Medical Genetics

1. Medical Genetics Human Genetic Variation Mutations vs Polymorphisms

2. 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).

3. Polymorphism • A polymorphism is a sequence difference compared to a reference standard that is present in at least 1–2% of a population. • Polymorphisms can be single bases or thousands of bases. • Polymorphisms may or may not have phenotypic effects.

4. Gene polymorphism e.g. Gene for hair colour Alleles If there are two or more alleles(several forms of the same genes occupy the same locus) and the rarest occurs at a frequency of more than 1% then this loci will be considered polymorphic.

5. Locus1 Possible Alleles: A1,A2 Locus2 Possible Alleles: B1,B2,B3 Basic terminology • Locus – location of a gene/marker on the chromosome. • Allele – one variant form of a gene/marker at a particular locus.

6. Advantages of Polymorphism - Polymorphic forms are produced as result of mutation in the genetic loci. - The advantages are possibly: - Production of more stable forms. - Production of such forms that give resistance against disease: e.g. Hb S Trait are resistance to malarial plasmodia. - Natural selection for survival of the fittest.

7. Clinical Importance of Polymorphism Contd….. Asgenetic markers Forensic Medicine e.g. DNA fingerprint of each individual differs due to polymorphic sites in many non-coding sequences e.g. Predisposing to a disease within families or populations

8. 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)

9. Genetic Disorders Mutations in the: * Genome * Chromosome or * Gene • Decrease or increase in the amount of genetic material • Abnormal genetic material • Increase or decrease in the amount of gene products (proteins). • Defective function of the protein. • - Increased function. • - Decreased or complete loss of function. Genetic Disease

10. - Environment - Genes Genetic variations cause inherited diseases Environmental Diseases Genetic Diseases Complex Diseases - Alzheimer disease - Cardiovascular Disease - Diabetes (type 2) - Parkinson Disease - Influenza - Hepatitis - Measles - Cystic fibrosis - Down syndrome - Sickle cell disease - Turner syndrome

11. Polymorphism • Gene confers an increased risk, but does not directly cause disease • No clear inheritance pattern • Common in population Mutation • Gene directly leads to disease • Mendelian pattern of inheritance • Rare

12. A little more basic terminology 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 or a loss of function. • RARE. 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. • COMMON.

13. Forms of genetic variations Single nucleotide substitution:replacement of one nucleotide with another Deletions or insertions: loss or addition of one or more nucleotides Changes in chromosome number, segmental rearrangements and deletions

14. Human Genetic Variation Most abundant type: SNPs-Single Nucleotide Polymorphisms GATTTAGATCGCGATAGAG GATTTAGATCTCGATAGAG ^ about 90% of all human genetic variations

15. 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.

16. 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.

17. How many variations are present in the average human genome ? SNPs appear at least once per 300-1000 basesaverage intervals. Considering the size of entire human genome (3.2X109 bp), the total number of SNPs is around to 5-10 million The insertion/deletions are very difficult to quantify

18. look at multiple sequences from the same genome region • use base quality values to decide if mismatches are true polymorphisms or sequencing errors How do we find sequence variations?

19. 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

20. 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

21. 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

22. 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

23. Original message:SAM AND TOM ATE THE JAM

24. Transposon and mutation Transposons are interspersed DNA repeats that can cause mutations and change the amount of DNA in the genome

25. TAHNK YOU