IntroductionWhy is human genetics important?

The family historyThe 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

~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

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

Normal female

Normal male

Single bar indicates mating

Normal parents and normal offspring

Single parent means partner is not significant for the analysis

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

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 ProteinModificationTransport / ReleaseComplex formation

Function

rRNAtRNAmiRNA

ChangeChangeIn the GeneIn the Gene

TranscriptionTranscriptionProfileProfile

ChangeChangeIn the ProteinIn the Protein

ProfileProfile

ChangesChangesIn theIn the

EnvironmentEnvironment

AABB

CC

CommonCommonDNADNA

VariantsVariantsXXYY

ZZ

CommonCommonDNADNA

VariantsVariants

Function

TACCACGTGGACTGAGGACCCCTCTTCAGACGG

TACCACGTGGACTGAGGACTCCTCTTCAGACGG

Single Nucleotide Polymorphism (SNP)

NCBI Human Genome SequenceComponents

Human DNA sequence

Human Transcriptome (mRNA)

Variation

A usable database

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.

Lander E, et al. Nature 409:860, 2001

Human Genome Project: Approach

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

The ENCODE (ENCyclopedia Of DNA Elements) Project

Science 2004, 306:636 - 640

What is a gene, post-ENCODE?

Genome Research 17:669, 2007

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)

Glucuronic acid

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

How does normal variation cause disease?

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.

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

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

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.

Short IRF5 Transcripts are More Stable

Normal DNA variation can result in:

Altered proteins with altered function

Altered gene expression

Altered mRNA stability

Altered mRNA splicing

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/

Normal Disease

What is our concept of disease?