The main objective of the course is to provide advanced information on the genetic basis of human disease and to understand the impact of new knowledge on the genome in the study of human molecular genetics.
After completing the course, the student will have knowledge on specific issues related to the analysis of the human genome and the molecular basis of genetic diseases . In particular, the student should know: the fundamentals of molecular pathology, the most commonly used techniques in molecular diagnosis of genetic diseases, and the main approaches for the genetic analysis of Mendelian and complex characters
Human genome organization Human gene organization, multigene families and pseudogenes. Human repeated sequences. Organization, distribution and function of RNA genes in humans Mendelian inheritance. Autosomal dominant and recessive inheritance. Complications of the patterns of inheritance : genetic heterogeneity , incomplete penetrance , variable expressivity, late onset , anticipation , imprinting and uniparental disomy , somatic and germline mosaicism; mitochondrial inheritance; interpretation of the pedigrees ( symbology ) . Sex-linked inheritance. X and Y linked genes; chromosome inactivation X; functional mosaicism resulting from the X chromosome inactivation, Determination and sex differentiation. Structure and function of chromosomes. Human karyotype: morphology and classification of human chromosomes; Kariotyping and chromosome banding; prenatal and postnatal chromosome analysis. Molecular cytogenetic techniques applications. Chromosomal abnormalities. Numerical chromosomal abnormalities and their effects (polyploidy, aneuploidy); meiotic and mitotic non-disjunction. Main human aneuploidy of autosomes and sex chromosomes. Structural chromosomal abnormalities and their effects; Balanced and unbalanced rearrangements; Mosaicism. Mutations and genome instability. Classes and molecular mechanisms of mutations. Genetic polymorphisms. Main types of DNA polymorphisms used as genetic markers (RFLP, microsatellites, SNPs). Molecular pathology: mutation for loss or gain of function in relation to dominance-recessiveness. Submicroscopic structural variants: copy number variants (CNVs) and their pathological effects; unequal crossing over as a mechanism that generates structural variant Repeat instability Mechanisms and classification of dynamic mutations: Fragile X Syndrome, Myotonic Dystrophy , Huntington disease, Kennedy Disease. Molecular pathology. Methods for the identification of point mutations: methods to identify new mutations. Genetic mapping of characters Mendelian and complex traits. Genetic markers, recombination frequency and construction of genetic maps. Linkage analysis and calculation of "lod score". Complex or multifactorial diseases: continuous and discontinuous characters; interaction with the environment; characters with threshold effect. Concept of heritability. Twins studies. Strategies for the identification of genetic factors involved in complex diseases. Non-parametric linkage analysis, case-control association studies, association studies extended to the whole genome (GWAS). Study of linkage disequilibrium and HapMap project. Identification and characterization of candidate genes for inherited diseases. Molecular analysis of the human genome. The Human Genome Project, mapping and genome sequencing The genetics of hereditary cancers. The tumor suppressor genes and the two-hit mechanism.