1.Introduction
- The germline is continuous
- Genetics, human genetics, medical genetics, somatic “genetics”
- Impact of genetic diseases on human health
- Relationships between genes, environment, and phenotypes
- Historical background of some fundamentals of genetics
- Mendel’s discoveries: the concept of the gene
- Mendel's laws
- Chromosome theory of inheritance
- Genes are linked to chromosomes
- Meiosis
- Genetic linkage and crossing-over
- Chromosome mapping
- The origin of genetic variability, mutations
- Nucleic acids transmit genetic information
- Avery’s unexpected discovery: DNA can carry genetic specificity
- The double helix
- Genetic information contained in DNA is encoded in the sequence of the four nucleotides
- The central dogma
- Crick’s adaptor hypothesis
- Discovery of tRNAs
- Discovery of mRNAs
- Establishment of the genetic code
2. Structure of Nucleic Acids
- The DNA double helix
- DNA topology
- Structure and functions of RNA (including slides on RNA viruses and their cycle)
3. Organization of Genomes
- Size, organization
- Repeated sequences
- Mammalian transposable elements (LINE, SINE, LTR, ERV)
- LINE transposition
4. Structure of Chromosomes
- Centromeres
- Origins of replication
- Telomeres
- Replication of the ends of linear chromosomes
- Telomerase
- Chromatin structure
- The nucleosome
- Higher-order chromatin structures
- Regulation of chromatin structure
- Histone modifications
5. DNA Replication
- Initiation, activation of replication origins
- Helicases, topoisomerases, primase, DNA polymerases
6. Mutations
- Different types of mutations
- Origin of mutations
7. DNA Damage and Repair
- Nature of DNA damage
- Chemical modifications of the bases (altered bases, missing bases)
- Deaminations
- Base oxidation
- Hydrolysis (base loss)
- Alkylations
- Pyrimidine dimers
- Base mismatches
- Intrabranch and interbranch crosslinks
- DNA-protein crosslinking
- Single-strand and double-strand breaks of the ribose-phosphate backbone
- Causes of DNA damage
- Spontaneous damage
- Induced damage by mutagenic "agents" (chemicals, UV and ionizing radiation)
- Ionizing radiation
- Chemical mutagens
- The Ames test detects the mutagenic potential of a substance
- Repair mechanisms and “trans-lesion” DNA synthesis (TLS)
- Repair of a damaged base
- Direct reversal of DNA damage
- Base excision repair (BER)
- Repair of bulky lesions
- Nucleotide excision repair (NER)
- Repair of mismatches (mismatch repair, MMR)
- Interstrand cross-link repair (ICL)
- Repair of double-strand breaks:
- Non-homologous end joining (NHEJ)
- Homologous recombination, gene conversion
- Clinical consequences of DNA repair defects
8. Cytogenetics and Concepts of Epigenetics
- Observation and description of chromosomes (banding)
- Chromosomal abnormalities
- Definition
- Different categories of abnormalities
- Numerical and structural abnormalities
- Cytogenetic nomenclature
- Balanced and unbalanced abnormalities
- De novo and inherited abnormalities
- Causes of aneuploidies
- Clinical consequences of abnormalities
- Autosomal aneuploidies
- Causes of Down syndrome
- Sex determination
- Sex chromosome abnormalities
- X chromosome inactivation
- DNA methylation and concepts of epigenetics
- Sex chromosome abnormalities
- Parental origin chromosomal abnormalities
- Parental imprinting
- Diploidy and uniparental disomies
- Causes of Prader-Willi and Angelman syndromes
9. Genome Expression: Transcription
- Initiation complex, transcription factors
- Elongation
- Termination and polyadenylation
- Intron splicing
10. Genes in Pedigrees and Populations
- Patterns of Mendelian pedigrees
- Complications compared to Mendelian pedigrees
- Genetics of multifactorial traits: the polygenic threshold theory
- Factors affecting allele frequencies
- Use of Hardy-Weinberg equilibrium in genetic counseling
- New mutations, selection, genetic drift
11. Mapping and Identification of Genes Controlling Monogenic Traits
- Positional cloning
- Functional cloning
- Genome-wide association studies
- Genome and exome sequencing
- Confirmation of the candidate gene
12. Human Genetic Variability and Its Consequences
- Types of variation between individual genomes (SNPs, repeat number, large-scale variants)
- Pathogenic DNA variants (missense, nonsense, frameshift mutations, dynamic mutations)
- Molecular pathology: understanding the impact of pathogenic variants
- Loss of function vs. gain of function
- Allelic heterogeneity in loss of function
- Haploinsufficiency
- Dominant negative effect
- Gain-of-function mutations often affect regulatory pathways
- Allelic homogeneity is not always linked to gain of function
13. Essentials of Molecular Biology (Methods):
- Cloning of DNA fragments in cells
- Electrophoresis
- Nucleic acid hybridization
- FISH
- Sanger DNA sequencing
- Southern blot, Northern blot
- PCR
- Transcriptomics by RNA microarray and RNAseq
- CGH array
- CRISPR/Cas9 and genome editing (very brief)