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Pharmacogenetics
 Refers to the genetic differences in individuals
    Different metabolic pathways
      Affecting response to drugs
      106,000 deaths in US
      Vitamin E helps cure cardiovascular disease in some.



Pharmacogenetics VS Pharmacogenomics

-Germline mutations                    -Somatic mutations in tumor cell
lines
Pharmacogenomics:
Dihydropyrimidine dehydrogenase (DPD); UDP-
glucuronosyltransferase 1-1 UGT1A; thiopurine S-
methyltransferase (TPMT); Cytidine deaminase CDA
 Ref: http://en.wikipedia.org/wiki/Pharmacogenetics
Somatic Cell Genetics
 Somatic Cell mutations
   Cancer
   Ageing
   Mosaicism



                           PKU: Phenylketonuria
                           hyperphenylalaninemia

                           Most Mutations are
                           recessive
type of mutation             mechanism                   frequency per cell division
                             1. mistakes in DNA
                             replication                ~10-10/basepair
point mutation               2. DNA damage by chemical ~10-5/gene
                             mutagens (or by radiation) ~0.5/cell
                             and misrepair
                             1. unequal crossing over
                             2. misalignment during DNA
                             replication
submicroscopic deletion or   3. insertion of mobile
                                                        included in the above
insertion                    element
                             4. DNA damage by chemical
                             mutagens (or by radiation)
                             and misrepair

                             1. unequal crossing over
microscopically visible
                             2. DNA damage by chemical
deletion, translocation or                              6 x 10-4
                             mutagens (or by radiation)
inversion
                             and misrepair

loss of a whole chromosome missegregation at mitosis     1 in 100
Genetics Of Globin Triplet
    Disorder




Ref: http://en.wikipedia.org/wiki/Hemoglobin
Genetics of Haemoglobin triplet
    disorder
     Sickle Cell Anemia:
         Mutation in HBB


CTC -> CAC; Glutamic acid ->
Valine




Ref:
http://en.wikipedia.org/wiki/Sickle-
Prevalence of Sickle Cell Anemia




Heterozygotes have distinct advantages over homozygotes.

Selective advantages in case of malaria infection.
Micro Array




Ref: http://en.wikipedia.org/wiki/DNA_microarray
MicroArray




  Ref: http://www.reproduction-online.org/content/130/1/1/F1.expansion.html
MicroArray




   http://en.wikipedia.org/wiki/DNA_microarray
MicroArray
                      Bioinformatics

1. Experimental Design
2. Standardization
    1. Background correction
    2. Normalization
    3. Differential expression
        Analysis
3. Statistical Analysis
4. Data Warehousing


        Probes and
          Genes
Application of MicroArray
 Expression Profiling
 Comparative Genome Hybridization
 Detecting protein bound region (Chip-Seq)
 Alternate Splicing
 Fusion Genes
 Tiling Array
Physical Map of Chromosome
Genetic Mapping
SSR Loci
 Micro-satellite markers
    Simple sequence Repeats (2-6 nt)
    Variable Number of Tandem Repeats (VNTR)



(CA)n repeat varies between alleles.

Repetitive regions vary in different alleles because of slipped strand mispairing
Lecture7,8

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Lecture7,8

  • 1. Pharmacogenetics  Refers to the genetic differences in individuals  Different metabolic pathways  Affecting response to drugs  106,000 deaths in US  Vitamin E helps cure cardiovascular disease in some. Pharmacogenetics VS Pharmacogenomics -Germline mutations -Somatic mutations in tumor cell lines Pharmacogenomics: Dihydropyrimidine dehydrogenase (DPD); UDP- glucuronosyltransferase 1-1 UGT1A; thiopurine S- methyltransferase (TPMT); Cytidine deaminase CDA Ref: http://en.wikipedia.org/wiki/Pharmacogenetics
  • 2. Somatic Cell Genetics  Somatic Cell mutations  Cancer  Ageing  Mosaicism PKU: Phenylketonuria hyperphenylalaninemia Most Mutations are recessive
  • 3. type of mutation mechanism frequency per cell division 1. mistakes in DNA replication ~10-10/basepair point mutation 2. DNA damage by chemical ~10-5/gene mutagens (or by radiation) ~0.5/cell and misrepair 1. unequal crossing over 2. misalignment during DNA replication submicroscopic deletion or 3. insertion of mobile included in the above insertion element 4. DNA damage by chemical mutagens (or by radiation) and misrepair 1. unequal crossing over microscopically visible 2. DNA damage by chemical deletion, translocation or 6 x 10-4 mutagens (or by radiation) inversion and misrepair loss of a whole chromosome missegregation at mitosis 1 in 100
  • 4. Genetics Of Globin Triplet Disorder Ref: http://en.wikipedia.org/wiki/Hemoglobin
  • 5. Genetics of Haemoglobin triplet disorder  Sickle Cell Anemia:  Mutation in HBB CTC -> CAC; Glutamic acid -> Valine Ref: http://en.wikipedia.org/wiki/Sickle-
  • 6. Prevalence of Sickle Cell Anemia Heterozygotes have distinct advantages over homozygotes. Selective advantages in case of malaria infection.
  • 8. MicroArray Ref: http://www.reproduction-online.org/content/130/1/1/F1.expansion.html
  • 9. MicroArray http://en.wikipedia.org/wiki/DNA_microarray
  • 10. MicroArray Bioinformatics 1. Experimental Design 2. Standardization 1. Background correction 2. Normalization 3. Differential expression Analysis 3. Statistical Analysis 4. Data Warehousing Probes and Genes
  • 11. Application of MicroArray  Expression Profiling  Comparative Genome Hybridization  Detecting protein bound region (Chip-Seq)  Alternate Splicing  Fusion Genes  Tiling Array
  • 12. Physical Map of Chromosome
  • 14. SSR Loci  Micro-satellite markers  Simple sequence Repeats (2-6 nt)  Variable Number of Tandem Repeats (VNTR) (CA)n repeat varies between alleles. Repetitive regions vary in different alleles because of slipped strand mispairing