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THE GENOME

THE GENOME. DESCRIBE THE MAIN FEATURES OF THE HUMAN GENOME INCLUDING DETAILS OF AT LEAST ONE SPECIFIC CHROMOSOME ELAINE WHITFIELD. THE HUMAN GENOME. The human genome actually consists of two genomes: - complex nuclear genome - simple mitochondrial genome. NUCLEAR

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THE GENOME

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  1. THE GENOME • DESCRIBE THE MAIN FEATURES OF THE HUMAN GENOME INCLUDING DETAILS OF AT LEAST ONE SPECIFIC CHROMOSOME • ELAINE WHITFIELD

  2. THE HUMAN GENOME The human genome actually consists of two genomes: - complex nuclear genome - simple mitochondrial genome

  3. NUCLEAR - 24 linear dsDNA molecules - 3200Mb - ~25 000 genes - 1.5% coding - most genes contain introns - 95% non-conserved - Mendelian inheritance (autosomes) MITOCHONDRIAL - 1 circular dsDNA - 16.6Kb - 37 genes - ~93% coding - no introns - ~2% non-conserved - Maternal inheritance The Two Genomes

  4. The Human Nuclear Genome • 1.5% coding (highly conserved) • 3% other highly conserved (e.g. enhancers, silencers) • ~45% transposon-based repeats • ~6.6% heterochromatin • ~44% other non-conserved (e.g. introns)

  5. The Human Genome Project • Plan to sequence human genome in 15 years launched in 1990 • IHGSC- >2 000 scientists in 20 institutes in 6 countries • Also, Celera – private company • Each project used slightly different technique based on shotgun sequencing • Draft sequences published in 2001 • ‘Finished’ sequence published 2004

  6. The Human Genome Project • Anonymous donor provided samples • Hierarchical or whole genome shotgun sequencing performed • Data analysed by sophisticated software packages (PHRED & PHRAP) • 1 000 nucleotides per second continuous throughput • Draft sequence assembled • Accuracy of 99.999% • Fill in gaps • Analyse & interpret data

  7. Hierarchical Shotgun Sequencing

  8. Whole-Genome Shotgun Sequencing

  9. Advantages & Disadvantages • Human genome >50% repeat sequences – complicates the correct assembly of the finished sequence • Hierarchical SS higher initial cost owing for need to create a map of clones • Whole-genome SS lower initial cost but greater expense in final stages resolving misassemblies • W-G – sequence derived from two different copies of genome – sequence assembly could be complicated by SNP’s & larger scale structural heterozygosity. H – each large insert clone derived from a single haplotype.

  10. Major Findings of HGP • Fewer genes than expected (draft sequence predictions – IHGSC- 30-40 000 Celera- 26-38 000) • Final sequence prediction IHGSC- 20-25 000 • 90% of genes encode polypeptides • 10% of genes are RNA genes (rRNA, tRNA, snRNA, snoRNA) • Great deal of alternative splicing >50% genes produce >1 mRNA • Gene distribution – GC rich densely packed with genes with small introns, GC poor few genes with large introns • Gene birth – retrotransposition, tandem duplication, segmental duplications • Horizontal gene transfer – >200 proteins with homologous to bacterial proteins

  11. Major Findings of HGP • Non-coding DNA – 98% • ~50% is interspersed repetitive DNA: - SINEs – 13% - LINEs – 20% • LTR retrotransposons – 8% • DNA transposons – 3% • Other repetitive element – processed pseudogenes, simple sequence repeats, segmental duplications, tandemly repeated sequence blocks (telomeres & centromeres)

  12. Medical & Biological Applications • >30 disease genes mapped inc. BRCA2 • Mechanism behind chromosomal deletion syndromes e.g. DiGeorge syndrome elucidated • Expansion of the search for suitable drug targets • Discovery of new family of proteins expressed almost exclusively in saliva glands responsible for ability to detect bitter taste.

  13. The X Chromosome

  14. The X Chromosome • 155Mb in length • Gene-poor, highly enriched in interspersed repeats, with a low G+C content (39%) compared with genome average (41%) • 1 098 genes (699 known, 132 novel coding sequences, 166 novel transcripts, 101 putative transcripts) • 700 pseudogenes

  15. The X Chromosome • Gene length is shorter (mean 49kb compared to 57kb on chr 13) • Contains largest known gene, dystrophin – Xp21.2 - 2.2Mb • CpG island frequency 5.25 per Mb consistent with low gene frequency • 173 non-coding RNA genes or pseudogenes (inc. XIST) • 2 transfer RNA genes • 13 microRNAs

  16. MAGE genes • MAGE gene products are members of cancer-testis antigen group • After assessment of the predicted proteome, most significant finding – MAGE domain in 32 genes • Only 4 other MAGE genes reported in genome • Characterised by their expression in a number of cancers • Normally expressed solely or predominantly in the testis • Potential targets for tumour immunotherapy

  17. Repetitive Sequences • 56% of euchromatic X chromosome sequence (genome average – 45%) • Alu family of SINEs below average (gene poor) • LTR transposons > average • LINEs L1 family >>average (X-29% genome ave 17%) involved in XCI ‘way station’ hypothesis • Based on their distribution other interspersed repeats are not strong candidates for ‘way stations’

  18. Evolution of the human X chromosome • Ohno proposed in 1967 that mammalian sex chromosomes evolved from an autosome pair • Autosomal origin is illustrated by alignment of the human X and chicken whole sequences • 30 regions of homology between human Xq and the end of chicken 4p • Most of human Xp (inc PAR1) matches a single block of chicken 1q

  19. XAR ( X-added region) – matches single block of chicken chromosome 1q • XCR (X-conserved region) – matches single section of chicken 4p • Xcen-p11.3 no clear picture of origin

  20. Medical Genetics & the X chromosome • Disproportionate number of disease conditions are associated with the X chromosome (4% of genes & 10 % of mendelian diseases) • Due to phenotypic consequence of a recessive mutation in males (if no Y counterpart) • Molecular basis of 168 X-linked phenotypes has been determined ( X sequencing has aided this process for 43) • 16 genes associated with non-syndromic X-linked mental retardation.

  21. The Next Steps:Genetic Variation Mapping • 2005 – HapMap project published - public database of common variation in the human genome: more than one million SNPs for which accurate and complete genotypes have been obtained in 269 DNA samples from four populations • 2006 – Copy number variant map from the same individuals used in HapMap project

  22. The Next Steps • To develop a definitive catalogue of protein coding genes (the proteome) using comparative genomics to align the human genome with the genomes of other animals • To sequence the remaining 20% of the genome which lies within heterochromatin, the gene-poor highly repetitive sequence – requires new technology to tackle this region

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