1. Lecture 41 Prof Duncan Shaw

2. Genetic Variation Already know that genes have different alleles - how do these arise? Process of mutation - an alteration/change in the genetic material Origin: –Internal (e.g. mistakes during replication of DNA) –External (e.g. radiation, chemicals) Most mutations have no effect or are harmful

3. Types of mutation Non-coding - not in part of gene that codes for protein - either no effect, or effect on gene expression Coding: –Synonymous - same amino acid –Missense - different amino acid –Nonsense - premature stop codon –Frameshift (deletion or insertion of bases) - change in structure of protein

4. Mutagenesis Mutagens are chemicals (or radiation, etc.) that cause heritable alterations in DNA sequence in somatic and germ cells New mutations are rare - most genetic characteristics are due to inheritance from parents Teratogens are chemicals (or radiation, etc.) that affect development of the embryo/foetus and may cause congenital abnormalities (e.g. thalidomide)

5. The human genome Its size is 3 x 10 9 bp (3000Mb) for a single copy Contains 23 pairs of chromosomes About 35,000 genes About 1 million sites in the DNA that vary between individuals (most with no effect on phenotype)

6. Meiosis and Recombination Chromosomes pair upDNA replication Chiasmata form Recombination 1st cell division 2nd cell divisionGametes Result: meiosis generates new combinations of alleles

7. How much genetic variation? About 35,000 genes in humans If each gene has only 2 allelic forms (probably an underestimate), then: –Number of possible genotypes = 3 35,000 = 10 16700 Far more than all the atoms in the Universe! Essentially, we are all genetically unique (except identical twins)

8. Significance of genetic variation Some alleles directly cause rare genetic diseases e.g. Cystic fibrosis, sickle-cell anemia - called simple or Mendelian genetic disease Many alleles contribute to the risk (or liability) of getting a common disease with genetic component - called complex or multifactorial disease e.g. Cancer, heart disease, asthma, schizophrenia, diabetes (polygenes)

10. How can you tell its a disease gene? For simple genetic disease, can track the disease gene through affected families - called linkage analysis For complex disease, can test whether certain alleles are found more frequently in patients than in healthy controls - called genetic association

11. UnlinkedLinked 1211 2111 2111 Parents Gametes Offspring 12 11 1211 1121