Genetics Study Notes PDF

**[Genetics:]** [Why do we estimate heritability?] - Quantitative Genetic studies tell us: - The importance of genetic and environmental influence - Provides a best-case scenario for genetic prediction - Allows us to estimate the success of gene identification efforts [Mole...

**[Genetics:]** [Why do we estimate heritability?] - Quantitative Genetic studies tell us: - The importance of genetic and environmental influence - Provides a best-case scenario for genetic prediction - Allows us to estimate the success of gene identification efforts [Molecular Genetic Research:] - The study of the structure and function of genes at the molecular level - Builds on quantitative genetics research to tell us: - What are the specific genetic factors? - How large is their effect? - How do they influence human trait variation or liability to disease? [Twins -- Natural experiment:] - Genotype 100% vs 50% - Sex - Age - Parents - In Utero Environment - Early life/Home environment [DNA Structure:] - Composed of two long strands that form a double helix, with each strand made up of smaller units called nucleotides - Each nucleotide consists of three components: - Phosphate group - Deoxyribose sugar - Nitrogenous base -- 4 types - Adenine (A) - Thymine (T) - Cytosine © - Guanine (G) - Watson-Crick base-pairing rules: A:T, C:G (hydrogen bonds) [DNA to mRNA:] Process of going from DNA to protein involves two major steps: transcription & translation - Transcription: (DNA mRNA) - Occurs in the nucleus of the cell - DNA sequence of a gene is copied into messenger RNA (mRNA) - Enzyme RNA polymerase binds to the DNA at a region called the promoter and unwinds the DNA strands - RNA polymerase reads one strand of the DNA and synthesises a complementary strand of mRNA - Once the mRNA is synthesised it detaches from the DNA and exits the nucleus into cytoplasm [From mRNA to Protein:] - Translation: (mRNA to Protein) - Occurs in the ribosomes, found in cytoplasm - mRNA serves as a template for assembling amino acids into protein - Transfer RNA (tRNA) molecules bring appropriate amino acids to the ribosomes where they are added to a growing chain to form a protein - The process continues until a stop codon is reached [Translation: The Codon Table] - Amino acids can be groups into chemically or structurally similar groups - Some DNA variation that leads to an amino acid change has little or no impact on protein structure/function [Part 2 Learning Objectives:] - The structure of DNA - The human genome project and why it was important - The different types of genetic diversity in human populations - Commonly used terms [The Human Genome Project:] - Published in 2003 - 3.1x10\^9 bases (3billion) - 22,000 protein coding genes (\~2%) - 3billion USD - 15 years [We vary genetically:] - No two people are genetically identical, except for MZ twins - Humans are 99.9% genetically identical - We mostly know where the 0.1% (3million bases) of DNA variation resides - Variation makes us unique [Classification of Genetic Variation:] - Mutation: change in DNA sequence from wild type -- often used as short-hand for pathogenic variant - Polymorphism or DNA variant: a variation of the DNA sequence (at a specific locus) that is present in more than 1% of the population (minor allele frequency; MAF \>1%) - Non-polymorphic: the DNA base does not vary in the population [Glossary of terms:] - **Genes:** Units of inheritance that are passed down to the next generation - **Locus:** Specific position in the genome - **Alleles:** the genes or variants found at the same locus on different homologous chromosomes are alleles - **Allele frequency:** refers to the number of alleles in the population - **Genotype:** combination of the two alleles at a specific locus [Many types of Genetic Variation:] - Small scale - Single Base Change (SNPs) - Medium scale - Copy Number Variation (CNVs) - Large scale - Chromosomal abnormalities - Change in the number of chromosomes (whole) - Change in the arrangement chromosomes (part) [Genotypes to Alleles & MAFs:] - TT individuals have two alleles = 200 T alleles in the controls - CT individuals have one T allele = 400 T alleles in controls - There are 600 T alleles in the controls - The total number of allele in the controls is 2000 (each person has two alleles 600/2000 =30%) Association Testing: - Chi-square 54.303 p = 1.72 x 10\^-13 - Odds ratio 1.615 (95% CI 1.421 -- 1.836) [Biological insights from 108 schizophrenic-associated genetic loci:] - 36,989 cases - 113,075 controls - 83 new loci - DRD2 - Several genes involved in glutamatergic neurotransmission [Latest Schizophrenic GWAS: ] - 67,390 cases - 94,015 controls - 294 independent SNPs - Enrichment of signal in the brain & in relevant cell types [Chromosomal micro-duplications and deletions:] - 1 copy -- deletion - 2 copy -- normal - 3 copy -- duplication [Association of 15q11.2 (BP1-BP2) deletion CNVs in controls with cognitive traits: ARHQ and AMHQ scores:] - ARHQ & AMHQ are reading/maths questionnaire used to detect dyslexia and dyscalculia [Dose-dependent alterations in brain structure in 15q11.2 (BP1-BP2) CNV carriers:] - Grey matter alterations in anterior cingulate cortex; CF dyscalculia - Grey matter alterations in insula and supramarginal gyrus; CF dyslexia - White matter alterations in left temporal lobe and corpus callosum [16p11.2 CNV region:] - Effect of the chromosome 16p11.2 duplication on BMI and head circumference - 16p11.2 Duplications and Deletions produce mirror phenotypes on obesity and many measures of brain imaging - Similar phenotypes are seen in a zebrafish model using the KCTD13 gene [DNA Variation and Health:] - Molecular Level: - Single base pair (SNP & SNV) - Multiple base pair changes \< 1000 bp - Sun-microscopic Level: - Structural variations \> 1000 \< \~5,000,000 bp in size - E.g., Copy Number Variation (CNVs) - Microscopic/Chromosomal/Cytogenetic Level: - Large Structural Re-arrangements - \~5,000,000 bp [Genetic Causes of Alzheimer's Disease:] - Causative Changes also identified in: - Presenilin 1: Chromosome 14 - Presenilin 2: Chromosome 1 [Rare Causative Variants in Families:] - Familial Dementias - Single gene disorders and in which intellectual disability is part of the phenotype [Developmental delay/Intellectual disability syndromes:] - 3q29 deletion/duplication syndrome - 1q21.1 deletion/duplication syndrome - 16q11.2 deletion syndrome - 15q13.3 deletion syndrome [22q11.2 deletion syndrome: ] - Fairly large chunk of long arm chromosome 22 missing from one chromosome - Missing chunk contain many genes - COMT, degradation of neurotransmitters, maps to deleted region [Rare recurrent CNVs -- pleiotropic effects:] - 1q21.1 Deletion Syndrome - Schizophrenia - Autism - ID - 3q29 Deletion Syndrome - Schizophrenia - ID - 15q13.3 Deletion - Schizophrenia - Epilepsy - ID - 16p11.2 - Autism - Schizophrenia - Epilepsy - ID [Zebrafish Model of Schizophrenia:] - Social behaviours and social preference is present in all social animals - Some of first symptoms of premorbid schizophrenia relate to impaired social functioning - Juvenile zebrafish show spectrum of social preference similar to humans [Genetic Markers: Single Nucleotide Polymorphisms (SNPs)] - Variation at single base position - 2 variants at position - Alternate base "common" - Frequent - Change does not usually effect amino acid