1CMSC 838T – Lecture 14CMSC 838T – Lecture 14X Genetics0 Analyzing genes & inheritanceX Comparative genomics 0 Extracting information from cross-genome comparisonsRecombination VCMap - Human Rat MouseCMSC 838T – Lecture 14OutlineX Genetics0 Inheritance0 Meiosis & recombination0 Linkage maps0 Genetic diseases0 PolymorphismsX Comparative genomics2CMSC 838T – Lecture 14GeneticsX Inheritance0 Mendel studied inheritance in garden peas in 18650 Tested 34 varieties of peas, growing 28,000 pea plants0 Found attributes determined by gene from each parentX Biology0 (Diploid) organisms maintain 2 copies of each chromosome0 Each parent contributes 1 copy during reproduction (meiosis)0 Chromosomes may be mixed during meiosis (recombination)0 Different versions exist for each gene (alleles)O Example – blue eyes vs. brown eyesCMSC 838T – Lecture 14Genetics – Inheritance X Phenotype determined by inherited genes3CMSC 838T – Lecture 14Genetics – Meiosis & RecombinationX Study of inheritanceCMSC 838T – Lecture 14Genetics – Linkage Maps X Biology of reproduction0 Genes located on same chromosome (syntenic) usually transmitted together0 Recombination may separate genes0 Probability → distance on chromosomeX Linkage map0 Examine inheritance data for populationO Usually for genetic diseases0 Estimate relative distance between genes0 May use SNP genetic markers0 Create linkage map0 Try to identify gene(s)Linkage map for corn4CMSC 838T – Lecture 14Genetics – Genetic DiseasesX Genetic diseases0 May be caused by single geneO Huntington’s, cystic fibrosis, sickle-cell anemia, etc…0 May be caused by interaction between multiple genesO Asthma, heart disease, cancerO Gene may be a risk factor for disease0 May be caused by multiple groups of genesO All showing same symptomX Clinical manifestation of genetics0 Susceptibility vs. resistance0 Variations in disease severity or symptoms0 Reaction to drugs (pharmacogenetics)CMSC 838T – Lecture 145CMSC 838T – Lecture 14Genetics – Polymorphisms & SNPsX Polymorphism0 Genetic variant appearing in > 1% of populationO Filter out spontaneous mutations0 May form alleles (versions of genes)X SNPs (Single Nucleotide Polymorphism)0 Very common, 3.7 million (human) in dbSNP as of April 20030 Occurring every ~1250 bases (on average) between individuals0 Most (estimated 99+%) have no effect on phenotypeO Occur in non-coding DNA, degenerate codons0 Serve as markers for genes in laboratoryO If SNP is known to be physically close to gene (linked)O Find SNP → identify allele, genetic disease0 A few thousand SNPs can characterize human genomeCMSC 838T – Lecture 14OutlineX GeneticsX Comparative genomics0 Genomes & model organisms0 Genomic rearrangement / synteny0 Genomic alignment0 Clusters of orthologous genes (COGs)0 Comparative gene analysis & prediction6CMSC 838T – Lecture 14Comparative GenomicsX Description0 Large scale comparison of genomes0 Understand biology of individual genome0 Discover principles governing genomesX Assumption0 Biology is shared by different species0 Analyzing multiple species together increases information0 Can understand human genes by studying their relatives (orthologs) in simpler organismsO Mouse & rat used extensively as model for humanCMSC 838T – Lecture 14Genomics – Genomes & Model OrganismsX Genome sequences in GenBank (April 2003)0 519 eukaryotes0 426 bacteria0 1310 viruses (incl. SARS corona virus)X Model organisms0 Focus of multiple studies due to scientific interest0 E. Coli, yeast, nematode worm, fruit fly, mustard plant, zebrafish, mouse, human30,000+3,300Homo sapien18,42497Caenorabditus13,601165Drosophila25,498119Arabidopsis6,03413.5Saccharomyces4,2884.6E. Coli4,1004.2Bacillus8341.11Rickettsia4700.58MycoplasmaGenesGenome (Mbp)Species7CMSC 838T – Lecture 14Genomics – Gene Order ComparisonX Chromosomal rearrangement0 Chromosomes can break at random location0 Fragments rejoined at random by DNA repair mechanismsX Comparing genomes between species0 Analyze rearrangements using locations of orthologs0 Gene order changed by rearrangements over time0 Genes w/ similar biological function tend to remain localizedX Synteny0 Same species – genes on same chromosome0 Multiple species – matching sections of chromosomes(with same genes in same order)CMSC 838T – Lecture 14Chromosomal Rearrangement – Genome PlotM. genitaliumM. pneumoniaeX Genome plot0 Dot matrix plot of genes0 Ortholog(common ancestor & function)0 Paralog(duplication)X Plot shows order of manyorthologspreserved8CMSC 838T – Lecture 14Chromosomal Rearrangement – Human MouseX Human and mouse genomes0 99% similar0 Can cut human genome into >100 piecesand map onto mouse genome fairly accuratelyHuman MouseCMSC 838T – Lecture 14Genomics – Genome AlignmentX Aligning genomes0 Must be able to align very long sequences0 Better alignments possible from similar genomes0 GLASS – recursively align genomes starting with long matches0 WABA – break genome into small overlapping pieces, alignX Genome visualization tools0 VISTAO Sequence alignment visualization toolO Emphasize regions of high similarity0 VCMapO Visualize locations of orthologs between genomes9CMSC 838T – Lecture 14VISTA – Comparing Human & Rat GenomesCMSC 838T – Lecture 14Virtual Chromosome Map – Human Rat MouseX VCMap0 Rat map framework markers in red0 Chromosome numbers in blue0 Conserved regions in common colorHuman MouseRat10CMSC 838T – Lecture 14Genomics – Clusters of Orthologous GenesX Comparing genomes to find orthologs0 Cluster orthologous genes (COG) between genomes0 COGs usually represent classes of metabolic function0 NCBI COG database stores relationships, annotationsX Example0 Relationship between several yeast and bacterial orthologsin NCBI COG databaseCMSC 838T – Lecture 14Genomics – Clusters of Orthologous GenesX Using COG database to predict gene function11CMSC 838T – Lecture 14Genomics – Comparative Analysis & PredictionX Comparing genomes to extract information0 Conserved regions identify genes & regulation factorsO ROSETTA – gene model + GLASS alignmentX Predict gene function based on 0 Cross annotation between genomes0 Genes for proteins in same pathway should be correlatedO Find correlated genes using clustering / statistics0 Gene fusionO Genes producing interacting proteins sometimes fuse to produce single proteinO Look for fused genesCMSC 838T – Lecture 14Genetics & Comparative GenomicsX Genetics0 Evaluation of inheritance