Session VII

1. Session VII Basic Biological Principles Previous sessions covered fundamental concepts of biology, genetics and molecular biology of genes in individual cells

2. Session VII This was in preparation for the remainder of the course which will focus on the science that Discovery Manager supports The Discovery of Disease Genes

3. Session VII What are disease genes? A large portion of human ill health has a genetic component Genetic causes of human disease fall into three categories Inherited genetic disease Somatic genetic disease Chromosomal aberration

4. What are disease genes? Inherited genetic diseases Discovery Manager supports the investigation of inherited genetic diseases Abnormal variants of genes passed from one generation to the next Many inherited genetic diseases are caused by a defect in a single gene cystic fibrosis muscular dystrophy phenylketonuria

5. Inherited genetic disease Genetic determination of most human hereditary diseases is complex Involves interaction of variants of more than one gene and the environment heart disease diabetes hypertension

6. How is Disease Gene Discovery Done? Characterize the disease traits--phenotype Examine the structure of the genome--genotype Correlate “variant” genotype with phenotype Identify chromosomal region associated with the variant genotype

7. The Process of Gene Discovery The first steps in this process, correlation of phenotype and genotype, use the principles of population genetics

8. Population Genetics • Population genetics focuses on the fate of genes in populations • The principles of population genetics underpin the analysis of genetics of normal biological variation • As an extension, these same principles underpin the analysis of the genetic variation associated with human genetic disease • In the next two weeks, focus on analysis of the genetic variation responsible for human disease

9. Definitions Locus: The specific place on a chromosome where a gene is located. A locus may have one or more genes in it. It is a physical location. Gene: The fundamental physical and functional unit of heredity that carries information from one generation to the next. Allele: One of the different forms (variants) of a gene that can exist at a locus.

10. Definitions • Homozygous gene pair: A gene pair having identical alleles in the two chromosome sets of the diploid individual. • Heterozygous gene pair: A gene pair having different alleles in the two chromosome sets of the diploid individual. • Genotype: The specific allelic composition of a gene or set of genes • Phenotype: The detectable outward manifestation of some genotype (measurable traits, ex. blood glucose level)

11. PopulationUnit of Study In Population Genetics ” A population in the genetic sense, is not just a group of individuals but a breeding group; and the genetics of a population is concerned not only with the genetic constitution of the individuals but also with the transmission of the genes from one generation to the next.” The quote is from Introduction to Quantitative Genetics by D. S. Falconer, 1960, Ronald Press.)

12. Key Concepts in Population Genetics Goals of population genetics • understand the genetic composition of a population • understand the forces that change that composition.

13. Key Concepts in Population Genetics Genetic variation within and between populations arises from the existence of various alleles at different loci.

14. Key Concepts in Population Genetics Fundamental measurement in population genetics is the frequency at which alleles occur at any gene locus

15. Key Concepts in Population Genetics • Frequency of a given allele can be changed by mutation, selection, or migration • Mutation may result in the creation of a disease gene

16. Key Concepts in Population Genetics The Ideal Situation In idealized population, where no forces of change are acting (such as mutation), a randomly interbreeding population shows constant genotypic frequencies for a given locus from generation to generation

17. Population Genetics and Classical Evolutionary Genetics Population genetics is the translation of Charles Darwin’s theory of evolution into precise genetic terms.

18. Darwin’s theory of evolution Principle of variation • Among individuals in any population there is variation in morphology, physiology, and behavior • This combination of characteristics is termed the phenotype of an individual

19. Darwin’s theory of evolution Principle of heredity • Offspring resemble their parents more than they resemble unrelated individuals • This principle describes the genetic basis of heredity or the genotype of an individual.

20. Darwin’s theory of evolution Principle of selection • Some forms are more successful at surviving and reproducing than other forms in a given environment • The selective process acts on variations in the genetic makeup of an organism (survival of the fittest)

21. Population Genetics • The description and measurement of genetic variation in populations (both functionally normal and abnormal variants) • Determines how that variation changes in time.

22. Variation The study of variation consists of two stages (correlation of phenotype and genotype) Stage 1: Describe the phenotypic variation----DM Study Variable Manager Stage 2: Translate these phenotypes into genetic terms and redescribe the variant genetically----DM Genotype Manager

23. Observation of Variation Population genetics deals with genotypic variation but by definition only phenotypic variation can be observed.

24. Observation of Variation The relationship between phenotype and genotype can vary from the very simple to highly complex. Simplest relationship between genotype and phenotype exists for traits that are qualitative. These traits include the various genetically determined blood groups which give qualitatively distinct phenotypes.

25. Observation of Variation The relationship between phenotype and genotype can vary from the very simple to highly complex. Highly complex relationships are found between genotype and quantitative traits. These are traits that vary over a range, like height. These relationships must be analyzed with statistical tools like distributions, covariance, and association. Most phenotypic traits are quantitative

26. Description of Variation The simplest description of genetic variation is the frequency distribution of genotypes (alleles) in a population The frequencies of all alleles of a gene always adds up to 1

27. Blood Group Locus MNThe Blood Group Locus MN has two alleles M and NThese alleles can exist in three possible combinations:MM, MN, NN Genotype Allele frequencies Population MM MN NN p(M) p(N) Eskimo 0.835 0.156 0.009 0.913 0.087 Australian 0.024 0.304 0.672 0.176 0.824 Egyptian 0.278 0.489 0.233 0.523 0.477 German 0.297 0.507 0.196 0.550 0.450 Chinese 0.332 0.486 0.182 0.575 0.425 Nigerian 0.301 0.495 0.204 0.548 0.452

28. Measurement of variation The simplest measure of genetic variation (as opposed to description) is the amount of heterozygosity at a locus in a population. This number is the frequency of heterozygotes at a locus.

29. Blood Group Locus MN Genotype Allele frequencies Population MM MN NN p(M) p(N) Eskimo 0.835 0.156 0.009 0.913 0.087 Australian 0.024 0.304 0.672 0.176 0.824 Egyptian 0.278 0.489 0.233 0.523 0.477 German 0.297 0.507 0.196 0.550 0.450 Chinese 0.332 0.486 0.182 0.575 0.425 Heterozygosity is simply equal to the frequency of the MN genotype in the population

30. Kinds of Variation Every species of organism examined has revealed considerable genetic variation, also know as polymorphism. A gene or a phenotypic trait is polymorphic if more than one form of the gene or trait is observed in a population. This genetic variation is the raw material for evolution and the emergence of disease genes.

31. Kinds of Variation DNA sequence polymorphisms These polymorphisms reside in coding sequence, in regulatory regions and in sequences between genes RFLP-restriction fragment length polymorphism VNTR-variable number tandem repeats SNP-single nucleotide polymorphisms.

32. Sources of Genetic Variation Recombination Mutation Immigration

33. Mutation Change in DNA that may alter the length or arrangement Causes of mutation Chemical mutagen or ionizing or ultraviolet radiation damage the DNA DNA polymerase does not operate with perfect fidelity DNA repair enzymes do not repair the damage

34. Macromutation Chromosomes break into pieces resulting in rearrangement or translocations ex. leukemias Repeat sequences such as VNTRs change their copy number ex. myotonic dystrophy Macromutations in the germ line (egg or sperm) accounts for the karyotypic differences between species

35. Micromutations Point mutations- a change from one nucleotide to another An example of a point mutation which alters the phenotype of an individual, is the point mutation in hemoglobin responsible for sickle cell anemia. Single nucleotide deletions or insertions- result in “frameshifts” Amino acid triplet reading frame is altered changing all amino acids down stream of the mutation

36. The Hardy Weinberg Law Infinitely large population—no such population actually exists Random mating must occur in the population—within a population, random mating can be occurring at some loci but not at others

37. The Hardy Weinberg Law No evolutionary forces affecting the population—these evolutionary forces include: Mutation Migration Selection No selective advantage for any genotype; that is, all genotypes produced by random mating are viable and fertile.

38. The Hardy Weinberg Law The Hardy Weinberg Law predicts three important conditions within a population: Allele frequencies predict genotype frequencies At equilibrium, allele and genotype frequencies do not change from generation to generation Equilibrium is reached in one generation

39. The Hardy Weinberg Law If there is no equilibrium, then one of the conditions is not being met Factors such as mutation may be playing a role in the population

40. Summary Heritable variation in the genome is the raw material for evolution Selective pressure acts on this variation Variants that confer reproductive or survival advantage are maintained What about disease genes????