genes are orthologous Possible Function • Conservation of important biological processes – Transcriptional element (cis-regulatory elements) – RNA processing machinery (spliceosome) – Developmental regulation Transcriptional Regulation • cis-regulatory elements are often conserved between species • Below is the 10kb upstream of PolA RNA Processing • Elements could represent RNA processing enzyme binding sites • Alternative splicing RNA Structure • Hypothesized that RNA structure may play a role in function • Many ultraconserved elements would have an RNA structure • Splicing recognition? Development • Defects in developmental genes/gene regulation is often lethal • Correlation of ultraconserved elements and developmental genes implies relationship Elemental Origins • Looked for elements in other sequenced genomes – C. elegans – D. melanogaster – C. intestinalis Elemental Origins • Found 24 of 481 elements • All were exonic • 17 show alternative spliced Elemental Origins • Elements have undergone a “freezing” of DNA code after chordate evolution • Most are older than 300 million years How are they conserved? • Evolution of high negative selection • Or • Evolution of hypomutable regions • Or a little of both High Negative Selection • Must have an important function • Sensitive to minor changes • RNA structure is very sensitive to changes Hypomutable Regions • Unlikely to be “hypomutable” • Possibly “hyperrepaired” Summary • 481 ultraconserved elements >200bp • Exonic found with RNA processing genes • Non-exonic found with transcription factors and developmental genes • 20x less change than expected • Connection to alternative splicing and RNA structure • Low diversity Questions • Could some of these be RNA genes? • Did they look for related elements not found in the same location in mice? • What happens if there is a mutation in one of these elements? • ???