Introduction Why is human genetics important? The family history The human genome project On the web The human geno

1. Outline Introduction Why is human genetics important? The family history The human genome project On the web The human genome NCBI Other web sites

2. “Everyone carries anywhere from five to fifty significant genetic flaws, and that virtually all diseases - even AIDS - have a genetic component” Francis Collins Director of the National Human Genome Research Institute NIH

3. Genetic Susceptibility ~80% Common Gene Variation Gene + Environment Delayed onset (usually adult) Coronary Heart Disease Hypertension Diabetes Cancer Vascular Disease Genetic Variation Genetic Disease Classic Medical Genetics ~20% Single gene Chromosome Early onset (usually pediatric) Marfan Syndrome PKU Cystic Fibrosis Neurofibromatosis Down syndrome

4. The Family History The Family History is a powerful tool for estimating genetic risk Obtain information on children, sibs, and parents Age/date of birth Health status Age at death Cause of death This is the ‘nuclear’ family Expand as necessary to grandparents, uncles & aunts, etc.

5. Normal female Normal male Single bar indicates mating Normal parents and normal offspring Single parent means partner is not significant for the analysis

6. Double bar indicates consanguineous mating Fraternal twins (not identical) Identical twins Number of children Affected Heterozygote Female X-linked carrier Dead Aborted or stillborn 2 6

7. Founders I 1 2 II 3 2 1 2 3 4 5 6 III 2 1 2 3 4 5 6 IV 1 2 3 4 5 6 Proband IV - 2 V 1 2

8. rRNA tRNA miRNA Modification Transport / Release Complex formation DNA RNA Protein Function

9. Common DNA Variants Common DNA Variants X A Y B C Z Changes In the Environment Change In the Gene Transcription Profile Change In the Protein Profile Function

10. Single Nucleotide Polymorphism (SNP) TACCACGTGGACTGAGGACCCCTCTTCAGACGG TACCACGTGGACTGAGGACTCCTCTTCAGACGG

11. NCBI Human Genome Sequence Components Human DNA sequence Human Transcriptome (mRNA) Variation A usable database

12. Human Genome Size: 2900- 3200 Mb (megabases = million bp) ~ 3 X 109 bp Genes: 25,000- 30,000 (exact number not known) Other: Most of DNA sequence is non-coding (Exons contain only <1.5% of DNA) Gene distribution uneven Non-coding regions may be important Why should we be excited about the human genome? We know the entire sequence of the genome and can locate genes and variants quickly.

13. Human Genome Project: Approach Lander E, et al. Nature 409:860, 2001

14. 25,790,861 TTTTTCTCCA TGAATCTTCG TTGTGCATAT ATGATAGTAA ATTATTTATA 25,790,811 GACTGTGTAT TTGAGTCTGA TCTTTTATAA GAAGCAGGAA TCTGGGCCTA 25,790,761 CCTTATGTTC ACGTCTTTTC ATTTTCAAGA CTTTTTTTTT AAATCTTGCA 25,790,711 TATATTTTCG GTTCTAAACT GATTCTCACC ACACATCCTT TCTTCTAGGC 25,790,661 ATTGGCACAT CTCCACTTAA TAGAATATGT TGGAGAACAA ACTGCTTTGC 25,790,611 TAATAAAGGT AAAATAAATG CTATAATAGA AGGCACTCCA GCCACTGTTC 25,790,561 TTTGATTTTG TGAAAAAAAT TAAAAAAAAA AAGCACTCTG GTAAGAACAG 25,790,511 GTCCCATTAA TTATGTAAAA AGGCACAGCA GGGAACCTGT TCTATCCTGT 25,790,461 GCAGCCCAGA GATGAAGGGA GACTTTTTCC GAAGAATATG TAATTACAGA 25,790,411 TGCCTGCTCT TTTGCTTTTA GCCTTTATTT AAAGCCTGTC TGAGAAGGAG 25,790,361 TGGGATTGAC ACCAGCCTCA GTAAATGAGT GCTGCAGGCG CCCCAGCCCC 25,790,311 AGGGGTCTGC CGGGCCATCA GGTCAATGTG ACCAGTGTGC GCAGCCACCA 25,790,261 CATGGGGATG AGGGGCAGGG TCACTCTGCC TCCCCATCCA GGGGGCTGGC 25,790,211 AGGTCTGGGC ATGGCTGGGC TTTGCTGGTA GAAACCCAGC AGAGGCTCCT 25,790,161 GGTGTGGGTG TGGCCCTGGC TTGCACACCT ATGTCTGCCT TGGTCTCGTG 25,790,111 ATGGGTAAGA GGAAGGACTA ACACCCTCGG GCCCCTCTGA GTCTCGCGGC 25,790,061 TGGTGGGTCT GACCCTAAGT GCATGCGATG GAACACTGCA GCTGCTATTG 25,790,011 TCCTCCTTCC AGATGGTCCC AGAGGAGCAG CGCCTCATAG CCGCCATTGT 25,789,961 CCTGGTGGTG TGGGTCTCAG CCCTGGCGTC GTCCCTGATT GACAACATCC 25,789,911 CGTTCACTGC TACCATGGTG AGTTGCACAT GTCCATGTCG ACGGCTCAAC 25,789,861 TTTAGCCTGG ACATAGCCTG GGGCTCACCC TCCCTTCCTA AGGCAGCAGA 25,789,811 GGATGAAGCC TGCCCCTCTG CTGCACTCAC AGGTGTAGAG GACGAAAGTG 25,789,761 AGCAGAGCCC AGGGCAGCTG GGTGGGGAGT GCCGAGAGCC CAGACTGCAG 25,789,711 GCTGGGAGCC GAGGCTCTGC AGCTGCCGTG GACAGCACGT CCTGGGGTGA 25,789,661 CTGGTGATCT CGAGGTCAGC CCCACTGAGA GCTGCCACCC CTCCCAGAAA 25,789,611 AGGCTGTGCT TGCTTGCTTG CTTTCTCTCT TTCTTTCTCT TTCTTTCTTT 25,789,561 CTCTCTCTCT TTCTTTCTTT CTTTCTTTCT TTTTCTTTCT TTCTTTCTTT 25,789,511 CCTTTCTGTC TTTCCTTCCC TCCCTCCCTC CCTCCCTTCC TTCCTTCTTT 25,789,461 CCTTCCTTCC TTCCTTCCTT CTTTCCTTCC TTCCTTCTTT CCTTCCTTCC

15. 25,790,861 TTTTTCTCCA TGAATCTTCG TTGTGCATAT ATGATAGTAA ATTATTTATA 25,790,811 GACTGTGTAT TTGAGTCTGA TCTTTTATAA GAAGCAGGAA TCTGGGCCTA 25,790,761 CCTTATGTTC ACGTCTTTTC ATTTTCAAGA CTTTTTTTTT AAATCTTGCA 25,790,711 TATATTTTCG GTTCTAAACT GATTCTCACC ACACATCCTT TCTTCTAGGC Exon 20 25,790,661 ATTGGCACAT CTCCACTTAA TAGAATATGT TGGAGAACAA ACTGCTTTGC 25,790,611 TAATAAAGGTAAAATAAATG CTATAATAGA AGGCACTCCA GCCACTGTTC Intron 20 25,790,561 TTTGATTTTG TGAAAAAAAT TAAAAAAAAA AAGCACTCTG GTAAGAACAG 25,790,511 GTCCCATTAA TTATGTAAAA AGGCACAGCA GGGAACCTGT TCTATCCTGT 25,790,461 GCAGCCCAGA GATGAAGGGA GACTTTTTCC GAAGAATATG TAATTACAGA 25,790,411 TGCCTGCTCT TTTGCTTTTA GCCTTTATTT AAAGCCTGTC TGAGAAGGAG 25,790,361 TGGGATTGAC ACCAGCCTCA GTAAATGAGT GCTGCAGGCG CCCCAGCCCC 25,790,311 AGGGGTCTGC CGGGCCATCA GGTCAATGTG ACCAGTGTGC GCAGCCACCA 25,790,261 CATGGGGATG AGGGGCAGGG TCACTCTGCC TCCCCATCCA GGGGGCTGGC 25,790,211 AGGTCTGGGC ATGGCTGGGC TTTGCTGGTA GAAACCCAGC AGAGGCTCCT 25,790,161 GGTGTGGGTG TGGCCCTGGC TTGCACACCT ATGTCTGCCT TGGTCTCGTG 25,790,111 ATGGGTAAGA GGAAGGACTA ACACCCTCGG GCCCCTCTGA GTCTCGCGGC 25,790,061 TGGTGGGTCT GACCCTAAGT GCATGCGATG GAACACTGCA GCTGCTATTG 25,790,011 TCCTCCTTCCAGATGGTCCC AGAGGAGCAG CGCCTCATAG CCGCCATTGT Exon 21 25,789,961 CCTGGTGGTG TGGGTCTCAG CCCTGGCGTC GTCCCTGATT GACAACATCC 25,789,911 CGTTCACTGC TACCATGGTGAGTTGCACAT GTCCATGTCG ACGGCTCAAC Intron 21 25,789,861 TTTAGCCTGG ACATAGCCTG GGGCTCACCC TCCCTTCCTA AGGCAGCAGA 25,789,811 GGATGAAGCC TGCCCCTCTG CTGCACTCAC AGGTGTAGAG GACGAAAGTG 25,789,761 AGCAGAGCCC AGGGCAGCTG GGTGGGGAGT GCCGAGAGCC CAGACTGCAG 25,789,711 GCTGGGAGCC GAGGCTCTGC AGCTGCCGTG GACAGCACGT CCTGGGGTGA 25,789,661 CTGGTGATCT CGAGGTCAGC CCCACTGAGA GCTGCCACCC CTCCCAGAAA 25,789,611 AGGCTGTGCT TGCTTGCTTG CTTTCTCTCT TTCTTTCTCT TTCTTTCTTT 25,789,561 CTCTCTCTCT TTCTTTCTTT CTTTCTTTCT TTTTCTTTCT TTCTTTCTTT 25,789,511 CCTTTCTGTC TTTCCTTCCC TCCCTCCCTC CCTCCCTTCC TTCCTTCTTT 25,789,461 CCTTCCTTCC TTCCTTCCTT CTTTCCTTCC TTCCTTCTTT CCTTCCTTCC

16. 25,790,861 TTTTTCTCCA TGAATCTTCG TTGTGCATAT ATGATAGTAA ATTATTTATA 25,790,811 GACTGTGTAT TTGAGTCTGA TCTTTTATAA GAAGCAGGAA TCTGGGCCTA 25,790,761 CCTTATGTTC ACGTCTTTTC ATTTTCAAGA CTTTTTTTTT AAATCTTGCA 25,790,711 TATATTTTCG GTTCTAAACT GATTCTCACC ACACATCCTT TCTTCTAGGC Exon 20 25,790,661 ATTGGCACAT CTCCACTTAA TAGAATATGT TGGAGAACAA ACTGCTTTGC 25,790,611 TAATAAAGGTAAAATAAATG CTATAATAGA AGGCACTCCA GCCACTGTTC Intron 20 25,790,561 TTTGATTTTG TGAAAAAAAT TAAAAAAAAA AAGCACTCTG GTAAGAACAG 25,790,511 GTCCCATTAA TTATGTAAAA AGGCACAGCA GGGAACCTGT TCTATCCTGT 25,790,461 GCAGCCCAGA GATGAAGGGA GACTTTTTCC GAAGAATATG TAATTACAGA 25,790,411 TGCCTGCTCT TTTGCTTTTA GCCTTTATTT AAAGCCTGTC TGAGAAGGAG 25,790,361 TGGGATTGAC ACCAGCCTCA GTAAATGAGT GCTGCAGGCG CCCCAGCCCC 25,790,311 AGGGGTCTGC CGGGCCATCA GGTCAATGTG ACCAGTGTGC GCAGCCACCA 25,790,261 CATGGGGATG AGGGGCAGGG TCACTCTGCC TCCCCATCCA GGGGGCTGGC 25,790,211 AGGTCTGGGC ATGGCTGGGC TTTGCTGGTA GAAACCCAGC AGAGGCTCCT 25,790,161 GGTGTGGGTG TGGCCCTGGC TTGCACACCT ATGTCTGCCT TGGTCTCGTG 25,790,111 ATGGGTAAGA GGAAGGACTA ACACCCTCGG GCCCCTCTGA GTCTCGCGGC 25,790,061 TGGTGGGTCT GACCCTAAGT GCATGCGATG GAACACTGCA GCTGCTATTG 25,790,011 TCCTCCTTCCAGATGGTCCC AGAGGAGCAG CGCCTCATAG CCGCCATTGT Exon 21 rs1800417 25,789,961 CCTGGTGGTG TGGGTCTCAG CCCTGGCGTC GTCCCTGATT GACAACATCC rs1800418 25,789,911 CGTTCACTGC TACCATGGTGAGTTGCACAT GTCCATGTCG ACGGCTCAAC Intron 21rs7175046 25,789,861 TTTAGCCTGG ACATAGCCTG GGGCTCACCC TCCCTTCCTA AGGCAGCAGA 25,789,811 GGATGAAGCC TGCCCCTCTG CTGCACTCAC AGGTGTAGAG GACGAAAGTGrs12594397 25,789,761 AGCAGAGCCC AGGGCAGCTG GGTGGGGAGT GCCGAGAGCC CAGACTGCAG 25,789,711 GCTGGGAGCC GAGGCTCTGC AGCTGCCGTG GACAGCACGT CCTGGGGTGA 25,789,661 CTGGTGATCT CGAGGTCAGC CCCACTGAGA GCTGCCACCC CTCCCAGAAA 25,789,611 AGGCTGTGCT TGCTTGCTTG CTTTCTCTCT TTCTTTCTCT TTCTTTCTTT 25,789,561 CTCTCTCTCT TTCTTTCTTT CTTTCTTTCT TTTTCTTTCT TTCTTTCTTT 25,789,511 CCTTTCTGTC TTTCCTTCCC TCCCTCCCTC CCTCCCTTCC TTCCTTCTTT 25,789,461 CCTTCCTTCC TTCCTTCCTT CTTTCCTTCC TTCCTTCTTT CCTTCCTTCC

20. The ENCODE (ENCyclopedia Of DNA Elements) Project Science 2004, 306:636 - 640

21. What is a gene, post-ENCODE? Genome Research 17:669, 2007

22. Splice variants for UDP glucuronosyltransferase 1 family (UGT1A) 23,430 kb 23,435 kb 23,440 kb 23,445 kb 1A8 1A10 1A9 1A7 1A6 1A5 1A4 1A3 1A1

23. Glucuronic acid

24. Gene Where expressed Substrates UGT1A1 Biliary tissue, colon, intestine, liver, stomach Etoposide UTG1A3 Biliary tissue, colon, liver, stomach Genistein UGT1A4 Biliary tissue, colon, intestine, liver Tamoxifen UGT1A6 Biliary tissue, brain, colon, kidney, larynx PCBs liver, lung, stomach UGT1A7 Esophagus, intestine, kidney, larynx heterocyclic amines UGT1A8 Colon, esophagus, intestine, kidney, larynx Benzo[a]phrene UGT1A9 Breast, colon, esophagus, liver, kidney, Nicotine (UGT1A4) ovary, prostate, skin, testis UGT1A10 Biliary tissue, colon, esophagus, intestine, Raloxifene orolaryngeal tissue, stomach Nagar and Remmel, UGT phramacogenetics, Oncogene (2006) 25, 1659–1672

25. How does normal variation cause disease?

26. Action of polymorphisms: Down/up regulate expression Directly affect protein function (amino acid substitution) Alter mRNA processing/stability Genetic disequilibrium with an unknown functional SNP

28. 5,10 N5,10-methyl-THF Methylenetetrahydrofolate reductase Homocysteine is a toxic intermediate product of protein catabolism. It is removed by either the remethylation to methionine or transulfuration to cysteine.

29. rs1801133 C to T substitution at nucleotide 677 Alanine to Valine substitution at codon 222 The altered protein (T allele) is thermolabile and is associated with reduced activity resulting in increased plasma homocysteine levels

30. TT genotypes had a diminished level of DNA methylation compared with those with the CC wildtype. The TT genotype is causally related to increased risk of coronary heart disease. The TT genotype is significantly more frequent in those with isolated cleft palate. Both hyperhomocysteinemia due to the 677T mutation and factor V Leiden are risk factors for recurrent venous thrombosis. They found that the risk of thrombosis appeared higher for individuals who had both risk factors. A positive association was found between aberrant methylation and the 677T allele. A second association of aberrant methylation was with homozygosity for the 2756G allele of methionine synthase.

31. 5,10 Methylenetetrahydropholate reductase 677C>T – rs1801133

32. Allelic Variation in Human Gene Expression Yan H., et al, Science 297:1143, 2002 Yan H et al. Science 297:1143, 2002

33. What does rs10954213 Do? Hypothesis: The G allele at rs10954213 results in production of long IRF5 transcripts that terminate using a downstream poly-A site. This may result in an alteration in mRNA stability.

34. Short IRF5 Transcripts are More Stable

35. Normal DNA variation can result in: Altered proteins with altered function Altered gene expression Altered mRNA stability Altered mRNA splicing

36. Genetics = Genetic Variation BIG VARIATION Mutation that causes a big change in gene function- Pathologic mutation Single Gene Abnormalities ‘Dominant’ ‘Recessive’ Chromosomal Disorders Trisomy, Deletion Not common – usually < 1/1000 SMALL VARIATION Mutation that causes a small-to-moderate change in gene function- polymorphic variation Diseases and conditions with genetic susceptibility Common ~1/2-1/100 NOTE: Both result from mutations. Called pathologic when the effect is big, and polymorphic variation when the effect is small.

37. The Human Genome Project and Beyond All Human Genes Identified Function & Expression Major Variation Mutations Minor Variation Polymorphisms Disease Susceptibility Therapeutic Development and Response

38. http://www.ncbi.nlm.nih.gov/

39. Established in 1988 as a national resource for molecular biology information, NCBI creates public databases, conducts research in computational biology, develops software tools for analyzing genome data, and disseminates biomedical information - all for the better understanding of molecular processes affecting human health and disease.

40. All Databases NCBI Web Site ------------- PubMed Protein Nucleotide Structure Genome Books CancerChromosomes Conserved Domains 3D Domains Gene Genome Project GENSAT GEO Profiles GEO Datasets HomoloGene Journals LocusLink MeSH OMIA OMIM PMC PopSet Probe PubChem BioAssay PubChem Compound PugChem Substance SNP Taxonomy UniGene UniSTS

41. Important databases in NCBI All Databases Everything PubMed On-line catalogue of published papers Abstracts .pdf files OMIM Information on genetic diseases SNP Common variants Gene Information on genes Map Viewer

42. http://www.ncbi.nlm.nih.gov/

48. British Dental Journal (2006); 200, 242. doi: 10.1038/sj.bdj.4813363 Teeth for grenades Sir, I congratulate Professor Gelbier on his series of articles on the development of dentistry in the past 125 years. However, I have to point out an error over the dates of the formation of the Armed Forces Dental Branches. The Royal Naval Dental Service was launched by Admiralty Order in Council on 22 January 1920, a year before the Army Dental Corps was authorised by Royal Warrant on 4 January 1921. The RAF Dental Service was inaugurated on 1 July 1930, although efforts to this end were started in 1925. Readers might wonder why front teeth were no longer required to fire breach-loading guns. In fact, a dental standard was introduced in 1678 for grenadiers requiring them to have sufficient front teeth to bite open the fuses of their grenades and in 1696 a similar one for musketeers to release the gunpowder in their cartridges. The removal of the front teeth of a man of military age became a punishable offence until 1856 when rim-fire and centre-fire cartridges were introduced. J. V. Holland Suffolk

49. OMIM On-line Mendelian Inheritance in Man Victor A. McKusick, M.D. Genetic Nosology: A systematic arrangement, or classification, of diseases