Transcript Introduction - University of Minnesota

Outline
Introduction
Why is human genetics important?
The family history
The human genome project
On the web
The human genome
NCBI
Other web sites
“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
Genetic Variation
Genetic Disease
Genetic Susceptibility
Classic
Medical Genetics
~20%
~80%
Single gene
Chromosome
Common Gene Variation
Gene + Environment
Early onset
(usually pediatric)
Delayed onset
(usually adult)
Marfan Syndrome
PKU
Cystic Fibrosis
Neurofibromatosis
Down syndrome
Coronary Heart Disease
Hypertension
Diabetes
Cancer
Vascular Disease
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.
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
2
6
Number of children
Affected
Heterozygote
Female X-linked carrier
Dead
Aborted or stillborn
Founders
I
1
2
II
1
2
3
4
5
2
6
4
5
III
1
2
3
4
2
5
IV
V
1
Proband
IV - 2
2
1
3
2
6
3
6
rRNA
tRNA
miRNA
DNA
RNA
Protein
Modification
Transport / Release
Complex formation
Function
Changes
In the
Environment
Common
DNA
Variants
A
B
C
Common
DNA
Variants
Change
In the Gene
Transcription
Profile
Change
In the Protein
Profile
X
Y
Z
Function
Single Nucleotide Polymorphism (SNP)
TACCACGTGGACTGAGGACCCCTCTTCAGACGG
TACCACGTGGACTGAGGACTCCTCTTCAGACGG
NCBI Human Genome Sequence
Components
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 genome
and can locate genes and variants quickly.
Human Genome Project: Approach
Lander E, et al. Nature 409:860, 2001
25,790,861
25,790,811
25,790,761
25,790,711
25,790,661
25,790,611
25,790,561
25,790,511
25,790,461
25,790,411
25,790,361
25,790,311
25,790,261
25,790,211
25,790,161
25,790,111
25,790,061
25,790,011
25,789,961
25,789,911
25,789,861
25,789,811
25,789,761
25,789,711
25,789,661
25,789,611
25,789,561
25,789,511
25,789,461
TTTTTCTCCA
GACTGTGTAT
CCTTATGTTC
TATATTTTCG
ATTGGCACAT
TAATAAAGGT
TTTGATTTTG
GTCCCATTAA
GCAGCCCAGA
TGCCTGCTCT
TGGGATTGAC
AGGGGTCTGC
CATGGGGATG
AGGTCTGGGC
GGTGTGGGTG
ATGGGTAAGA
TGGTGGGTCT
TCCTCCTTCC
CCTGGTGGTG
CGTTCACTGC
TTTAGCCTGG
GGATGAAGCC
AGCAGAGCCC
GCTGGGAGCC
CTGGTGATCT
AGGCTGTGCT
CTCTCTCTCT
CCTTTCTGTC
CCTTCCTTCC
TGAATCTTCG
TTGAGTCTGA
ACGTCTTTTC
GTTCTAAACT
CTCCACTTAA
AAAATAAATG
TGAAAAAAAT
TTATGTAAAA
GATGAAGGGA
TTTGCTTTTA
ACCAGCCTCA
CGGGCCATCA
AGGGGCAGGG
ATGGCTGGGC
TGGCCCTGGC
GGAAGGACTA
GACCCTAAGT
AGATGGTCCC
TGGGTCTCAG
TACCATGGTG
ACATAGCCTG
TGCCCCTCTG
AGGGCAGCTG
GAGGCTCTGC
CGAGGTCAGC
TGCTTGCTTG
TTCTTTCTTT
TTTCCTTCCC
TTCCTTCCTT
TTGTGCATAT
TCTTTTATAA
ATTTTCAAGA
GATTCTCACC
TAGAATATGT
CTATAATAGA
TAAAAAAAAA
AGGCACAGCA
GACTTTTTCC
GCCTTTATTT
GTAAATGAGT
GGTCAATGTG
TCACTCTGCC
TTTGCTGGTA
TTGCACACCT
ACACCCTCGG
GCATGCGATG
AGAGGAGCAG
CCCTGGCGTC
AGTTGCACAT
GGGCTCACCC
CTGCACTCAC
GGTGGGGAGT
AGCTGCCGTG
CCCACTGAGA
CTTTCTCTCT
CTTTCTTTCT
TCCCTCCCTC
CTTTCCTTCC
ATGATAGTAA
GAAGCAGGAA
CTTTTTTTTT
ACACATCCTT
TGGAGAACAA
AGGCACTCCA
AAGCACTCTG
GGGAACCTGT
GAAGAATATG
AAAGCCTGTC
GCTGCAGGCG
ACCAGTGTGC
TCCCCATCCA
GAAACCCAGC
ATGTCTGCCT
GCCCCTCTGA
GAACACTGCA
CGCCTCATAG
GTCCCTGATT
GTCCATGTCG
TCCCTTCCTA
AGGTGTAGAG
GCCGAGAGCC
GACAGCACGT
GCTGCCACCC
TTCTTTCTCT
TTTTCTTTCT
CCTCCCTTCC
TTCCTTCTTT
ATTATTTATA
TCTGGGCCTA
AAATCTTGCA
TCTTCTAGGC
ACTGCTTTGC
GCCACTGTTC
GTAAGAACAG
TCTATCCTGT
TAATTACAGA
TGAGAAGGAG
CCCCAGCCCC
GCAGCCACCA
GGGGGCTGGC
AGAGGCTCCT
TGGTCTCGTG
GTCTCGCGGC
GCTGCTATTG
CCGCCATTGT
GACAACATCC
ACGGCTCAAC
AGGCAGCAGA
GACGAAAGTG
CAGACTGCAG
CCTGGGGTGA
CTCCCAGAAA
TTCTTTCTTT
TTCTTTCTTT
TTCCTTCTTT
CCTTCCTTCC
25,790,861
25,790,811
25,790,761
25,790,711
25,790,661
25,790,611
25,790,561
25,790,511
25,790,461
25,790,411
25,790,361
25,790,311
25,790,261
25,790,211
25,790,161
25,790,111
25,790,061
25,790,011
25,789,961
25,789,911
25,789,861
25,789,811
25,789,761
25,789,711
25,789,661
25,789,611
25,789,561
25,789,511
25,789,461
TTTTTCTCCA
GACTGTGTAT
CCTTATGTTC
TATATTTTCG
ATTGGCACAT
TAATAAAGGT
TTTGATTTTG
GTCCCATTAA
GCAGCCCAGA
TGCCTGCTCT
TGGGATTGAC
AGGGGTCTGC
CATGGGGATG
AGGTCTGGGC
GGTGTGGGTG
ATGGGTAAGA
TGGTGGGTCT
TCCTCCTTCC
CCTGGTGGTG
CGTTCACTGC
TTTAGCCTGG
GGATGAAGCC
AGCAGAGCCC
GCTGGGAGCC
CTGGTGATCT
AGGCTGTGCT
CTCTCTCTCT
CCTTTCTGTC
CCTTCCTTCC
TGAATCTTCG
TTGAGTCTGA
ACGTCTTTTC
GTTCTAAACT
CTCCACTTAA
AAAATAAATG
TGAAAAAAAT
TTATGTAAAA
GATGAAGGGA
TTTGCTTTTA
ACCAGCCTCA
CGGGCCATCA
AGGGGCAGGG
ATGGCTGGGC
TGGCCCTGGC
GGAAGGACTA
GACCCTAAGT
AGATGGTCCC
TGGGTCTCAG
TACCATGGTG
ACATAGCCTG
TGCCCCTCTG
AGGGCAGCTG
GAGGCTCTGC
CGAGGTCAGC
TGCTTGCTTG
TTCTTTCTTT
TTTCCTTCCC
TTCCTTCCTT
TTGTGCATAT
TCTTTTATAA
ATTTTCAAGA
GATTCTCACC
TAGAATATGT
CTATAATAGA
TAAAAAAAAA
AGGCACAGCA
GACTTTTTCC
GCCTTTATTT
GTAAATGAGT
GGTCAATGTG
TCACTCTGCC
TTTGCTGGTA
TTGCACACCT
ACACCCTCGG
GCATGCGATG
AGAGGAGCAG
CCCTGGCGTC
AGTTGCACAT
GGGCTCACCC
CTGCACTCAC
GGTGGGGAGT
AGCTGCCGTG
CCCACTGAGA
CTTTCTCTCT
CTTTCTTTCT
TCCCTCCCTC
CTTTCCTTCC
ATGATAGTAA
GAAGCAGGAA
CTTTTTTTTT
ACACATCCTT
TGGAGAACAA
AGGCACTCCA
AAGCACTCTG
GGGAACCTGT
GAAGAATATG
AAAGCCTGTC
GCTGCAGGCG
ACCAGTGTGC
TCCCCATCCA
GAAACCCAGC
ATGTCTGCCT
GCCCCTCTGA
GAACACTGCA
CGCCTCATAG
GTCCCTGATT
GTCCATGTCG
TCCCTTCCTA
AGGTGTAGAG
GCCGAGAGCC
GACAGCACGT
GCTGCCACCC
TTCTTTCTCT
TTTTCTTTCT
CCTCCCTTCC
TTCCTTCTTT
ATTATTTATA
TCTGGGCCTA
AAATCTTGCA
TCTTCTAGGC
ACTGCTTTGC
GCCACTGTTC
GTAAGAACAG
TCTATCCTGT
TAATTACAGA
TGAGAAGGAG
CCCCAGCCCC
GCAGCCACCA
GGGGGCTGGC
AGAGGCTCCT
TGGTCTCGTG
GTCTCGCGGC
GCTGCTATTG
CCGCCATTGT
GACAACATCC
ACGGCTCAAC
AGGCAGCAGA
GACGAAAGTG
CAGACTGCAG
CCTGGGGTGA
CTCCCAGAAA
TTCTTTCTTT
TTCTTTCTTT
TTCCTTCTTT
CCTTCCTTCC
Exon 20
Intron 20
Exon 21
Intron 21
25,790,861
25,790,811
25,790,761
25,790,711
25,790,661
25,790,611
25,790,561
25,790,511
25,790,461
25,790,411
25,790,361
25,790,311
25,790,261
25,790,211
25,790,161
25,790,111
25,790,061
25,790,011
25,789,961
25,789,911
25,789,861
25,789,811
25,789,761
25,789,711
25,789,661
25,789,611
25,789,561
25,789,511
25,789,461
TTTTTCTCCA
GACTGTGTAT
CCTTATGTTC
TATATTTTCG
ATTGGCACAT
TAATAAAGGT
TTTGATTTTG
GTCCCATTAA
GCAGCCCAGA
TGCCTGCTCT
TGGGATTGAC
AGGGGTCTGC
CATGGGGATG
AGGTCTGGGC
GGTGTGGGTG
ATGGGTAAGA
TGGTGGGTCT
TCCTCCTTCC
CCTGGTGGTG
CGTTCACTGC
TTTAGCCTGG
GGATGAAGCC
AGCAGAGCCC
GCTGGGAGCC
CTGGTGATCT
AGGCTGTGCT
CTCTCTCTCT
CCTTTCTGTC
CCTTCCTTCC
TGAATCTTCG
TTGAGTCTGA
ACGTCTTTTC
GTTCTAAACT
CTCCACTTAA
AAAATAAATG
TGAAAAAAAT
TTATGTAAAA
GATGAAGGGA
TTTGCTTTTA
ACCAGCCTCA
CGGGCCATCA
AGGGGCAGGG
ATGGCTGGGC
TGGCCCTGGC
GGAAGGACTA
GACCCTAAGT
AGATGGTCCC
TGGGTCTCAG
TACCATGGTG
ACATAGCCTG
TGCCCCTCTG
AGGGCAGCTG
GAGGCTCTGC
CGAGGTCAGC
TGCTTGCTTG
TTCTTTCTTT
TTTCCTTCCC
TTCCTTCCTT
TTGTGCATAT
TCTTTTATAA
ATTTTCAAGA
GATTCTCACC
TAGAATATGT
CTATAATAGA
TAAAAAAAAA
AGGCACAGCA
GACTTTTTCC
GCCTTTATTT
GTAAATGAGT
GGTCAATGTG
TCACTCTGCC
TTTGCTGGTA
TTGCACACCT
ACACCCTCGG
GCATGCGATG
AGAGGAGCAG
CCCTGGCGTC
AGTTGCACAT
GGGCTCACCC
CTGCACTCAC
GGTGGGGAGT
AGCTGCCGTG
CCCACTGAGA
CTTTCTCTCT
CTTTCTTTCT
TCCCTCCCTC
CTTTCCTTCC
ATGATAGTAA
GAAGCAGGAA
CTTTTTTTTT
ACACATCCTT
TGGAGAACAA
AGGCACTCCA
AAGCACTCTG
GGGAACCTGT
GAAGAATATG
AAAGCCTGTC
GCTGCAGGCG
ACCAGTGTGC
TCCCCATCCA
GAAACCCAGC
ATGTCTGCCT
GCCCCTCTGA
GAACACTGCA
CGCCTCATAG
GTCCCTGATT
GTCCATGTCG
TCCCTTCCTA
AGGTGTAGAG
GCCGAGAGCC
GACAGCACGT
GCTGCCACCC
TTCTTTCTCT
TTTTCTTTCT
CCTCCCTTCC
TTCCTTCTTT
ATTATTTATA
TCTGGGCCTA
AAATCTTGCA
TCTTCTAGGC
ACTGCTTTGC
GCCACTGTTC
GTAAGAACAG
TCTATCCTGT
TAATTACAGA
TGAGAAGGAG
CCCCAGCCCC
GCAGCCACCA
GGGGGCTGGC
AGAGGCTCCT
TGGTCTCGTG
GTCTCGCGGC
GCTGCTATTG
CCGCCATTGT
GACAACATCC
ACGGCTCAAC
AGGCAGCAGA
GACGAAAGTG
CAGACTGCAG
CCTGGGGTGA
CTCCCAGAAA
TTCTTTCTTT
TTCTTTCTTT
TTCCTTCTTT
CCTTCCTTCC
Exon 20
Intron 20
Exon 21 rs1800417
rs1800418
Intron 21 rs7175046
rs12594397
The ENCODE (ENCyclopedia Of DNA Elements) Project
Science 2004, 306:636 - 640
What is a gene, post-ENCODE?
Genome Research 17:669, 2007
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
Glucuronic acid
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
liver, lung, stomach
PCBs
UGT1A7
Esophagus, intestine, kidney, larynx
heterocyclic amines
UGT1A8
Colon, esophagus, intestine, kidney, larynx
Benzo[a]phrene
UGT1A9
Breast, colon, esophagus, liver, kidney,
ovary, prostate, skin, testis
Nicotine (UGT1A4)
UGT1A10
Biliary tissue, colon, esophagus, intestine,
orolaryngeal tissue, stomach
Raloxifene
Nagar and Remmel, UGT phramacogenetics, Oncogene (2006) 25, 1659–1672
How does normal variation cause disease?
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
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.
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
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 reductase
677C>T – rs1801133
Allelic Variation in Human Gene Expression
Yan H., et al, Science 297:1143, 2002
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 functionPathologic 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.
The Human Genome Project and Beyond
All Human Genes Identified
Function &
Expression
Major Variation
Mutations
Minor Variation
Polymorphisms
Disease Susceptibility
Therapeutic 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 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
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
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. Holland
Suffolk
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/
What is our concept of disease?
Normal
Disease