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  1. 1. Human Genetics Weibin Shi Michele Sale
  2. 2. Contact Information <ul><li>Shi: [email_address] ; 243-9420 </li></ul><ul><li>Sale: [email_address] ; 982-0368 </li></ul>
  3. 3. Recommended textbooks <ul><li>Medical Genetics </li></ul><ul><li>-Jorde, Carey, Bamshad & White </li></ul><ul><ul><ul><li>Mosby, ISBN 13: 978-0-323-04035-8 </li></ul></ul></ul><ul><li>Human Molecular Genetics </li></ul><ul><li>- Strachan T, Read A </li></ul><ul><li>Garland Science,ISBN-10: 0815341822 </li></ul>
  4. 4. Overview of course content <ul><li>1: Organization of the human genome </li></ul><ul><li>2: Genetic variation </li></ul><ul><li>3. Patterns of inheritance </li></ul><ul><li>4: Population genetics </li></ul><ul><li>5: linkage disequilibrium </li></ul><ul><li>6: Genetic epidemiology </li></ul><ul><li>7: Applied research in human genetics </li></ul>
  5. 5. Organization of the human genome
  6. 6. Human genome sequence published - February 2001
  7. 7. Genes are found in the nucleus and mitochondria
  8. 8. Nuclear genome packaged with proteins to form chromatin
  9. 9. Human chromosomes 23 pairs 46 chromosomes 22 pairs – autosomes 1 pair sex chromosomes 46,XY Normal male
  10. 10. Human chromosomes 46,XX Normal female
  11. 11. A little more basic terminology
  12. 12. Human genome = nuclear genome + mitochondrial genome
  13. 13. NUCLEAR GENOME 24 distinct chromosomes (22 autosomal + X + Y) 3,200 Mbp 25,000 genes Mitochondrial genome 16,569 bp 37 genes
  14. 14. <ul><ul><li>Small (16.5 kb) circular DNA </li></ul></ul><ul><ul><li>rRNA, tRNA and protein encoding genes (37) </li></ul></ul><ul><ul><li>1 gene/0.45 kb </li></ul></ul><ul><ul><li>Very few repeats </li></ul></ul><ul><ul><li>No introns </li></ul></ul><ul><ul><li>93% coding </li></ul></ul><ul><ul><li>Genes are transcribed as multimeric transcripts </li></ul></ul><ul><ul><li>Maternal inheritance </li></ul></ul>Human Mitochondrial Genome
  15. 15. <ul><li>24 of 37genes are RNA coding </li></ul><ul><ul><li>22 tRNA </li></ul></ul><ul><ul><li>2 ribosomal RNA (23S, 16S) </li></ul></ul><ul><li>13 of 37 genes are protein coding </li></ul><ul><li>some subunits of respiratory complexes </li></ul><ul><li>and oxidative phosphorylation enzymes </li></ul>What are the mitochondrial genes?
  16. 16. mt encoded nuclear NADH dehydrogenase 7 subunits 35 subunits Cytochrome b-c1 comp 1 subunit 10 subunits Cytochrome C oxidase 3 subunits 10 subunits ATP synthase complex 2 subunits 14 subunits Limited autonomy of mitochondrial genome
  17. 17. Two independent ATG located in Frame-shift to each other, second stop codon is derived from TA + A (from poly-A) Two overlapping genes encoded by same strand of mt DNA (unique example)
  18. 18. Mitochondrial codon table
  19. 19. 3,200 Mb 23 (XX) or 24 (XY) linear chromosomes 25,000 genes 1 gene/120kb Introns in the most of the genes 1.5 % of DNA is coding Genes are transcribed individually Repetitive DNA sequences (45%) Inherited from both parents Human Nuclear Genome
  20. 20. Human Nuclear Genome In human nuclear genome gene-rich regions are separated by gene deserts Chr. 19 has the highest gene density Chr. 13 & Y show the lowest gene density
  21. 21. Human genome base content <ul><li>41% CG in average </li></ul><ul><li>38% CG for Chr. 4 and Chr. 13 </li></ul><ul><li>49% for Chr. 19 </li></ul><ul><li>Regions with wide swings in CG content </li></ul><ul><li>(e.g. from 33.1% to 59.3%) </li></ul><ul><li>Gene density correlates with higher CG content </li></ul>
  22. 22. CpG dinucleotide depletion <ul><li>Expected frequency is 4.2% </li></ul><ul><li>Observed frequency is five times lower </li></ul>
  23. 23. Location of CpG islands in the gene CpG islands in the regulatory areas of human genes
  24. 24. Human nuclear genome <ul><li>Gene density varies widely </li></ul><ul><li>Averagely 9 exons per gene </li></ul><ul><li>363 exons in titin gene </li></ul><ul><li>Certain genes are intronsless </li></ul><ul><li>Largest intron is 800 kb (WWOX gene) </li></ul><ul><li>Smallest introns – 10 bp </li></ul><ul><li>Average 5’ UTR 0.2-0.3 kb </li></ul><ul><li>Average 3’ UTR 0.77 kb </li></ul><ul><li>Largest protein: titin: 38,138 aa </li></ul>
  25. 25. Gene density varies substantially between chromosomal regions
  26. 26. Genes vary in size and exon content
  27. 27. INTRONLESS GENES <ul><li>Interferon genes </li></ul><ul><li>Histone genes </li></ul><ul><li>Many ribonuclease genes </li></ul><ul><li>Heat shock protein genes </li></ul><ul><li>Many G-protein coupled receptors </li></ul><ul><li>Various neurotransmitters receptors and hormone receptors </li></ul>
  28. 28. Genes within genes
  29. 29. Classical gene families: members exhibit a high degree of sequence similarity alpha-albumin serum albumin vitamin D-binding protein four placenta-specific genes, primates only CS = chorionic somatomammotropin
  30. 30. Gene families: gene products bearing short conservative amino acid motifs DEAD box proteins are involved in mRNA splicing and translation initiation; DEAD box (Asp-Glu-Ala-Asp) WD proteins take part in a variety of regulatory functions, GH (Gly-His) should be at 23-41 aa distance from WD (Trp-Aps)
  31. 31. Gene superfamily: Proteins that are functionally related in a general sense, but show only weak homology
  32. 32. Functionally similar genes are occasionally clustered, but usually dispersed throughout the genome
  33. 33. Non-coding RNA genes <ul><li>Code for functional RNA </li></ul><ul><li>ncRNA represent 98% of all transcripts in a mammalian cell </li></ul><ul><li>ncRNA can be: </li></ul><ul><ul><li>Structural </li></ul></ul><ul><ul><li>Catalytic </li></ul></ul><ul><ul><li>Regulatory </li></ul></ul>
  34. 34. How many genes in the nuclear genome? ~3000 RNA genes in the nuclear genome ~10% of human gene count have not been taken into account in gene counts
  35. 35. Non-coding RNA <ul><li>tRNA – transfer RNA: involved in translation </li></ul><ul><li>rRNA – ribosomal RNA: structural component of ribosome, where translation takes place </li></ul><ul><li>snoRNA – small nucleolar RNA: functional/catalytic in rRNA maturation </li></ul><ul><li>Antisense RNA: gene regulation/silencing </li></ul>
  36. 36. microRNA <ul><li>A new class of non-coding RNA gene </li></ul><ul><li>Products are 19~25 nt RNAs </li></ul><ul><li>Precursors are 70-100 nt. </li></ul><ul><li>Block translation or result in degradation of target mRNA </li></ul>
  37. 38. Tandem repeats and interspersed repeats
  38. 39. Satellite DNA is repetitive DNA that could be separated by centrifugation Equilibrium density gradient centrifugation Sheared DNA in Cesium Chloride gradient
  39. 40. Satellite DNA Alpha –satellite (Centromere DNA) Microsatellite Minisatellite
  40. 41. Microsatellite di-, tri-, and tetra-nucleotide repeats ~10% of the nuclear genome TGC T C A T C A T C A T C A GC TGC T C A T C A ------GC TGC C A C A C A C A C A C A C A C A GC TGC C A C A C A C A C A ------GC TGC T C AG T C AG T C AG T C AG GC TGC T C AG T C AG --------GC
  41. 43. Minisatellites 1 tgattggtct ctctgccacc gggagatttc cttatttgga ggtgatggag gatttc agga 61 attttttagg aattttttta atggattacg ggattttagg gttctaggat tttaggatta 121 tggtatttta ggatttactt gattttggga ttttaggatt gagggatttt agggtttcag 181 gatttcggga tttcaggatt ttaagttttc ttgattttat gattttaaga ttttaggatt 241 tacttgattt tgggatttta ggattacggg attttagggt ttcaggattt cgggatttca 301 ggattttaag ttttcttgat tttatgattt taagatttta ggatttactt gattttggga 361 ttttaggatt acgggatttt agggtgctca ctatttatag aactttcatg gtttaacata 421 ctgaatataa atgctctgct gctctcgctg atgtcattgt tctcataata cgttcctttg Repeat: AGGAATTTTT <ul><li>6-64 bp repeating pattern </li></ul>
  42. 44. α -Satellite repeat <ul><li>171 bp sequence repeat </li></ul>
  43. 45. Interspersed repetitive DNA <ul><li>SINE (Short interspersed nuclear elements): </li></ul><ul><ul><li>Alu, ~0.3 kb, ~10,7% of human DNA (1,200, 000 copies) </li></ul></ul><ul><ul><li>MIR, ~0.13 kb, 3% of human DNA (500,000 copies) </li></ul></ul><ul><li>LINE (Long interspersed nuclear elements): </li></ul><ul><ul><li>~0.8 kb, ~21% of human DNA (~1,00,000 copies) </li></ul></ul>
  44. 46. Chromosomal location of repeats
  45. 47. <ul><li>Non-functional copy of a gene </li></ul><ul><ul><li>Non-processed pseudogene </li></ul></ul><ul><ul><ul><li>Nonfunctional copies of the genomic DNA sequence of a gene </li></ul></ul></ul><ul><ul><ul><li>Contain exons, intron, and flanking sequences </li></ul></ul></ul><ul><ul><li>Processed pseudogene </li></ul></ul><ul><ul><ul><li>Nonfunctional copies of the exonic sequences of a gene </li></ul></ul></ul><ul><ul><ul><li>Reverse-transcribed from an RNA transcript </li></ul></ul></ul><ul><ul><ul><li>No 5’ promoter </li></ul></ul></ul><ul><ul><ul><li>No introns </li></ul></ul></ul><ul><ul><ul><li>Often includes polyA tail </li></ul></ul></ul><ul><ul><li>Both include events that make the gene non-functional </li></ul></ul><ul><ul><ul><li>Frameshift </li></ul></ul></ul><ul><ul><ul><li>Stop codons </li></ul></ul></ul><ul><li>Could be as high as 20-30% of all Genomic sequence predictions could be pseudogene </li></ul><ul><li>We assume pseudogenes have no function, but we really don’t know! </li></ul>Pseudogenes
  46. 48. Human Genome Organization HUMAN GENOME Genes and gene- related sequences Extragenic DNA Nuclear genome 3,200 Mb 25,000 genes Mitochondrial genome 16.5 kb 37 genes Coding DNA Noncoding DNA Unique or low copy number Moderate to highly repetitive Pseudogenes Gene fragments Introns, untranslated sequences, etc. Tandemly repeated Interspersed repeats Unique or moderately repetitive Two rRNA genes 22 tRNA genes 13 polypeptide- encoding genes
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