Functional Neurogenomics - 1 Flashcards
Neurdevelopmental disorders
Disruption of events that lead to brain development
Inability to reach cognitive, emotional & motor developmental milestones
Heterogeneous = Multifactoral & polygenic
Mutations: Chr. rearrangement, CNVs, small indels, point mutations
Rare genetic disorders
Alterations of single nucleotides
Overlap with neuropsychiatric disorders, but are genetically defined
Neuropsychiatric disorders
Persistant, pervasive & pathological pattern of abnormal mood…
Promise of genetics
Unbiased, causal, new disease mechanisms, target genes & therapeutics = personalized medicine
Heritability
= Proportion of variation in a trait explained by inherited genetic variants
= How well differences in peoples genes account for differences in their traits
Variation/Variance
How much a trait differs between people in a group
Heritability is a ratio of variance
Genetic influences on variation
Additive: Sum of the effect of each allele at all loci which influence the phenotype
Non-additive: Interaction between alleles at the same locus (dominance) or at different loci (epistasis)
Chromosomal linkage
Genes located physically close to each other on the same chromosome are more likely to be inherited as pair
Increased distance between two genes –> Increased probability of meiotic cross overs
Use genetic maps!
Twin studies
Compare the rate of the trait sharing between MZ & DZ twins
MZ share all genetic variability, DZ share half their genetic variability
Mendelian laws
- Segregation: Each inherited trait is defined by a gene pair
- Independent assortment: Inheritance of one trait is not dependent of another
- Dominance: Express the allele form that is dominant
Complex traits
Quantitative traits = Range of variation
Do not follow Mendelian inheritance laws
Many genes, that exert a small influence contributing to the disease, none by themselves can cause/explain the disease/trait
Complex traits described by genetic architecture
Number of variants influencing a phenotype
Magnitude of their effect on the phenotype
Population frequency of these variants
Interactions with these variants with each other & environment
Nature of Variants
Single Nucleotide Variant (SNV)
Coding variants
Non-coding variants
Indels
Short tandem repeats
Structural variant - Copy Number Variantion
Frequency of variants
Common genetic variants - MAF >/=5%
Low-freuqency variants: MAF >/=1 but <5%
Rare genetic variants: MAF <1%
Variant alleles
Matching human reference sequence or not
Being more frequent in population
Matching most recent common ancestor between human & chimpanze
Based on the disease association
Catalogue common human variation
1.Sequence lots of individuals to discover variants
2. Catalogue common variants & haplotype blocks
3. Genotype much larger set of individuals
4. Estimate population specific properties
Haplotypes
Specific set of alleles obeserved on a single chromosome
Arises because of recombination (more over time)
Linkage disequilibirum
Non-random association between alleles at different loci
Loci in equilibrium segragate independently
Loci in disequilibirum segragte dependently = Linked
Depends on location = The closer together, the more in disequilibrium
Epigenomics
Set of chemical modifications to DNA & histones in the cell –> Alter gene expression
3D genome organization
Fractual globules: Polymer forms a globule made of smaller globules
Predicts that contact probability is a function of distance betweem two sides
Equilibrium globule: Polymer more attracted to itself –> Many knots
Collapses in globule to minimalize contact to surroundings
