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 Diseases
- Cystic fibrosis
- Down syndrome
- Sickle cell disease
- T urner syndrome
Complex Diseases Environmental
Diseases
- Alzheimer disease
- Cardiovascular
Disease
- Diabetes (type 2)
- Parkinson Disease
- Influenza
- Hepatitis
- Measles
Environment Genes

 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

-
-
-
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.

 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)

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

SNPs appear at least once per 0.3-1-kb average intervals.
Considering the size of entire human genome (3.2X10
9 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

• 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
AGGAAAAGAACATAACAAG A ACTATTTTTCGCCCGAACTC B6
AGGAAAAGAACATAACAAG G ACTATTTTTCGCCCGAACTC C3H
B6
C3H

Most abundant type:
SNPs-Single Nucleotide Polymorphisms
GATTTAGATC G CGATAGAG
GATTTAGATC T CGATAGAG
^ about 90% of all human genetic variations

For a variation to be considered a SNP, it must occur in at least 1% of the population .

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

 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.

 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

•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/

 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 are used as genetic markers to identify genes responsible for disease susceptibility or a particular trait.

 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

 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
 Nonsense mutation results in premature termination of translation
 truncated polypeptides often are nonfunctional
 Point mutation in non-coding region may affect transcription, RNA splicing, and protein assembling

di-, tri-, and tetra-nucleotide repeats
TGC C A C A C A C A C A C A C A C A GC
TGC C A C A C A C A C A ------GC
TGC T C A T C A T C A T C A GC
TGC T C A T C A ------GC
TGC T C AG T C AG T C AG T C AG GC
TGC T C AG T C AG --------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


•
Huntington disease
 Kennedy disease
Normal Disease Gene
CAG 9-35 37-100 Huntingtin
CAG 17-24 40-55 a ndrogen receptor
 Spino-cerebellar Ataxia CAG 19-36 43-81 Ataxin 1
 Machado Joseph D
 Myotonic dystrophy
CAG 12-36 67-75
CTG 5-35 50-400
SCA
DM
 Fragile X CGG CCG GCC 6-50 200-1000 FMR1
Many result in neurodegeneration
Severity of many diseases increases with the number of repeats

• 6-64 bp repeating pattern
1 tgattggtct ctctgccacc gggagatttc cttatttgga ggtgatggag gatttc agga
61 attttttagg aattttttta atggattacg ggattttagg gttctaggat tttaggatta
121 tggtatttta ggatttactt gattttggga ttttaggatt gagggatttt agggtttcag
181 gatttcggga tttcaggatt ttaagttttc ttgattttat gattttaaga ttttaggatt
241 tacttgattt tgggatttta ggattacggg attttagggt ttcaggattt cgggatttca
301 ggattttaag ttttcttgat tttatgattt taagatttta ggatttactt gattttggga
361 ttttaggatt acgggatttt agggtgctca ctatttatag aactttcatg gtttaacata
421 ctgaatataa atgctctgct gctctcgctg atgtcattgt tctcataata 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

 1 per 800 births
 Large tongue
 Flat face
 Slanted eyes
 Single crease across palm
 Mental retardation

Some are not

 Short
 Absence of a menstrual period
 Produce little estrogen
 Sterile
 Extra skin on neck

 Gene directly leads to disorder
 Mendelian pattern of inheritance
 Rare
 Gene confers an increased risk, but does not directly cause disorder
 No clear inheritance pattern
 Common in population