Transcript Introduction to Medical Genetics

Human Genetic Variation
Weibin Shi
Genetic variations underlie
phenotypic differences
Wilt Chamberlain,
a famous NBA basketball player
(7 feet, 1 inch; 275 pounds)
Willie Shoemaker,
a famous horse racing jockey
(4 feet, 11 inches;
barely 100 pounds).
Genetic variations cause
inherited diseases
Genetic Diseases
Complex Diseases
Environmental
Diseases
- Cystic fibrosis
- Alzheimer disease
- Influenza
- Down syndrome
- Cardiovascular
Disease
- Hepatitis
- Sickle cell disease
- Turner
syndrome
- Diabetes (type 2)
- Measles
- Parkinson Disease
- Environment
- Genes
Basic terminology

Locus – location of a gene/marker
on the chromosome.

Allele – one variant form of a
gene/marker at a particular locus.
Locus1
Possible Alleles: A1,A2
Locus2
Possible Alleles: B1,B2,B3
A little more basic terminology
Polymorphism:
-
-
Variations in DNA sequence (substitutions, deletions,
insertion, etc) that are present at a frequency greater
than 1% in a population.
Have a WEAK EFFECT or NO EFFECT at all.
Ancient and COMMON.
Mutation:
-
-
Variations in DNA sequence (substitutions, deletions,
etc) that are present at a frequency lower than 1% in a
population.
Can produce a gain of function and a loss of function.
Recent and RARE.
Some Facts

In human beings, 99.9% bases are same

Remaining 0.1% makes a person unique

Different attributes / characteristics / traits
• how a person looks
• diseases he or she develops

These variations can be:



Harmless (change in phenotype)
Harmful (diabetes, cancer, heart disease, Huntington's
disease, and hemophilia )
Latent (variations found in coding and regulatory regions, are
not harmful on their own, and the change in each gene only
becomes apparent under certain conditions e.g. susceptibility
to heart attack)
Forms of genetic variations
Single nucleotide substitution: replacement of
one nucleotide with another
Microsatellites or minisatellites: these tandem
repeats often present high levels of inter- and
intra-specific polymorphism
Deletions or insertions: loss or addition of one
or more nucleotides
Changes in chromosome number, segmental
rearrangements and deletions
How many variations are present
in the average human genome ?
SNPs appear at least once per 0.3-1-kb average intervals.
Considering the size of entire human genome (3.2X109 bp),
the total number of SNPs is around to 5-10 million
Potentially polymorphic microsatellites are over 100,000 across
the human genome
The insertion/deletions are very difficult to quantify and
the number is likely to fall in between SNPs and microsatellites
How do we find sequence
variations?
• look at multiple sequences
from the same genome region
• use base quality values to decide if
mismatches are true polymorphisms or
sequencing errors
Vcam1 : Coding-NonSynonymous
AGGAAAAGAACATAACAAGAACTATTTTTCGCCCGAACTC B6
AGGAAAAGAACATAACAAGGACTATTTTTCGCCCGAACTC C3H
B6
C3H
Human Genetic Variation
Most abundant type:
SNPs-Single Nucleotide Polymorphisms
GATTTAGATCGCGATAGAG
GATTTAGATCTCGATAGAG
^
about 90% of all human genetic variations
What is the difference between
SNP and mutation?
For a variation to be considered a SNP,
it must occur in at least 1% of the population.
Life cycle of SNP
(long way from mutation to SNP)
Appearance of
new variant
by mutation
Survival of rare allele
Increase in allele frequency
after population expand
New allele is fixed
in population as novel polymorphism
Basic facts about SNPs

SNPs occur every 300-1000 bases in human genome;

Two of every three SNPs involve the replacement of
cytosine (C) with thymine (T);

SNPs can occur in both coding (gene) and noncoding
regions of the genome;

Many SNPs have no effect on cell function, but others
could predispose people to disease or influence their
response to a drug.
Single base changes
 Transitions


Purine to purine or pyrimidine to pyrimidine
A to G or G to A T to C or C to T
 Transversions

Purine to pyrimidine or pyrimidine to purine
SNP Databases
•NCBI dbSNP
http://www.ncbi.nlm.nih.gov/SNP/index.html
•Human Genome Variation Database (HGVbase)
http://hgvbase.org/
International HapMap Project
http://snp.cshl.org/
Classification of SNPs

1. Coding SNPs


Synonymous: when single base substitutions do not
cause a change in the resultant amino acid
Non-synonymous: when single base substitutions
cause a change in the resultant amino acid

2. Non-coding SNPs that influence gene
expression

3. Non-coding silent SNPs
SNPs as gene mapping markers
SNPs are used as genetic markers to identify
genes responsible for disease susceptibility
or a particular trait.
Point mutations

Not all single base pair differences are SNPs

They can be a mutation if least abundant allele has
a frequency < 1% in a population
Causes of gene mutations
Consequences of mutations
 Most
-
mutations are neutral
97% DNA neither codes for protein or RNA, nor indirectly
affects gene function
A new variant in the 1.5% coding regions may not result
in a change in amino acid
Variants that change amino acid may not affect function
 Certain
mutations have functional effect
and even cause disease
-
Gain-of-function mutations often produce dominant
disorders
Loss-of-function mutations result in recessive disease
Consequences of mutations

Missense mutations differ in severity


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
Nonsense mutation results in premature
termination of translation


conservative amino acid substitution substitutes
chemically similar amino acid, less likely to alter function
nonconservative amino acid substitution substitutes
chemically different amino acid, more likely to alter
function
consequences for function often context-specific
truncated polypeptides often are nonfunctional
Point mutation in non-coding region may affect
transcription, RNA splicing, and protein assembling
Microsatellite
di-, tri-, and tetra-nucleotide repeats
TGCCACACACACACACACAGC
TGCCACACACACA------GC
TGCTCATCATCATCAGC
TGCTCATCA------GC
TGCTCAGTCAGTCAGTCAGGC
TGCTCAGTCAG--------GC
The second abundant genetic variation in the human
genome
Usually have no functional effect, but some do
Trinucleotide repeats-associated
diseases
 Characterized
by expansion of threebase-pair repeats



few repeats to hundreds of repeats
expansion results in abnormal protein, disease
number of repeats may expand in subsequent
generations
Triplet repeat expansion
•

Normal
Disease

Huntington disease
Kennedy disease
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Spino-cerebellar Ataxia CAG 19-36

Machado Joseph D
CAG 12-36 67-75
Myotonic dystrophy
CTG 5-35 50-400
Fragile X
CGG CCG GCC 6-50 200-1000


Gene
CAG 9-35 37-100
Huntingtin
CAG 17-24 40-55 androgen receptor
43-81
Ataxin 1
SCA
DM
FMR1
Many result in neurodegeneration
Severity of many diseases increases with
the number of repeats
Minisatellite
• 6-64 bp repeating pattern
1
61
121
181
241
301
361
421
tgattggtct
attttttagg
tggtatttta
gatttcggga
tacttgattt
ggattttaag
ttttaggatt
ctgaatataa
ctctgccacc
aattttttta
ggatttactt
tttcaggatt
tgggatttta
ttttcttgat
acgggatttt
atgctctgct
gggagatttc
atggattacg
gattttggga
ttaagttttc
ggattacggg
tttatgattt
agggtgctca
gctctcgctg
cttatttgga
ggattttagg
ttttaggatt
ttgattttat
attttagggt
taagatttta
ctatttatag
atgtcattgt
ggtgatggag
gttctaggat
gagggatttt
gattttaaga
ttcaggattt
ggatttactt
aactttcatg
tctcataata
gatttcagga
tttaggatta
agggtttcag
ttttaggatt
cgggatttca
gattttggga
gtttaacata
cgttcctttg
These occur at more than 1000 locations in the human genome
Usually have no functional effect
Transposon and mutation
Transposons are interspersed DNA repeats that can cause mutations and
change the amount of DNA in the genome
Nondisjunction
Trisomy
Trisomy 21
Down Syndrome
Down Syndrome
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1 per 800 births
Large tongue
Flat face
Slanted eyes
Single crease
across palm
Mental retardation

Some are not
Turner Syndrome
Turner Syndrome
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Short
Absence of a
menstrual period
Produce little
estrogen
Sterile
Extra skin on neck
Polymorphism
Mutation

Gene confers an increased
risk, but does not directly
cause disorder
Mendelian pattern of
inheritance

No clear inheritance pattern
Rare

Common in population

Gene directly leads to
disorder

