introduction why is human genetics important? the family history the human genome project on the web...
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IntroductionWhy is human genetics important?
The family historyThe human genome project
On the webThe human genomeNCBIOther web sites
Outline
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“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 InstituteNIH
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~20%
ClassicMedical Genetics
Single geneChromosome
Early onset(usually pediatric)
Marfan SyndromePKU
Cystic FibrosisNeurofibromatosis
Down syndrome
Genetic Disease
Genetic Variation
~80%
Genetic Susceptibility
Common Gene VariationGene + Environment
Delayed onset(usually adult)
Coronary Heart DiseaseHypertension
DiabetesCancer
Vascular Disease
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The Family History is a powerful toolfor estimating genetic risk
Obtain information on children, sibs, and parentsAge/date of birth
Health statusAge at death
Cause of death
This is the ‘nuclear’ family
Expand as necessary to grandparents, uncles & aunts, etc.
The Family History
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Normal female
Normal male
Single bar indicates mating
Normal parents and normal offspring
Single parent means partner is not significant for the analysis
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Double bar indicates consanguineous mating
Fraternal twins (not identical)
Identical twins
Number of children
Affected
Heterozygote
Female X-linked carrier
Dead Aborted or stillborn
62
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2 3
I
II
III
IV
2
1 2
1 2 3 4 5 6
1 2 3 4 5 6
1 2 3 4 5 6
Founders
ProbandIV - 2V
1 2
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DNA RNA ProteinModificationTransport / ReleaseComplex formation
Function
rRNAtRNAmiRNA
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ChangeChangeIn the GeneIn the Gene
TranscriptionTranscriptionProfileProfile
ChangeChangeIn the ProteinIn the Protein
ProfileProfile
ChangesChangesIn theIn the
EnvironmentEnvironment
AABB
CC
CommonCommonDNADNA
VariantsVariantsXXYY
ZZ
CommonCommonDNADNA
VariantsVariants
Function
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TACCACGTGGACTGAGGACCCCTCTTCAGACGG
TACCACGTGGACTGAGGACTCCTCTTCAGACGG
Single Nucleotide Polymorphism (SNP)
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NCBI Human Genome SequenceComponents
Human DNA sequence
Human Transcriptome (mRNA)
Variation
A usable database
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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 genomeand can locate genes and variants quickly.
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Lander E, et al. Nature 409:860, 2001
Human Genome Project: Approach
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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 TCTTCTAGGC25,790,661 ATTGGCACAT CTCCACTTAA TAGAATATGT TGGAGAACAA ACTGCTTTGC 25,790,611 TAATAAAGGT AAAATAAATG CTATAATAGA AGGCACTCCA GCCACTGTTC25,790,561 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
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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 TAATAAAGGT AAAATAAATG 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 TCCTCCTTCC AGATGGTCCC AGAGGAGCAG CGCCTCATAG CCGCCATTGT Exon 21 25,789,961 CCTGGTGGTG TGGGTCTCAG CCCTGGCGTC GTCCCTGATT GACAACATCC 25,789,911 CGTTCACTGC TACCATGGTG AGTTGCACAT 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
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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 TAATAAAGGT AAAATAAATG 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 TCCTCCTTCC AGATGGTCCC AGAGGAGCAG CGCCTCATAG CCGCCATTGT Exon 21 rs1800417 25,789,961 CCTGGTGGTG TGGGTCTCAG CCCTGGCGTC GTCCCTGATT GACAACATCC rs1800418 25,789,911 CGTTCACTGC TACCATGGTG AGTTGCACAT GTCCATGTCG ACGGCTCAAC Intron 21 rs7175046 25,789,861 TTTAGCCTGG ACATAGCCTG GGGCTCACCC TCCCTTCCTA AGGCAGCAGA 25,789,811 GGATGAAGCC TGCCCCTCTG CTGCACTCAC AGGTGTAGAG GACGAAAGTG rs12594397 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
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The ENCODE (ENCyclopedia Of DNA Elements) Project
Science 2004, 306:636 - 640
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What is a gene, post-ENCODE?
Genome Research 17:669, 2007
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1A8
1A9
1A7
1A6
1A5
1A4
1A3
1A10
1A1
23,435 kb 23,440 kb23,430 kb 23,445 kb
Splice variants for UDP glucuronosyltransferase 1 family (UGT1A)
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Glucuronic acid
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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 PCBsliver, 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, Raloxifeneorolaryngeal tissue, stomach
Nagar and Remmel, UGT phramacogenetics, Oncogene (2006) 25, 1659–1672
Gene Where expressed Substrates
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How does normal variation cause disease?
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Action of polymorphisms:
Down/up regulate expressionDirectly affect protein function (amino acid substitution)Alter mRNA processing/stabilityGenetic disequilibrium with an unknown functional SNP
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N5,10-methyl-THF
Methylenetetrahydrofolate reductase
5,10
Homocysteine is a toxic intermediate product of protein catabolism. It is removed by either the remethylation to methionine or transulfuration to cysteine.
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rs1801133C to T substitution at nucleotide 677Alanine 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
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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.
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5,10 Methylenetetrahydropholate reductase677C>T – rs1801133
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Yan H et al. Science 297:1143, 2002
Allelic Variation in Human Gene Expression Yan H., et al, Science 297:1143, 2002
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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.
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Short IRF5 Transcripts are More Stable
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Normal DNA variation can result in:
Altered proteins with altered function
Altered gene expression
Altered mRNA stability
Altered mRNA splicing
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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 changein 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.
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The Human Genome Project and BeyondThe Human Genome Project and Beyond
All Human Genes Identified
Function &Expression
Major VariationMutations
Minor VariationPolymorphisms
Disease SusceptibilityTherapeutic Development and Response
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http://www.ncbi.nlm.nih.gov/
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What does NCBI do?
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.
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All DatabasesNCBI Web Site-------------PubMedProteinNucleotideStructureGenomeBooksCancerChromosomesConserved Domains3D DomainsGeneGenome ProjectGENSATGEO ProfilesGEO DatasetsHomoloGeneJournalsLocusLinkMeSHOMIAOMIMPMCPopSetProbePubChem BioAssayPubChem CompoundPugChem SubstanceSNPTaxonomyUniGeneUniSTS
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Important databases in NCBI
All Databases Everything
PubMed On-line catalogue of published papersAbstracts.pdf files
OMIM Information on genetic diseases
SNP Common variants
Gene Information on genesMap Viewer
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http://www.ncbi.nlm.nih.gov/
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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. HollandSuffolk
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OMIM
On-line Mendelian Inheritance in Man
Victor A. McKusick, M.D.Genetic Nosology: A systematic arrangement, or classification, of diseases
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GeneCards™ is a database of human genes, their products and their involvement in diseases. It offers concise information about the functions of all human genes that have an approved symbol, as well as selected others.
http://www-bimas.cit.nih.gov/cards//index.shtml
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http://snpper.chip.org/
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GeneTests http://www.genetests.org/
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Normal Disease
What is our concept of disease?