CH8.1 - Genomes and Genomics

Genomes and Genomics

• Genome Definition: All hereditary information specifying an organism.

  • Haploids: Complete hereditary information.

  • Diploids: Complete haploid complement.

• Examples of Genomes:

  • Viral Genome (SFP10 Bacteriophage):

    • Double-stranded DNA.

    • Size: 157 kilobases (157,950 base pairs).

    • Haploid (one copy of each gene).

  • E. coli Genome:

    • Size: 4.6 megabases (4,639,221 base pairs).

    • Haploid (one copy of each gene).

  • Human Genome:

    • Diploid (2n).

    • Karyotype: Shows metaphase-arrested chromosomes.

    • Two copies of each autosome (chromosomes 1-22).

    • Sex chromosomes (X and Y in males).

    • Genome: 22 autosomes + 2 sex chromosomes (one of each pair).

• Increase in Genome Sequencing:

  • Exponential increase over the past 25 years.

  • Data from NCBI (National Center for Biotechnology Information).

  • 1980s: Few genomes sequenced.

  • Exponential increase in viruses, prokaryotes, and eukaryotes.

• Landmark Genome Sequencing Events:

  • First genome sequenced: Bacteriophage (small genome).

  • First cellular organism: Haemophilus influenza (bacteria, 1995).

  • First eukaryotic organism: Saccharomyces cerevisiae (yeast, 1996).

  • Human genome: Completed in 2003.

    • Took 13 years and $1 billion.

    • Now: Less than 24 hours and around $1,000.

• Genome Annotation:

  • Locating genes and critical sequences (regulatory sequences).

  • Assigning putative functions.

• Computational Approaches:

  • Identifying genes and regulatory sequences by comparison with previously studied genomes.

  • Algorithms to identify gene-like features:

    • Start codon.

    • Shine-Dalgarno sequence.

    • Codons and stop codons.

    • Consensus sequences (promoter sequences).

      • Minus 10 consensus (TATAAT).

      • Minus 35 consensus.

    • Intrinsic terminator (base complementarity followed by T's).

• Comparative Genomics:

  • Using previously studied genomes to assign gene functions.

  • Looking for genes with homology (sequence similarity).

  • Homologs: Genes with sequence similarity; may suggest evolutionary relationship or similar function.

  • Orthologs: Homologs with clear functional relationship (same function in different species).

• Synteny:

  • Conservation of gene order on the chromosome in different species.

  • Example: Homologs between humans and mice with similar order on chromosomes.

• Unassigned Functions:

  • Some genes still have no assigned function, leaving room for discovery.

• Types of Sequences in Genomes:

  • Coding sequences: Direct synthesis of proteins (only 1.5% in humans).

  • Non-coding sequences: Much more abundant than coding sequences.

    • Transposons and retrotransposons: ~45% of the human genome.

      • SINEs (Short Interspersed Nuclear Elements).

      • LINEs (Long Interspersed Nuclear Elements).

    • Additional repetitive sequences.

    • Miscellaneous unique sequences.

    • Introns: Non-coding sequences that interrupt exons in pre-mRNA (removed during mRNA processing).

• Variation in Human Genomes:

  • Genotypic differences (nucleotide level) may or may not produce phenotypic differences.

  • Single Nucleotide Polymorphism (SNP):

    • Single nucleotide change.

    • Approximately one SNP per 1,000 base pairs in the human genome.

    • Example: Four individuals with a SNP; one has T, others have C.

  • Haplotype:

    • Groups of SNPs or other genetic variations close together on a chromosome.

    • Tend to segregate together (not separated by recombination).

  • Tag SNP:

    • Particular SNP bordering a haplotype.

    • Indicates what the rest of the haplotype sequence looks like.

  • Haplotypes as markers for certain populations.

• Human vs. Chimpanzee Genomes:

  • Total genomic difference: 4%.

  • Differences include SNPs, chromosomal insertions, duplications, and other arrangements.

  • Duplications can come from transposons.

  • Determining if differences occurred in humans or chimpanzees:

    • Compare sequences to a distantly related outgroup (e.g., orangutan).

    • Example: Gene X sequence differs between humans and chimps, orangutan matches chimps, so the change occurred in the human lineage.

• Molecular Basis of Human Genetic Disease:

  • Linkage Analysis:

    • Mapping disease condition relative to genetic polymorphisms (SNPs, deletions).

    • Example: Early-onset Alzheimer's linked to PS1 gene on chromosome 14.

    • Process:

      • Look at pedigrees of affected families.

      • Collect DNA from affected and unaffected individuals.

      • Follow which SNPs or haplotypes the disease segregates with.

      • SNPs and genetic markers from chromosome 14 (D14S43 SNP) segregated with Alzheimer's.

    • Researchers focused on the D14S43 region of chromosome 14, finding 19 expressed genes.

    • Mutations in S182 (later named PS1) were present in affected individuals, not in unaffected.

    • Looking at affected versus unaffected genomes and disease segregation with SNPs and other genetic markers.