At the end of the theoretical and practical teaching activities, the student will be able to:
The Human Molecular Genetics course aims to introduce the fundamental principles of genomics, formal and clinical genetics, as well as the main genetic analysis techniques, enabling students to understand the molecular bases of constitutional genetic diseases and their implications in pharmaceutical practice. The course is designed to provide the concepts necessary for the critical analysis and interpretation of advances in personalized medicine, integrating the ethical, technological, and clinical aspects of human genetics.
The general objectives of this course are as follows:
The course emphasizes understanding of molecular mechanisms and scientific reasoning.
The course begins with an in-depth exploration of human genomics, detailing the molecular structure of DNA and RNA, replication and repair mechanisms, as well as the organization of genes and chromosomes. It emphasizes genome diversity: repeated sequences, coding and non-coding genes, and mechanisms of genetic variability (SNVs, CNVs).
The section on formal genetics introduces the fundamental principles of genotype and phenotype, inheritance of hereditary traits, and pedigree interpretation. It details the different modes of inheritance: autosomal dominant, autosomal recessive, X-linked and mitochondrial, with clinical examples illustrating each mechanism.
The study of constitutional genetic disorders focuses on chromosomal abnormalities (number and structure), monogenic diseases (such as RASopathies, chromatinopathies, ciliopathies), diseases related to genomic imprinting, triplet repeat expansion disorders, and polygenic or multifactorial diseases (analyzed notably by GWAS).
The section on oncogenetics examines carcinogenesis mechanisms, DNA repair, and major hereditary cancer predispositions (breast/ovary, colon), incorporating Knudson’s theory and the concept of loss of heterozygosity.
The course then presents detection and analysis techniques for genetic diseases, from chromosomal studies (karyotype, FISH, CGH-array, SWGS, genome mapping) to gene analysis (PCR, Southern blotting, NGS) and functional studies (RNA and protein analysis, cellular and animal models).
Finally, aspects of clinical genetics are addressed: contexts of consultation and genetic counseling, diagnostics (prenatal, postnatal, preimplantation, predictive), and screening strategies. The course concludes with an overview of innovative therapeutic strategies: cellular, proteomic, transcriptomic, and genomic therapies.
1.1.1. Definition of the Genome
1.1.2. Molecular Structures of DNA and RNA
1.1.2.1. Molecular Structure of DNA
– Chemical Composition of Nucleotides
– Bonds Between Nucleotides
– Double Helix Structure
1.1.2.2. Molecular Structure of RNA
– Chemical Composition
– Primary, Secondary, Tertiary Structure
– Post-Transcriptional Modifications
– Functional Roles Related to Structure
1.1.3. DNA Replication and Post-Replicative Repair Mechanisms
1.1.3.1. DNA Replication Process
1.1.3.2. Fidelity Mechanisms
– Base Complementarity
– DNA Polymerase Proofreading Activity
– Post-Replicative Repair Systems (MMR, BER, NER, HR, NHEJ)
1.1.3.3. Importance of Genetic Stability
1.1.4. Gene Structure
1.1.5. Organization of Nuclear DNA
1.1.5.1. Human Chromosomes
– Chromosome Structure
– Peculiarities of Sex Chromosomes and X Chromosome Inactivation
1.1.5.2. Chromatin Structure
1.1.5.3. Chromatin Conformation
– Chromosome Territories
– Compartments A and B
– Topologically Associated Domains (TADs)
– Enhancer-Promoter Loops
1.1.6. Organization of Mitochondrial DNA
1.2.1. Repeated Sequences
1.2.1.1. Tandemly Repeated DNA
– Satellites
– Minisatellites and Telomeric Repeats
– Microsatellites
1.2.1.2. Dispersed Repetitive DNA: Mobile Genetic Elements
– DNA Transposons
– LINE Retrotransposons
– SINE Retrotransposons
– HERV–LTR Retrotransposons
1.2.1.3. Segmental Duplications, Pseudogenes and Retro-pseudogenes
1.2.2. Coding Genes
1.2.2.1. Structure of Coding Genes
1.2.2.2. Transcription
– Promoter and RNA Polymerases
– Pre-messenger RNA
– Post-transcriptional Modifications and mRNA Formation (splicing, capping, polyadenylation, RNA editing)
1.2.2.3. Translation
– Role of Ribosomes and tRNAs
– mRNA Quality Control by NMD
– Post-translational Modifications (cleavage, chemical modifications)
– Protein Folding
1.2.3. Non-coding Genes
1.2.3.1. Small Non-coding RNAs (<200 nucleotides)
– tRNAs
– rRNAs
– snRNAs
– snoRNAs
– piRNAs
– miRNAs
– siRNAs
1.2.3.2. Long Non-coding RNAs (>200 nucleotides)
– Antisense RNAs
– Other lncRNAs
1.3.1. SNVs (Single Nucleotide Variants)
1.3.2. CNVs (Copy Number Variations)
– Genotype and Phenotype
– Gene Alleles
– Homozygosity and Heterozygosity
– Dominance and Recessivity of Alleles
– Pedigree: An Essential Tool
2.2.1. Autosomal Dominant Inheritance
2.2.1.1. Principles
2.2.1.2. Particularities
– Incomplete Penetrance
– Variable Expressivity
– Genetic Heterogeneity, Phenocopy, Pleiotropy
– De Novo Mutation
– Parental Germline Mosaicism
– Somatic Mosaicism
– Parental Genomic Imprinting (maternal or paternal)
– Homozygosity Dominance
Clinical vignettes: Marfan Syndrome, Type 1 Neurofibromatosis, Familial Hypercholesterolemia, Achondroplasia, Osteogenesis Imperfecta
2.2.1.3. Molecular Mechanisms of Dominance
– Gain-of-function Mutations
– Dominant Negative Mutations
– Loss-of-function Mutations and Haploinsufficiency
2.2.2. Autosomal Recessive Inheritance
2.2.2.1. Principles
Clinical vignette: Cystic Fibrosis
2.2.2.2. Particularities
– Consanguinity
– Allelic Heterogeneity
– Incomplete Penetrance
– Pseudo-dominance
2.2.2.3. Molecular Mechanisms of Recessivity
– Loss-of-function Mutations
– Hypomorphic Mutations
2.2.3. X-linked Inheritance
2.2.3.1. Principles (recessive/dominant)
Clinical vignettes: Hemophilia A and B, Duchenne Muscular Dystrophy, Rett Syndrome
2.2.3.2. Particularities
– Mosaicism in Women
– Incomplete Penetrance and Variable Expressivity
– De Novo Mutations
– Lethality in Males
– Similar Expression in Both Sexes
– Preferential Impact on Women due to Functional Mosaicism
2.2.4. Mitochondrial DNA Inheritance
2.2.4.1. Principles
2.2.4.2. Particularities
– Homoplasmy and Heteroplasmy
– Incomplete Penetrance and Variable Expressivity
Clinical vignette: Leber Hereditary Optic Neuropathy
3.1.1. Sex Chromosome Number Abnormalities
3.1.1.1. 45,X Constitution and Variants
Clinical vignette: Turner Syndrome
3.1.1.2. 47,XXY Constitution and Variants
Clinical vignette: Klinefelter Syndrome
3.1.1.3. Other Sex Chromosome Number Variations
– 47,XXX and 47,XYY
– 48,XXXX; 48,XXXY; 48,XXYY; 49,XXXXY
3.1.2. Autosomal Number and Structural Abnormalities
3.1.2.1. Autosomal Number Abnormalities
– Trisomies (21, 18, 13)
Clinical vignette: Trisomies 21, 18, 13
– Triploidy
Clinical vignette: Triploidy
3.1.2.2. Balanced Autosomal Structural Abnormalities
– Reciprocal Translocations
– Robertsonian Translocations
– Balanced Insertions
– Balanced Inversions
Clinical vignette: Syndrome F
3.1.2.3. Unbalanced Autosomal Structural Abnormalities
– Isochromosomes
Clinical vignette: Pallister-Killian Syndrome
– Ring Chromosomes
– Deletions and Duplications
Clinical vignettes: Cri-du-chat Syndrome, 22q11 Microdeletion, Williams-Beuren Syndrome, Smith-Magenis Syndrome
– CNVs with Incomplete Penetrance and Variable Expressivity
3.2.1. RASopathies
Clinical vignette: Noonan Syndrome
3.2.2. Chromatinopathies and Cohesinopathies
Clinical vignettes: Kabuki Syndrome, Cornelia de Lange Syndrome
3.2.3. Ciliopathies
Clinical vignette: Joubert Syndrome
3.2.4. TGF-β Signaling Pathway Diseases
Clinical vignette: Loeys-Dietz Syndrome
3.3.1. Definitions
3.3.2. 15q11q13 Region
Clinical vignettes: Prader-Willi Syndrome, Angelman Syndrome
3.3.3. 11p15 Region
Clinical vignettes: Beckwith-Wiedemann Syndrome, Silver-Russell Syndrome
3.4.1. Definitions
3.4.2. Pathophysiological Mechanisms
3.4.3. Triplet Repeat Expansion Diseases
Clinical vignettes: Fragile X Syndrome, Myotonic Dystrophy, Huntington Disease
3.5.1. GWAS Studies
3.5.2. Personalized Medicine
4.1.1. Endogenous Lesions
4.1.2. Exogenous Lesions
4.1.3. DNA Repair Mechanisms
4.1.3.1. Direct Lesion Repair
– Photolyase for thymine dimers
– Methyltransferases for m6G, m1A, m3C
4.1.3.2. Post-replicative Repair Systems (MMR, BER, NER, HR, NHEJ)
(see 1.1.3.2)
4.2.1. Sporadic Cancers and Hereditary Predisposition
4.2.2. Knudson's Theory
4.2.3. Loss of Heterozygosity
4.2.4. Hereditary Cancer Predispositions
4.2.4.1. Breast and Ovarian Cancer (BRCA1 and BRCA2 genes)
4.2.4.2. Colon Cancers (Lynch Syndrome, Familial Adenomatous Polyposis)
5.1.1. Standard Karyotype
5.1.2. FISH Technique
5.1.3. Molecular Karyotyping
5.1.3.1. CGH-arrays (Comparative Genomic Hybridization)
5.1.3.2. SWGS (Shallow Whole Genome Sequencing)
5.1.3.3. Optical Genome Mapping
Summary Table
5.2.1. PCR and Sanger Sequencing
5.2.2. Southern Blotting
5.2.3. Methylation-specific PCR (MS-PCR)
5.2.4. High-throughput Sequencing (NGS, Next Generation Sequencing)
5.2.4.1. NGS Short Reads (Whole Exome Sequencing, Whole Genome Sequencing)
5.2.4.2. NGS Long Reads (Nanopore, PacBio)
Summary Table
5.3.1. RNA Analysis
5.3.1.1. Targeted cDNA Analysis (Reverse Transcriptase function)
5.3.1.2. Transcriptome (RNA-Seq)
5.3.2. Protein Analysis
5.3.2.1. Western Blotting
5.3.2.2. Proteome
5.3.3. Cellular Models (in vitro analyses)
5.3.3.1. Cell Cultures, Stem Cells and Organoids
5.3.3.2. Cell Transfection and Transduction
5.3.3.3. Mutagenesis Methods: Genome Editing (CRISPR-Cas9)
5.3.4. Animal Models (in vivo analyses)
5.3.4.1. Zebrafish Models
5.3.4.2. Mouse Models
6.2.1. Postnatal Diagnosis
6.2.2. Prenatal Diagnosis
6.2.2.1. Amniocentesis
6.2.2.2. Chorionic Villus Sampling / Trophoblast Biopsy (CVS)
6.2.3. Preimplantation Diagnosis
6.2.4. Predictive Diagnosis
6.3.1. Preconceptional Screening (Carrier Screening)
6.3.2. Prenatal Screening (NIPT test)
6.3.3. Neonatal Screening (Guthrie, Neonatal Genetic Testing)
7.1.1. Organ Transplantation
7.1.2. Stem Cell Transplantation
7.1.2.1. Donor Stem Cells
7.1.2.2. Stem Cells Obtained by Therapeutic Cloning or iPSC, with Genome Editing
7.3.1. Small Interfering RNAs (siRNA)
7.3.2. Antisense Oligonucleotides (ASO)
7.4.1. Activation of a Partially Functional Gene Promoter or a Compensatory Gene
7.4.2. Gene Therapy (“gene drug”)
lecture, diagrams on the board, clinical illustrations on Power Point slides
Identical examination mode in the first and second session. Written examination, with multiple choice questions.
The exact modalities of the assessment are subject to change when the examination timetable is drawn up, depending on the practical constraints that the faculty administration may face, or in the event of illness/force majeure/emergency with a work placement, preventing the student from taking the examination on the date initially scheduled.
Webcampus (syllabus and powerpoint slides)
| Training | Study programme | Block | Credits | Mandatory |
|---|---|---|---|---|
| Bachelor in Pharmacy | Standard | 0 | 3 | |
| Bachelor in Pharmacy | Standard | 2 | 3 |