Introduction Why is human genetics important? The human genome project On the web The human genome NCBI Other web sites Outline
Jan 11, 2016
IntroductionWhy is human genetics important?The human genome project
On the webThe human genomeNCBIOther web sites
Outline
“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
At the present time, the Family History is the 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
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
DNA RNA Protein
DNA replicationRNA
transcription
RNA reverse transcription
ProteintranslationRNA editing
AlternativeRNA splicing
ModificationTransport / ReleaseComplex formation
DNA RNA ProteinModificationTransport / ReleaseComplex formation
Function
rRNAtRNAiRNA
ChangeChangeIn the GeneIn the Gene
TranscriptionTranscriptionProfileProfile
ChangeChangeIn the ProteinIn the Protein
ProfileProfile
ChangesChangesIn theIn the
EnvironmentEnvironment
AABB
CC
CommonCommonDNADNA
VariantsVariantsXXYY
ZZ
CommonCommonDNADNA
VariantsVariants
Function
~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
TACCACGTGGACTGAGGACCCCTCTTCAGACGG
TACCACGTGGACTGAGGACTCCTCTTCAGACGG
Single Nucleotide Polymorphism (SNP)
Human Genome DatabaseComponents
Human DNA sequence
Human Transcriptome (mRNA)
Variation
HUMAN GENOME
Size: 2900- 3200 Mb (megabases = million bp) ~ 3 X 109 bp
Genes: 35,000- 40,000 (exact number not known)
Other: Most of DNA 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.
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
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
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
1 2 3 4 5TATATACCAATTTGATAACA CATGTG
regulatoryelement
Gene Structure
Protein Structure
CuA CuB
NH3
EGFLS TMR
COOH
regulatoryelement
CATbox
TATAbox
Action of polymorphisms:
Down/up regulate expressionDirectly affect protein function (amino acid substitution)Alter mRNA processing/stabilityGenetic disequilibrium with an unknown functional SNP
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.
5,10 Methylenetetrahydropholate reductase
rs1801133C to T substitution at nucleotide 677Alanine to Valine substitution at codon 222
The altered protein is thermolabile and is associated with reduced activity resulting in increased plasma homocysteine levels
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.
5,10 Methylenetetrahydropholate reductase677C>T – rs1801133
Yan H et al. Science 297:1143, 2002
Allelic Variation in Human Gene Expression Yan H., et al, Science 297:1143, 2002
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.
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
http://www.ncbi.nlm.nih.gov/
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.
All DatabasesNCBI Web Site-------------PubMedProteinNucleotideStructureGenomeBooksCancerChromosomesConserved Domains3D DomainsGeneGenome ProjectGENSATGEO ProfilesGEO DatasetsHomoloGeneJournalsLocusLinkMeSHOMIAOMIMPMCPopSetProbePubChem BioAssayPubChem CompoundPugChem SubstanceSNPTaxonomyUniGeneUniSTS
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
http://www.ncbi.nlm.nih.gov/
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
OMIM
On-line Mendelian Inheritance in Man
Victor A. McKusick, M.D.Genetic Nosology: A systematic arrangement, or classification, of diseases
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
http://snpper.chip.org/
GeneTests http://www.genetests.org/
Other Databases:
The Genome Databasehttp://www.gdb.org
Variation Databases and Related Siteshttp://www.genomic.unimelb.edu.au/mdi/dblist/dblist.html
Two-Dimensional Gel Electrophoresis Databases - Lists http://www.lecb.ncifcrf.gov/EP/EPemail.html
Normal Disease
What is our concept of disease?
The Future: Major Issue
What is normal?
Normal Disease
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