Human Mendelian Disorders. Genetic Technology. What is Genetics? Genes are DNA 9/3/2008. Multifactorial Disorders

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1 Human genetics: Why? Human Genetics Introduction Determine genotypic basis of variant phenotypes to facilitate: Understanding biological basis of human genetic diversity Prenatal diagnosis Predictive testing Development of intelligent therapies Correction of genetic defects Human Identification for forensics, evolution Class Objectives 1. To provide an understanding of the basic principles of genetics. 2. To provide an understanding of the genetic basis of human disease and current approaches to treatment and prevention of genetic disorders. 3. To relate the study of human genetics to major advances in molecular genetics and biotechnology. 4. To provide an awareness of the interaction between genetic and environmental factors underlying birth defects and the development of human disease. Class Objectives 5. To relate human genetics to current issues in genetic screening, genetic counseling and genetic engineering. 6. To provide an awareness of the relationship of the individual genome to the genetic makeup of the human population and its ramifications to human diversity. 7. To provide a learning opportunity for students enrolled in Biological and Health Sciences applicable to career areas including biomedical technology, pre-medical, secondary education, special education, and nursing. Course Topics Cell Biology and Biochemistry Review Classical Mendelian Genetics DNA and Chromosomes Molecular Genetics Immunity and Cancer Genetic Counseling, Gene Therapy, Ethics Population/Evolutionary Genetics Grading Lab Work (Lab participation and reports, Lab questions,) 35% Lecture quizzes 30% Final l Exam 20% Family Tree 10% Problem sets 10% Class participation 5% 1

2 2. Gene Cell 1. DNA Human Mendelian Disorders 4. Genome 3. Chromosome 7. Population 5. Individual 6. Family (pedigree) Disorder Achondroplasia Cystic fibrosis Defective protein Growth factor receptor Chloride transporter Phenotype Dwarfism Lung, digestive pathology Duchenne s muscular Dystrophin Muscle function dystrophy Hemophilia Factor VIII Blood clotting defect Familial Hypercholesterolemia LDL receptor High cholesterol, heart disease Multifactorial Disorders Genetic Technology Breast Cancer Biopolar affective disorder Dyslexia Diabetes mellitus Hypertension Neural tube defects Schizophrenia Seizure disorders - manic depression - adult onset & obesity - folic acid - 1% affected What is Genetics? Genetics is the study of heredity and its variation. Human genetics: What's different? Nothing (in principle) i Unmatched by other organisms for phenotypic complexity Genes are DNA Genes are the basic unit of inheritance. Genes are composed of DNA (deoxyribonucleic acid) Genes direct the formation of proteins. Different versions of the same gene are called alleles. Alleles result from the process called mutation. All genes are nucleic acids (RNA and DNA) but not all nucleic acids are genes. 2

3 Somatic versus Germline Cells Somatic cells comprise the majority of an individual s body. During development distinct types of cells make proteins using different subsets of genes. Germline cells within the testis or ovary produce gametes (sperm or ovum) Germline cells retain the ability to form all of the types of cells, both germline and somatic cells. The complete set of genetic information characteristic of the organism. The genome includes: Genome All of the genes present in an organism and Other DNA sequences that do not encode genes Together somatic cells and germline cells comprise the entire body of an individual. The Human Genome Individuals Consists of 3 billion base pairs of DNA Includes 28,000 to 34,000 genes Is organized as 23 pairs of chromosomes Individuals carry two alleles of each gene. Genotype is the combination of alleles that an individual possesses. Phenotype is the visible trait that results from a particular genotype. Family Inheritance of traits can be observed in families. A pedigree indicates the structure of a family schematically. Population A population is a group of interbreeding individuals who possess a particular collection of alleles or gene pool. 3

4 QuickTime and a TIFF (Uncompressed) decompressor are needed to see this picture. 9/3/2008 Species Comparisons Comparison of DNA sequences indicates the amount of similarity between two species. 98% of human DNA sequences are shared with chimpanzee. Many genes present in humans are also present in mice, fish, fruit flies, yeast, and bacteria. Humans are very similar On average, two random people share the same DNA sequence in 99.9% of their genome. Studies of variation indicate humans arose in Africa and migrated across the globe with relatively little change. Humans are also very different On average two random people differ at 3 million base pairs (approximately one nucleotide of every thousand). A few genes can have a big impact on appearance. Understanding the relationship between genotype and phenotype 1) Experimental organisms: manipulate genotype, determine phenotype 2) Humans: assay phenotypes, determine genotype (statistics) How are traits determined? Genetic Risk Traits can be determined predominantly by one gene. Mendelian traits result from variation in alleles of one gene. Traits can be determined by multiple genes. Polygenic traits result from variation in several genes. Traits can be determined by genes and environment. Multifactorial traits result from effects of one or more genes and the environment. Absolute risk Relative risk Empiric risk Risk factor the probability that an individual will develop a condition or trait the likelihood that an individual from one group will develop a condition in comparison to another group (usually the general population) risk determined by observing incidence of a trait in the population a situation that alters incidence of a disease (or trait) 4

5 Brief History Human Genome Decoded 2001 How Genetic Diseases Differ from Other Diseases One can predict recurrence risk in other family members Predictive testing is possible Different t populations have different characteristic frequencies Correction of the underlying genetic defect may be possible Our First Assignment Developing a family history according to recommendations of the American Society of Human Genetics. Building a pedigree of some trait using that pedigree to consider whether it could have a genetic component. Pedigree Analysis Human Pedigree Symbols Parents Offspring Unaffected Male Unaffected Female Affected male Affected female 5

6 An Ideal(ized) Pedigree Royal Pedigree of Porphyria Disease No disease Assuming pedigrees like this are available (they never are), how do you find linked molecular markers (and clone the gene)? 1) Obtain polymorphic markers for loci that "span the genome" 2) Identify closely linked flanking markers 3) Narrow non-recombinant interval and test candidates for causality Geneology DNA Testing 6