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A lecture outline for cmsc 838t, focusing on genetics and comparative genomics. Topics include inheritance, meiosis and recombination, linkage maps, genetic diseases, polymorphisms, and snps. Comparative genomics covers genome sequences, gene order comparison, chromosomal rearrangement, and clusters of orthologous genes. Real-world examples and model organisms are used to illustrate concepts.
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CMSC 838T โ Lecture 14
0 Analyzing genes & inheritance
0 Extracting information from cross-genome comparisons
Recombination VCMap - Human Rat Mouse
0 Inheritance 0 Meiosis & recombination 0 Linkage maps 0 Genetic diseases 0 Polymorphisms
CMSC 838T โ Lecture 14
0 Mendel studied inheritance in garden peas in 1865 0 Tested 34 varieties of peas, growing 28,000 pea plants 0 Found attributes determined by gene from each parent
0 (Diploid) organisms maintain 2 copies of each chromosome 0 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 โ blue eyes vs. brown eyes
CMSC 838T โ Lecture 14
0 May be caused by single gene O Huntingtonโs, cystic fibrosis, sickle-cell anemia, etcโฆ 0 May be caused by interaction between multiple genes O Asthma, heart disease, cancer O Gene may be a risk factor for disease 0 May be caused by multiple groups of genes O All showing same symptom
0 Susceptibility vs. resistance 0 Variations in disease severity or symptoms 0 Reaction to drugs (pharmacogenetics)
CMSC 838T โ Lecture 14
0 Genetic variant appearing in > 1% of population O Filter out spontaneous mutations 0 May form alleles (versions of genes)
0 Very common, 3.7 million (human) in dbSNP as of April 2003 0 Occurring every ~1250 bases (on average) between individuals 0 Most (estimated 99+%) have no effect on phenotype O Occur in non-coding DNA, degenerate codons 0 Serve as markers for genes in laboratory O If SNP is known to be physically close to gene (linked) O Find SNP โ identify allele, genetic disease 0 A few thousand SNPs can characterize human genome
0 Genomes & model organisms 0 Genomic rearrangement / synteny 0 Genomic alignment 0 Clusters of orthologous genes (COGs) 0 Comparative gene analysis & prediction
CMSC 838T โ Lecture 14
0 Chromosomes can break at random location 0 Fragments rejoined at random by DNA repair mechanisms
0 Analyze rearrangements using locations of orthologs 0 Gene order changed by rearrangements over time 0 Genes w/ similar biological function tend to remain localized
0 Same species โ genes on same chromosome 0 Multiple species โ matching sections of chromosomes (with same genes in same order)
M. genitalium
M. pneumoniae
0 Dot matrix plot of genes 0 Ortholog (common ancestor & function) 0 Paralog (duplication)
CMSC 838T โ Lecture 14
0 99% similar 0 Can cut human genome into >100 pieces and map onto mouse genome fairly accurately
Human Mouse
0 Must be able to align very long sequences 0 Better alignments possible from similar genomes 0 GLASS โ recursively align genomes starting with long matches 0 WABA โ break genome into small overlapping pieces, align
O Sequence alignment visualization tool O Emphasize regions of high similarity 0 VCMap O Visualize locations of orthologs between genomes
CMSC 838T โ Lecture 14
0 Cluster orthologous genes (COG) between genomes 0 COGs usually represent classes of metabolic function 0 NCBI COG database stores relationships, annotations
0 Relationship between several yeast and bacterial orthologs in NCBI COG database
CMSC 838T โ Lecture 14
0 Conserved regions identify genes & regulation factors O ROSETTA โ gene model + GLASS alignment
0 Cross annotation between genomes 0 Genes for proteins in same pathway should be correlated O Find correlated genes using clustering / statistics 0 Gene fusion O Genes producing interacting proteins sometimes fuse to produce single protein O Look for fused genes
0 Evaluation of inheritance based on phenotypes 0 Use variation in inheritance rate to derive linkage maps
0 Extract information from multiple genomes 0 Techniques for mapping and comparing genomes
0 Reveals selective pressure on mutations 0 Can provide hints to gene location & function
