Learning outcomes

See the ‘content’ section.

Goals

Genetics is playing an increasingly important role in the biomedical field, both in terms of diagnosis and therapeutic perspectives. The genetics course approaches the basic concepts from a specifically human angle, from molecular genetics to population genetics. The structure of DNA and genes and the regulation of their expression in eukaryotes are studied. The study of gene transmission is illustrated by examples of dominant, recessive and X-linked diseases. The main genetic syndromes, of chromosomal or gene origin, are illustrated (molecular and phenotypic aspects and genetic counselling). Notions of multifactorial inheritance are discussed. Cytogenetics, the organisation of the human genome and the principles of genetic mapping are explained using examples to help students understand their current applications. The course focuses on understanding mechanisms and reasoning.

Content

1. Introduction 
  • The germ line is continuous
  • Genetics, human genetics, medical genetics, somatic ‘genetics
  • Impact of genetic diseases on human health
  • Relationships between genes, environment and phenotypes
  • History of some of the fundamentals of genetics
    • Mendel's discoveries: the concept of the gene
    • Mendel's laws
    • The chromosomal theory of heredity
    • Genes are linked to chromosomes
    • Meiosis
    • Genetic linkage and crossover
    • Chromosome mapping
    • The origin of genetic variability, mutations
    • Nucleic acids transmit genetic information
    • Avery's unexpected discovery: DNA can carry genetic specificities
    • The double helix
    • The genetic information contained in DNA is contained in the sequence of 4 nucleotides
    • The central dogma
    • The Crick adapter hypothesis
    • The discovery of tRNA
    • The discovery of mRNA
    • Establishing the genetic code
2. Structure of nucleic acids
 
  • The DNA double helix
  • DNA topology
  • Structure and functions of RNA (with a few slides on RNA viruses and their cycle)
3. Organisation of genomes
  • Size and organisation
  • Repeat sequences
  • Mammalian transposable elements (LINE, SINE, LTR, ERV)
  • LINE transposition
4. Chromosome structure
  • Centromeres
  • Origins of replication
  • Telomeres
  • Replication of linear chromosome ends
  • Telomerase
  • Chromatin structure
  • The nucleosome
  • Higher-order chromatin structures
  • Regulation of chromatin structure
  • Histone modifications
5. DNA replication
  • Initiation and activation of the origins of replication
  • Helicases, topoisomerases, primase, DNA polymerases,
6. Mutations
  • The different types of mutation
  • Origin of mutations
 
7. DNA damage and repair
  • Nature of DNA damage
  • chemical modifications of bases (altered bases, missing bases)
  • Deaminations
  • Oxidation of bases
  • hydrolysis (loss of base)
  • alkylations
  • pyrimidine dimers
  • base mismatches
  • ‘intra-strand and inter-strand ‘bridging
  • bridging between DNA and proteins
  • single- and double-strand breaks in the ribose-phosphate backbone
  • Causes of DNA damage
    • spontaneous damage 
    • damage induced by mutagenic ‘agents’ (chemical, UV and ionising radiation)
      • Ionising 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 large lesions
  • Nucleotide excision repair (NER)
  • 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 notions of epigenetics
  • Observation and description of chromosomes (banding)
  • Chromosomal abnormalities
  • definition
  • The different categories of anomalies
  • Numerical and structural abnormalities
  • Cytogenetic nomenclature
  • Balanced and unbalanced abnormalities
  • New and inherited abnormalities
  • Causes of aneuploidies
  • Clinical consequences of anomalies
  • Autosomal aneuploidies
  • Causes of Down's syndrome
  • Sex determination
  • Sex chromosome abnormalities
  • Inactivation of the X chromosome
  • DNA methylation and notions of epigenetics
  • Sex chromosome abnormalities
  • Parental chromosome abnormalities
    • Parental imprinting
    • Diploidism and uniparental disomy
    • Causes of Prader-Willy and Angelman syndrome

9. Genome expression: transcription

  • The initiation complex, transcription factors
  • Elongation
  • Termination and polyadenylation
  • Splicing of introns
10. Genes in pedigrees and populations
 
  • Profiles of Mendelian pedigrees
  • Complications of Mendelian pedigrees
  • Genetics of multifactorial traits: the polygenic threshold theory
  • Factors affecting allele frequencies
  • use of the Hardy-Weinberg equilibrium in genetic counselling
  • 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 candidate gene.
12. genetic variability in humans and its consequences
 
  • Types of variation between individual genomes (SNPs, number of repeated sequences, large-scale variations)
  • pathogenic DNA variants (missense mutations, nonsense mutations, phase shifts, dynamic mutations)
  • molecular pathology: understanding the effects of pathogenic variants
  • loss of function vs gain of function
  • allelic heterogeneity in loss of function
  • haploinsufficiency
  • negative dominant effect
  • gains of function often affect regulatory circuits
  • allelic homogeneity is not always linked to a gain of function
13. Molecular biology elements (methods) :
 
cellular cloning of DNA fragments
electrophoresis
nucleic acid hybridisation
FISH
Sanger DNA sequencing
Southern blot, Northern blot
PCR
transcriptomics using RNA microdammers and RNAseq
CGH array
CRISPR/Cas9 and genome editing (very brief)

 

Exercices

Tutorial sessions.

Teaching methods

Ex-cathedra classes and tutorials.

Assessment method

Multiple-choice questionnaire on the material covered in the ex-cathedra lessons and tutorials.

Sources, references and any support material

PowerPoint’ type support
 
 reference manuals :
 
Human Molecular Genetics (4th Ed.) Authors: STRACHAN Tom, READ Andrew

Language of instruction

French