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Human Genetic Diversity ((Genetic variation in Population (vulnerable to…
Human Genetic Diversity
frequency in a population > 1%
Genetic Polymorphism
how DNA sequence varies between different alleles?
SNPs
:star:SIZE : 1bp
:red_flag:number of Alleles : 2
:checkered_flag: frequency : 1/1000bp
distribution
most: noncoding gene
exonic SNPs
SYNONYMOUS
NONSYNONYMOUS
introduce/ change stop codon
alter splice sites
Indel
simple
:red_flag:number of Alleles : 2 (有/無)
:star:SIZE : 1bp ~ >100bp
multiallelic
:red_flag:number of Alleles : >2
microsatellite (STRs)
:star:unit SIZE : 2bp ~ 5bp
:check:Detection : PCR
minisatellite (VNTRs)
:star:unit SIZE : 10bp ~ 100bp
:check:Detection : Southern blot
Mobile element
Alu
LINE
mechanism : retrotransposition
CNVs
:star:SIZE : 200bp ~ 2Mb
:red_flag:number of Alleles : >=2
:check:Detection : CGH
Inversion
:star:SIZE : few bp ~ >1Mb
:red_flag:number of Alleles : 2 (2 orientations)
application
prenatal diagnosis
detection of carriers of deleterious alleles
forensic application
determine paternity
personalized medicine
frequency in a population < 1%
Mutation
3 Categories of Mutation
Genome Mutation
:red_flag:Origin : Missegregation
:checkered_flag:Frequency : 2~4/100 cell division
eg. Aneuploidy
:warning: 三種中freq.最高；但多數viable所以少見
Chromosome Mutation
:red_flag:Origin : Chromosomal rearragement
:checkered_flag:Frequency : (1/2)/100 cell division
eg. Translocation
:warning: freq.次高；但rarely perpetuate to next the generation, 因為子代通常incompatible with survival or normal reproduction
Regional Mutation
意義：affect the structure or regional organiztion of chromosome
起因：
主要為homologous recombination
duplication, deletion
any spontaneous double-stranded DNA breaks, eg. UV-light 造成 TT-dimer
translocation, inversion
Gene Mutation
:red_flag:Origin：Base pair mutation
errors introduced during process of DNA replication
failure to repair DNA
Proofreading enzyme : DNA repair enzyme
TIMING
DNA replication error >> 通常多數可以被修復
無法辨識造成Permanent mutation
Transition
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Transversion
:checkered_flag:Frequency : 10^-10bp/cell division
:warning: freq.最低；但通常viable，所以常見
2 Types of Cell
Germline >> pass on to next generation
Somatic cells >> somatic mosaicism(eg. cancer cell)
Overall Mutation Rate
care what?
evolutionary biologist :
per locus per cell division
medical geneticists :
per disease locus per generation
:check:通常使用
mutation rate on average
1*10^-6
per locus per generation
varies from gene to gene
gene size : 越大,freq越高
fraction of mutant allele that give observable phenotype
mutational mechanism
mutational hotspots 的多寡
parents'
age
advanced age > younger
reason
Oogenesis
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Spermatogenesis
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gender
Female > male
reason
Oogenesis
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Spermatogenesis
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Mutation Outcomes
Silent mutation
missense mutation
nonsense mutation
frameshifts ( :warning: indel 的 basepairs非3的倍數)
affect RNA transcription, processing,translation
transcription
translation
point mutations in UTRs
processing
splicing mutation
mutation at "splicing sites"
mutation "within introns", creating alternative spliced products
:frowning_face: beta-thalassemia
Contiguous gene syndrome
Diseases
:frowning_face: Duchenne dystrophy
deletion within dystrophin gene on X
:frowning_face: Familial hypercholesterolemia
recombination between different members of the Alu family class within introns of LDL receptor gene
:frowning_face: Hemophilia A
insertion of LINE
Dynamic mutation : amplification of trinucleotide repeat sequences
:frowning_face: Huntington disease
:frowning_face: Fragile X syndrome
Genetic variation in
Individual Genome
detection
target : amount and types of variation (including de novo mutation) in conditions of complex or unknown etiology
direct analysis of individual's diploid genome
Whole-Genome Sequencing
Whole-Exome Sequencing
Genetic variation in
Population
is concerned with 2 factors
Genetic Factors (先天)
Environmental and Social Factors (後天)
Disease alleles with different freq. in different pop.
:frowning_face:sickle cell anemia :red_flag: Africa
:frowning_face:cystic fibrosis :red_flag: European & Caucasian
delta CCR5 :red_flag:Euorpean & Russian <gentic flow>
Hardy-Weinberg Law
意義：calculate genotype frequency from allele frequency
Equilibrium
p = dominant allele frequency
q = recessive allele frequency
p^2 = homozygous dominant frequency
2pq = heterozygous dominant frequency
q^2 = homozygous recessive frequence
p^2 + 2pq + q^2 = 1
前提
large population
random mating
negligible amount of mutation
negligible amount of selection
negligible amount of migration
vulnerable to altering gene frequency
small population
nonrandom mating
stratification 階層
Assortive mating 選種交配
Consanguinity 近親結婚
selection
Gentic Drift
2 Type of Genetic Drift
Founder effect
:frowning_face:Ellis-van Creveld Syndome
dwarfism, polydactyly
Old-order Amish
定義：
founder of a new group happens to carry a rare allele
that allele will have a far higher frequency comparative to the population from which they derived
Bottle-neck effect
定義：fluctuation in allele frequency due to chance
vulneralbe to small population
mutation
fitness(f)
f = 0
：mutated allele cause death or infertility(genetic lethal), H-W law 維持
f >0
： allele frequency 改變
意義：number of offspring of affected parents who survive to reproductive age, compared with the number of those who dont carry the mutant wllele(0~1)
migration
Gene Flow
定義：mixing of genetic informations among interbreeding populations