AIMS AND CONTENT

LEARNING OUTCOMES

Knowledge of the mode of inheritance of genetic disorders in humans and the underlying molecular mechanisms. Comprehension of experimental approaches for the detection of genetic factors associated to human diseases. Basic concepts on population genetics.

AIMS AND LEARNING OUTCOMES

The course aims to provide an in-depth understanding of the multiple inheritance patterns of genetic diseases and their underlying molecular causes. In addition, we will present the variety of experimental approaches to the study of human genetic diseases, including cytogenetic techniques and new DNA sequencing technologies. We will also address aspects of bioinformatics related to DNA sequencing and approaches to investigate the functional impact of variants. We will then address the basic concepts of tumor genetics and population genetics. Finally, the course will provide information on the inheritance of common polygenic and multifactorial disorders and present methods for identifying genetic susceptibility factors.

TEACHING METHODS

The course is organized in frontal lessons held in English. The topics included in the syllabus will be explained by the professor through PowerPoint presentation, also using examples from scientific papers. Students will be stimulated to ask questions and formulate answers using interactive modalities.

The practical Laboratory session will be held at the laboratories of the Unit of Medical Genetics at Gaslini Institute (Genova).

Any Student with documented Specific Learning Disorders (SLD), or with any special needs, should contact the Lecturer(s) and to the dedicated SLD Representative in the Department before class begins, in order to liaise and arrange the specific teaching methods so that the learning aims and outcomes may be met.

SYLLABUS/CONTENT

• MENDELIAN INHERITANCE AND GENETIC DISORDERS

Inheritance in Men: A brief History

Monogenic Disorders with Mendelian inheritance

Autosomal dominant disorders                                                                              

Autosomal recessive disorders                                                                               

Other Monogenic Disorders     

Chromosome X inactivation and X-linked disorders 

Y-linked disorders 

Mitochondrial inheritance 

Beyond Mendel. Complex monogenic disorders

Genetic Heterogeneity    

Allelic Heterogeneity    

Variable expressivity and Incomplete penetrance

Lethal alleles

Sex-limited traits 

Dynamic mutations and disease anticipation    

De novo mutations, gonadal and somatic mosaicisms                                             

Imprinting disorders and parent-of-origin gene expression 

• MUTATIONS IN GENETIC DISORDERS

Polymorphic variants

Classification of Mutations  

Chromosomal disorders and Cytogenetics

Human Karyotype 

Numerical and structural chromosomal abnormalities: classifications and mechanisms                

Abnormalities of Sex chromosomes  

Copy number variants (CNVs)

Point Mutations

DNA level: base substitution and base deletion/insertion

Protein level: Coding mutations

- Allelic heterogeneity in Cystic Fibrosis, as example 

- Nonsense mediated mRNA decay

Protein level: Non-Coding mutations

- Mutations affecting splicing                                                                                      

- Intronic mutations affecting non-coding functional elements                                    

Functional level: Loss- or gain-of-function  

• IDENTIFYING MUTATIONS IN GENETIC DISORDERS

Conventional Cytogenetics for detection of chromosomal abnormalities

Karyotyping and chromosome banding

International System for human Cytogenetics Nomenclature (ISCN)

Cytogenetics in the clinical practice                                                                            

Molecular Cytogenetics for detection of Copy Number Variants (CNVs)

Fluorescence in sit hybridization (FISH)

Comparative Genomic Hybridization (CGH)

DNA microarrays

- CGH Arrays 

- SNP Arrays

- DNA microarrays in the clinical practice

Sequencing

Sequencing methods (Overview)

Analysis of Sequencing data  

Genetic Databases and Genome Browsers

Applications of Sequencing methods in human genetics                                         

Genetic Testing

- NGS: Exome Sequencing and interpretation of variants in the clinical setting         

- NGS: Detection of Structural Variations (NIPT)                                                        

- Long Reads Sequencing (Repeats and GC regions, De Novo Assembly)     

• FUNCTIONAL GENETICS

   Interpreting the functional role of mutations by cellular approaches

Silencing

Overexpression

Gene editing

Precision medicine in genetics 

Pharmacological targeting of mutations in Cystic Fibrosis

• POPULATION GENETICS

Hardy-Weinberg Equilibrium

Factors influencing H.W. equilibrium Mutation                                                            

Genetic drift

Migration                                                        

Non-random mating

Natural selection                

Neutral Theory       

• POLYGENIC AND MULTIFACTORIAL DISORDERS

Complex inheritance

Variance and Heritability  

Concordance in twins, relative risk ratio, empiric risks 

Discontinuous and Continuous traits

Mapping of complex traits

Linkage disequilibrium

Association studies                                                                       

Sequencing studies and Gene Burden test.   

• CANCER GENETICS

Definitions and classifications

Principles of cancer genetics

Oncogenes and tumor suppressor genes

Mechanisms underlying tumorigenesis

Hereditary Cancel syndromes

• FUNCTIONAL GENETICS LABORATORY

Bioinformatic pipelines for NGS data analysis

Spatial profiling of gene expression by RNA scope, single-cell RNAseq and cell imaging

Advanced cell models (iPS cells and neurons, 2D and 3D epithelial respiratory cell models

Functional tests (ion imaging, patch-clamp and MEA electrophysiology)

RECOMMENDED READING/BIBLIOGRAPHY

Lecture notes and reviews covering the whole course will be available for the students in Aulaweb. In addition, students will be provided with files containing genetic problems with solutions

Recommended reference textbook:

• Strachan & Read - Human Molecular Genetics. Bios Scientific Publisher.

TEACHERS AND EXAM BOARD

LESSONS

LESSONS START

II semester, March.

Class schedule

HUMAN GENETICS AND LABORATORY

EXAMS

EXAM DESCRIPTION

The exam is carried out as oral test in English or in Italian, as preferred by the student. The final vote is expressed out of 30.

ASSESSMENT METHODS

The oral exam, in English or Italian, will allow to test students on most of the content of the course, by assessing their knowledge on human genetics, as well as the acquired ability to connect different topics and to eventually solve genetic problems.

Proficiency in English language, if opted by the student, will not be evaluated, but it must be sufficient to show the student’s knowledge of the subjects, with an adequate level of expertise.

Exam schedule