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Principles of Inheritance (Genetic Variation (Variations in Populations…
Principles of Inheritance
Genetic Variation
Detecting Variation
PCR & Gel Elecrophoresis
Measure tandem repeats
Patters of 1+ nucleotides that are repeated
Different lengths
VNTRs
Variations in Nucleotide Tandem Repeats
Tandem repeats are targeted and amplified
Fragments separated by gel electrophoresis
Microarrays
Detect SNP genotype
Detects for heterozygous or homozygous
Oligonucleotides matching allele attach to microarray chip
Variation & Disease
Genotype to Phenotype
Altered gene product
Variations on coding/regulatory regions
Sickle cell anemia
Inherited
Cellular phenotype
Cell shape
Physiological phenotype
Oxygen not carried efficiently through blood
Block capillaries
B-globin protein
Healthy people carry HbA allele
Sickle cell carries HbS allele
Heterozygous HbA-HbS
No sickle cell anemia symptoms
Enough HbA to compensate
Genetic Variation
Different Sequences
Tandem repeats
Thousands of nucleotides in length, nearly identical, next to each other
Simple-sequence repeats
2 nucleotides
Difference sequences lead to genetic variation
Variations not always observable
Noncoding regions
DNA polymorphisms
1 of 2+ alleles at locus that differs in single nucleotide base or variable numbers of tandem nucleotide repeats
Noncoding regions
DNA markers
High-density genetic maps
Variations in Populations
Variation in Gene Copy Number
Genetic differences in individuals
CNV
Copy number variations
Identifies by fluorescence intensity in microarry analysis
More copies on chromosome, higher the intensity
Can be coding or noncoding tandem repeats
Effect of Gene Copy Number on Phenotype
AMY1 gene
codes for starch digesting enzyme, amylase
Varies across individuals' ancestral diet
Low carb diets, have few copies
B-globin Variations
Sickle cell anemia
Heterozygous individuals have advantage against malaria
Different haplotypes can be in same region; or same haplotype in different regions
Meiosis
Inheritance of Chromosomes
Gametes - Passing Genes to Next Generation
Asexual reproducing organisms
Produce exact offspring
Sexually reproducing organisms
Produce genetically different offspring
Sperm and ovum are not produced by mitosis
Gametes pass on genes
Cells go from diploid to haploid in 2 rounds of meiotic cell division
Prophase I
Chiasmata
Crossing over
Exchange of genetic information and chromosome segments
Recombinant Chromatids
Pairing homologous chromosomes
Synapsis
Bivalent unit, of a pair of synapsed chromosomes
Non-sister chromatids
Chromatids attached to different centromeres
Sister Chromatids are genetically identical
Genetically similar, not identical
Chiasmata
Forms from homologous chromosome breakage & reunion
Random crossing over on paired homologous chromosomes
Condensation & Synapsis
Pairing of and physical connection
Homologous chromosomes
Synaptonemal complex
Forms between chromosomes & holds them together during synapsis
Meiosis I
Reductional Division
Anaphase I
Homologous chromosomes separate; sister chromatids do not
Telophase I
Daughter cells move to prophase II
Metaphase I
Homologous pairs line up in cell center
Prophase I
Chiasmata present
Abnormal Variation in Chromosome Number
Homologous chromosomes (meiosis I) or sister chromatids (meiosis II) fail to separate
Some chromosomes will have extra, others will be missing
Nondisjunction
Can be lethal
Meiosis II
Equal Division
Prophase II
Nuclear envelope breaks down; chromosomes condense
Metaphase II
Chromosomes align at cell center
Anaphase II
Sister chromatids separate
Telophase II
Nuclear envelope reforms
No chromosome duplication
Mendelian Inheritance
Segregation
1st Law: Law of Segregation
2 alleles of gene segregate into different gametes during gamete formation in both parents
Alternative versions of genes account for variations in inherited trains
Each trait offspring will inherit 2 copies of gene, if 2 locus differ, dominant allele determines final trait
Independent Assortment
2nd Law: Law of Independent Assortment
Independent assortment of genes in different chromosomes reflects, nonhomologous chromosomes can orient in 2 different but equal ways
Dependent on nonhomologous chromosome alignment at metaphase plate during meiosis I
Genes located on same chromosome, will not show independent assortment
Sex Chromosomes and Linkage
Genetic Linkage
Recombination of Homologous Chromosomes
Linked genes can be broken
Inherited separately
Chromosomes line up on chiasmata
Recombination of Alleles
Gene position does not change
Gene association changes
Linked genes must be close enough together to be inherited together
Recombination frequency
Determines distance between genes on chromosome
Directly adjacent linked genes will have less or no recombination frequency
X-Chromosome Linked Genes
p arm (short arm); q arm (long arm)
Dystrophin gene
Muscle cell development
HPRT1 gene
Mutated turns int arthritis, colour blind, haemophilia
Linked genes
Genes positioned close together on same chromosome
Inherited together
Constructing Linkage Maps
Linkage Map
Shows distance between chromosomes and order of genes on chromosome
Visual representation for how to see what members are carriers or not, homozygous, or heterozygous; Shows what traits each member has
Genetic Mapping in Humans
High-density linkage map
Identify genetic loci
SNPs map
Map of human genes for various characteristics
Recombination frequency
Genome Wide Association Studies
Looks at SNP-linkage map for association between phenotype and mapped SNP
EX: HMGA2 gene
1cm in height
2 C alleles
0.8cm taller than people with 2T alleles
CT allele
0.4cm taller than people with 2C alleles
Genes on X-Chromosome
Colour Blindness
Ishihara colour test
Red-green colour blindness
Circle with one colour, number with another colour
Recessive
Heterozygous woman will not show colour blindness; homozygous will
Hemizygous
Males that inherit trait, will be colour blind
Haemophilia
50% probability woman pass trait on to son
Gene encodes for protein to blood clot
50% chance daughter or son gets it
Less likely for girl to get it; she needs to be homozygous
Segregation of Alleles
50% chance that heterozygous woman will pass on trait to children; if they are carriers
50% chance heterozygous woman will inherit trait
Applied Lecture
Nondisjunction and Disease
Meiosis
Meiotic spindle distributed chromosomes to daughter cells without error
Occurs
Members of pair of homologous chromosomes do not move apart properly during meiosis I
Sister chromatids fail to separate during meiosis II
Resutls
One gamete receives 2 of same type of chromosome, another receives none
Failure of either 2 homologous chromosomes to pass to separate cells during first meiotic division, or of 2 chromatids of chromosome to pass to separate cells during second meiotic divion
Mitosis can lead to cell lineages with extra or missing chromosomes
Result
1 daughter cell receives extra copy of 1 chromosome, 1 daughter receives no copy of chromosome
Aneuploidy
Abnormal number of chromosomes
Genes are over or under expressed
Cancer
Mitotic chromosome instability is cancer cell feature
Weakened or overactive mitotic checkpoint facilitate chromosome instability
Developmental Abnormalities
Self-abort
1/3
1/4 occur before pregnancy detectable
Chromosomal abnormalities account for 40-50%
Survival
Goes Wrong
Monosomy
Absence of chromosome in gamete, combines with normal gamete
Trisomy
Presence of 2 of same kind of chromosome in 1 gamete
Autosome Alteration - Down Syndrome
3 copies of chromosome 21
1/700 children
Developmental challenges
Broad face, hands, nasal bridge, wide-set eyes
Heart, immune & skeletal defects
Correlation between likelihood of down syndrome and mother's age
Prolonged meiosis 1 arrest
Experiment
Characterized amniotic fluid
Compare relative differences
Proteins that show greater than 2-fold difference
Molecular interactions
Sex Chromosome Alterations
Klinefelter Syndrome
Extra X chromosome in male
47 chromosomes, XXY
1/500-1000 men
Turner Syndrome
Monosomy of X chromosome in females
45 chromosomes, XO
Usually spontaneous abortion
1/5000 births
Phenotype
Short, stock stature
Webbed neck
Wide spread nipples
Real Life Example
South Africa's women's track and field
Gender test
Result
External female genitalia
Intersex condition
Hyperandrogenism
Triple testosterone level than other woman
Had to go through hormone therapy
Physical mental and physical evaluations
Transforming Normal Cells to Cancer Cells
Cell division no longer regulated by cell cycle
Uncontrolled growth and cell division alteration
Cells go through cell cycle unchecked
Mitotic Checkpoint
Anticancer drug isolated from tree bark
Binding tubulin subunits and stabilizing microtubules against depolymerization
Cells stay in metaphase-anapphase, leads to apoptosis
Taxol
Chemo drug
Interrupts spindle dynamics
Can't pull apart sister chromatids
Cell death
Applied Lecture
GWAS
Pedigree
Identify DNA marker found associated with (co-segregates) the gene of interest
Track gene within family without knowing mutation
Complex Traits
Multiple genes contribute to trait or disease
Genome Wide Association Study
Is there observed association between marker and trait
Linkage between trait and polymorphic SNPs
Looks at whole population
Determines which parts genome associates with
Genome-wide identification of association between trait and molecular markers
Revealing candidate genes for further studies
Studies
Cardiovascular disease
Large populations
Genetic associations
Correlation between marker and disease
Multiple sclerosis
Represent Data
Manhattan plot
Dots represent SNP
Negative logarithms are greatest - 15
Strongest associations have smallest P-value - 10^-15
Padget's disease of the bone (PDB)
Excessive breakdown and formation of bone, followed by disorganized bone remodeling
100 locations in human genome associated with risk of developing schizophrenia
1 SNPs associated to height
BMI
Identify susceptible genes
Investigate interactions in environments