Historical views of heredity and inheritance
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Bricks and mortar theory by Hippocrates - Elements are originated from all parts of the body and became concentrated in male semen. This will be developed and formed into human in the womb
- Inheritance is an acquired characteristics
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Blueprint theory by Aristotle - Transmission of information from parents to offspring
- Heredity is partly assymetric
- Transmission is particulate (definitely one trait or another)
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Lamarckian Inheritance - To explain while some features persisted while others disappeared
- Traits acquired/ lost when depends on need
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Modern genetics introduced by Darwin and Mendel
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Darwin's blending inheritance - Offspring inherit the parents' average characteristic
- All parts of the parents can contribute to the evolution and development of the offspring (Pangenesis)
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Mendel's particulate inheritance 1. Law of segregation
2. Law of independent assortment
3. Law of dominance
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Exception to independent assortment - Linked genes Genes can be linked together if it is located close together on the same chromosome
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Rediscovery of Mendel's work
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Allele One of two or more versions of DNA sequence at a given genomic location
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Conflict between Mendelian and Biometrician
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Debates between Mendelian and Biometrician - Do the hereditary and evolutionary properties for a trait like height were the same as those for Mendel's peas?
- Whether inheritance of complex trait was by 'blending' of parental phenotypes (Darwin) which was seen as different to the inheritance of discrete characters as in Mendel's peas
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Biuometrician's claim Traits are continuous (Blending inheritance) and heritable
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Mendelian's claim Mendelian genetics work in inheritance
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Achondroplasia <90cm height
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Marfan Syndrome >200cm height
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Emergence of Biometrical genetics
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Whar are Galton's claims in trait hereditary? 1. Traits like height, weight, arm length are normally distributed, not binary
2. Traits are resemble between parents and offspring
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Galton's claim(1): Traits are "normally distributed" means 1. A trait has a mean value given a population
2. A trait can be subject to mathematical transformation
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What Galton use to study continuous variation in organism? - Regression
- Correlation
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Galton's claim(2): Traits are resemble between parents and offspring - When measuring the height of parents and offspring, the mid-parental height has almost no deviation to their offspring height
- Therefore, traits are resemble between parents and offspring
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Brownlee's Multi-Gene model to explain Mendelian inheritance in the blending inheritance model 1. Parents and Child: 0.5 correlation because parents transmit 50% of their genome to their child
2. Parents and Grandchild: 0.25 correlation
3. Parents and Great-grandchild: 0.125 correlation
- These correlations are based on Mendelian's segregation law
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Polygenic Model
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Fisher`s Infinitesimal model - Polygenic inheritance :A quantitative trait could be explained by Mendelian inheritance if several genes affect the trait
- Include additive and dominant factors
- Resemblance between relatives occur due to their genetic covariance
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Fisher's single locus model Assume:
1. Dominant allele is not known
2. A locus either follows dominant or additive
- Used to determine whether the locus follow dominant or additive
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Fisher's single locus model, assume A2A2= -a and A1A1= a 1. If d>0 : A1 is dominant to A2
2. If d<0 A2 is dominant to A1
3. If d=a/-a: Complete dominance (Heterozygote)
4. If d=a/-a: Over-dominance
5. If d=0: Locus is additive
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Continuous distribution of quantitative traits Alleles in our genome is limited but environmental factors are not. Therefore, traits are also influenced by environmental factors
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Fisher's partitioning variance Genetic and non-genetic factors
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Three genetic factors (G) 1. Additive (A)
2. Dominance
3. Epistasis: Interaction between additive factors/ additive - dominant factors
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Non-genetic factor Environment (E)
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Phenotypic variance (P) Interaction between genetic and environmental factors (GxE)
2. P= G+E+GxE
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Heritability How much of the variation in a trait is due to variation in genetic factors (G)
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Genetic Architecture - Composition of various genetic factors upon a phenotype
- Include additive, dominance and epiptasis
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Genetics To identify genetic factor associated with traits/disease but also study the contribution of a genetic factors
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Trait is not dichotomy (contrast between two things) The features of an organisms are due to the individual's genotype and environment
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Allele
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Allele and Allele frequencies - Proportion of chromosomes in population carrying the allele of traits/disease
- Different combination of alleles determine traits or diseases
- Allele frequencies indicate the proportion of observed genotypes in a given population
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Allele transmission to next generation - Same with Mendel's first law
- Totally independent and not influenced by environmental factors
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Hardy-Weinberg Equilibrium
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Do segregation in Mendelian inheritance law affected by the segregant (allele)? No. This is called "stable"
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Hardy-Weinberg principle - Assumed that allele frequencies will not change from generation to generation
- p2+2pq+q2=1
- p+q=1
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Assumptions of Hardy-Weinberg equilibrium 1. Random mating
2. No natural selection
3. Equal genotype frequencies in two sexes
4. No mutation/migration
5. No differential viability
6. Infinite population size
However, all of these are not realistic!
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Mendelian segregation Preserved in any organism with sexual reproduction regardless of allele frequency in the population
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Chi-Square Test
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Chi square Use statistics to determine whether a locus of interest is under HWE or not
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Null hypothesis There is no difference between observed value and the expected value
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Degree of freedom (DF) - Number of phenotypic possibilities in the cross
- Example DF: 3(AA,Aa,aa)-1=2
- If the level of significance read from the table is greater than 0.05/5%, the null hypothesis is not rejected
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When the null hypothesis is supported by analysis Assumptions
1. Mating is random
2. Normal gene segregation
3. Independent assortment
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When the null hypothesis is not supported by analysis Assumptions
1. Non-random occur
2. Genes are not randomly segregating because they are linked on the same chromosome/inherited together.
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Introduction of Heritability
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Model to describe heritability 1. Fisher's model
2. Falconer's model
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Falconer's Model Mathematical formula used in twin studies to estimate the relative contribution of genetics vs environment to variation in a particular trait
- Heritability of the trait based on the difference between twin correlations
- Heritability=2(rMZ-rMD)
- Where r=concordance of the phenotype, MZ=Monozygotic Twins, DZ= Dizygotic twins
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Heritability
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Phenotypic similarity in family depends on 1. Genetic relationship
2. Traits
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Total phenotypic variance for a character? - VP=VG+VE
- Combined effects of genotypic and environmental variance
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Genetic variance (VG) - The variance among the mean phenotypes of different genotypes
-Additive genetic variance(VA): Variation due to the additive effects of alleles
- Dominance genetic variation (VD): Variation due to dominance relationships among alleles
- Epistatic genetic variation (VI): Variation due to interactions among loci
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Environmental variance (VE) The variance among phenotypes expressed by replicate members of the same genotype
- Differences between monozygotic twins are due to environmental factors
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Dominance genetic variance (VD) Due to dominance deviations which describe the extent to which heterozygotes are not exactly intermediate between the homozygotes
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Additive genetic variance (VA) - Responsible for the resemblance between parents and offspring
- The basis for the response to selection
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Degree of relatedness and the components of phenotypic covariance 1. Identical twins: VA+VD+VE
2. Parent-offspring:1/2VA
3. Full siblings:1/2VA+1/4VD+VE
4. Grandparent-Grandchild:1/4VA
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Heritability of a trait - A measure of the degree resemblance between relatives
- Estimates the degree of variation in a phenotypic trait in a population that is due to genetic variation between individuals in that population that is due to genetic variation between individuals in that population
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Narrow sense heritability (h2) The proportion of trait variance that is due to additive genetic factors
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Broad sense heritability (H2) The proportion of trait variance that is due to all genetic factors including VD, VA, VI
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Normal Distribution
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Two quantities that describe a normal distribution 1. Mean
2. Variance
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Deviation - Distribution of a trait in a population= Proportion of individuals that have each of the possible phenotypes
- In normal distribution, half points are above and half points are below mean
- One standard deviation are located in the mean
- The distribution of a trait in a population implies nothing about its inheritance
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Covariance A measure of the joint variability of two random variables (trait)
- Example: Measure the height deviation of father and son in a population
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Resemblance between family members - When there is genetic variation for a character, there will be a resemblance between relatives
- Relatives will have more similar trait values to each other compared to unrelated individuals
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Resemblance between relatives -Depends on the degree of relationship
- Use slope, not correlation coefficients to compute resemblance of family members
- Identical twin=100%, Full siblings=50%, Parent-offspring=50%, Half-sibling=25%
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Morgan Experiment
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Morgan's experiment Proved that chromosomes are the location of Mendel's heritable factors from his fly experiment
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Centimorgan The frequency of crossing over
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Linkage Map/ Genetic Map If the frequency of how often genes crossover is known, the percentage can be used to estimate how far apart the genes are from one another on a chromosome
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Genes
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Definition of gene - A core unit of the heredity that control the development of a trait
- Mendel's "discrete particle" in particulate inheritance actually indicated the concept of "gene"
- Those consist of DNA sequences and produces functional elements
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How many genes can make protein in human? 20,000 genes make proteins and most of them involve in determining traits
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Genotype The part of the genetic makeup of a cell which determine one of its characteristics
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Phenotype The set of observable characteristics of an individual resulting from the interaction of its genotype with the environment
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Components in a gene Gene contain exons, introns, UTRs and promoter in its transcript
- Gene can have various transcripts due to alternative splicing
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Exon A region of a trascribed gene present in the final functional RNA molecule
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Intron Any nucleotide sequence within a gene that is removed by RNA splicing during maturation of the final RNA product
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UTR Either of two sections, one on each side of a coding sequence on a strand of mRNA
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Promoter The section of DNA that controls the initiation of RNA transcription as a product of a gene
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Cells and Chromosomes
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Where does genetic recombination occur in meiosis? In meiosis I and it occur between Prophase I and Metaphase I
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Pros of asexual reproduction - Produce more offspring as it takes less time
- Require less energy
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Cons of asexual reproduction - No variation in offspring
- Less variation in population
- Mutation can slightly increase variations
- Fragile to environmental change
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Pros of sexual reproduction - Increase variation in offspring
- More resistant to many environmental forces because of genetic variation
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Cons of sexual reproduction - Require two organisms for mating
- Requires more cellular energy
-More time required for offspring development
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Elements in Chromosomes
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Ploidy Number of homologous sets of chromosomes in a cell
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Locus A fixed position on a chromosome that may be occupied by one or more gene
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The nuclear genome Consist of 6 billion nucleotides in 46 chromosomes
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Chromosomes
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Hereditary factors Genes and allele that are located on chromosomes
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Autosomal chromosomes/ autosomes Pairs number 1 to 22
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Sex chromosomes/ somatic cells Pair number 23
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Mitochondrial chromosomes in mitochondria - Haploid
- Maternal transmission
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Karyotype - Visualize chromosome shapes, structures and behaviors of chromosomes during cell division
- Autosomes in metaphase are arranged from the longest to shortest and from number 1 to 22
- Chromosomes number 23 are either XX/XY
- p arm=short, q arm= not p
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Mutation
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Saltationists Claim that evolution take place suddenly (saltating)( so that change instantaneous transition into a new species
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Gradualists Believe gradual process of evolution given large-scale variability in a population
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Gene can be defined in terms of their behavior as fundamental units based on: 1. Hereditary Transmission
2. Genetic recombination 3. Mutation
4. Gene function
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Darwinian view on mutation - Most mutations have an impact on certain traits
- Natural selection is the primary force of evolution
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Post-Mendelian geneticists' view on mutation Natural selection plays little or modest role but occurrence of mutation would be a major evolution force
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"Hopeful Monster" hypothesis by Richard Goldschmidt - Macroevolution through macromutations
- Called "Hopeful Monsters" because they were the embodiment of large phenotypic changes that had the potential to succeed as new species (saltation)
- Change early development and thus cause large effects in the adult phenotype
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Developmental macromutations Mutations in developmentally important genes could produce large phenotypic effects
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Neo-Darwinism - Natural selection is assumed to play much more important role than mutation
- Creating new characters in the presence of genetic recombination
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Kimura's view: Neutral mutation - The rate of substitution is so high that if each mutation improved fitness, the gap between the most fit and typical genotype would be large
- This rapid rate of mutation means that the majority of the mutations were neutral
- Mutations had little/ no effect on the fitness of the organism
- Not all mutations affect on/ completely determine our trait, including diseases
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Mutation is an old term Describe the situation for permanent change in evolutionary process
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Variant - The change in the nucleotide sequences
- Since a change in nucleotide sequence may not be permanent, variants are often called: genetic variant, variation or genetic variation
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Polymorphism Describe a variant with a frequency above 1% but broadly variants that we know the frequency in certain population
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Mutation
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Saltationists Claim that evolution take place suddenly (saltating)( so that change instantaneous transition into a new species
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Gradualists Believe gradual process of evolution given large-scale variability in a population
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Mutation and Population
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Out of Africa Theory - Explains the origin of modern human beings
- A small subset of this population migrated out in the past 100,000 years and rapidly expanded throughout a broad geographical region
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Non-Afracan populations have different variant frequency due to 1. Bottleneck
2. Long migration history
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Coalescent Theory - Two sample lineages find common ancestor
- A model how an allele sampled from a population may have originated from a common ancestor
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Stochastic When coalescence occurs is a stochastic (random probability( process
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Genomic study of population structure
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Implications of HapMap project and 1000 Genome Project - Variant frequency is uniquely represented in each population so can identify the population structure
- Genomic data are useful and fundamental resource to identify genes associated with disease and genetic variant in patients
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Genomic study of population structure
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Implications of HapMap project and 1000 Genome Project - Variant frequency is uniquely represented in each population so can identify the population structure
- Genomic data are useful and fundamental resource to identify genes associated with disease and genetic variant in patients
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Genetic variant by size
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SNV - Single Nucleotide Variant - Substitution of one/another base pair at a particular location in the genome
- Also called SNP if the allele frequency in a population is known
- A point mutation because it only affects a single nucleotide of nucleic acid
- There are 3,500,000 SNVs per individual (more in African)
- Everyone have different compositions of SNVs so there us variability in traits
- The ratio of heterozygous and homozygous SNVs is 2:1
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Indel - Insertion/Deletion - 1-1000bp changes in our genome
- There are ~300,000 to 600,000, indels per individual (more in African)
- Less than SNVs as indels have a large phenotypic effect than SNVs so more selective pressure
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Indels can be divided to 1. Microsatellite polymorphism
2. Mobile element insertion polymorphism
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Microsatellite polymorphism 2-4 nucleotide unit repeated in tandem 5-24 times
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Mobile element insertion polymorphism Cause human genetic diversity through retrotransposition
- Involves transcription into RNA
- Reverse transcription into DNA sequence
- Insertion into another site in genome
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SV - Structural variant - A genomic change >1000bp
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SV can be divided to 1. Copy Number Variant (CNV) - Deletion/Duplication
2. Copy Number Neutral Variants (CNNV) - Inversion/Insertion/ Translocation
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Small variants SNVs and indels
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Large variants SVs
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SV in the gnomAD project - Represent population structure as small variants
- More singleton SVs are observed in larger SVs
- Singleton: The variant only seen in an individual (rare)
Rare: It's under strong natural selection so only seen in few individuals
- Size of SVs are correlated with the effect size of SVs
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Genetic variant by size
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SNV - Single Nucleotide Variant - Substitution of one/another base pair at a particular location in the genome
- Also called SNP if the allele frequency in a population is known
- A point mutation because it only affects a single nucleotide of nucleic acid
- There are 3,500,000 SNVs per individual (more in African)
- Everyone have different compositions of SNVs so there us variability in traits
- The ratio of heterozygous and homozygous SNVs is 2:1
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Indel - Insertion/Deletion - 1-1000bp changes in our genome
- There are ~300,000 to 600,000, indels per individual (more in African)
- Less than SNVs as indels have a large phenotypic effect than SNVs so more selective pressure
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Genetic variant by Frequency
Selection and Frequency |
- Natural selection work on trait so the frequency of variants that contribute to trait can be changed
- Level of natural selection is varied by traits and diseases
- Some traits are favored by selection, therefore, the frequency variants increase
- According to Polygenic model, a single variant is lilkely contributing partially/highly partially to a trait. Therefore, there is a wide range of the frequency of variants |
Selection and Allele Frequency |
- Allele frequencies can be changed by selection - Increase beneficial alleles and removes deleterious one
- Traits not favored over mating are likely under natural selection (high selective pressure)
- Natural selection tends to make allele with higher fitness more common over time, resulting in Darwinian evolution |
Fecundity |
- Based on fertility ratio (FR)
- Lower fecundity: Higher selective pressure on the trait
- If a trait is not suited to mating/.reproduction, allele for this trait disappeared in a population
- Similar to reproductive fitness |
FR |
Calculated based on the number of children individuals in that group had compared with the general population
- If a disease have 0.5 FR, they have average half as many children as the general population |
Penetrance |
The proportion of individuals carrying a particular variant of a gene that also express an associated trait |
Fitness |
- Determine the allele frequency in population
- If fitness is not affected by variant, it will be remained in a population, ultimately increasing its frequency |
Genetic variant by Transmission
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Type of genetic variants by transmission mode 1. Inherited variants
2. De novo variants
3. Somatic variants
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De novo variants - new variants arise during cell division
- different nucleotide changes compared to DNA template
- Errors are not present in genome thus called de novo=new
- Errors in somatic cell: de novo somatic variants
- Errors in germ cells: de novo germline variants
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Mutability/Mutation rates How much errors are occured during replication
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Mutation signatures The pattern of somatic mutations in disease
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Human germline mutation rate 1.0~1.5x 10-8 bp per generation
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How many total of de novo variant from mother and father ? - ~70 de novo variants
- 80% of de novo variants are from father's sperm
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Main contributor to de novo variants - Advanced parental age
- Father is higher than mother- Because spermatogonial cells continue to divide throughout life which allow the progressive accumulation of mutations due to errors during DNA replication/failure to repair non-replicative DNA damage between cell divisions
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Rarest variants Have greatest potential to carry for disorders
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Variant frequency and its penetrance for disease - Inverse relationship
- Allele frequency is low but penetrance is high
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Genetic variant by consequence
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Missense variants Single base pairs substitution produce different amino acid
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Trucating variants A genetic variant which results in a shorter version of the protein being produced
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Nonsense mediated decay Destroys the mRNA leading to no protein
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Noncoding variants - Variants located outside the coding regions
- Located in promoters, transcription factor binding sites, enchancers
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Protein isoform Protein that are similar to each other and perform similar roles within the cells
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Variant annotation - The process of assigning functional information to DNA variants
- Can be varied by transcript
- A gene can have more than one transcript
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Two schemes for variant annotation 1. Per gene annotation: Choose the most critical consequence by the variant per gene
2. Per-transcript annotation: All consequence for every transcript
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Linkage Disequilibrium and Haplotype
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Linkage disequilibrium (LD) - Non-random association of alleles at two or more loci in a given population
- LD between two alleles is related to time of the mutation events, genetic distance and population history
- LD around an ancestral mutation on founder chromosome
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Haplotype A group of alleles in an organism that are inherited together from a single parent
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