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Single-Gene Inheritance & Multifactorial Inheritance (5 Major Types of…
Single-Gene Inheritance & Multifactorial Inheritance
Petterns of Single-Gene Inheritance
AKA "Mendelian" inheritance
:question:意義：occur in fixed and predictable proportions among the offspring of specific types of mating (follow
mendelian inheritance pattern
)
OMIM = online version of
Mendelian Inheritance in Man
Single-gene inheritance Disease
Autosomal Inheritance
Autosomal Dominant (AD)
:question: Dominant Phenotype意義：occurs when a phenotype is expressed in
heterozygotes as well as homozygotes
(or compound heterozygotes)
Pure dominant Inheritance
:question: 意義：similar severity in Heterozygotes & Homozygotes
:frowning_face: Huntington's Disease
Incompletely dominant Inheritance
:question: 意義： Heterozygotes & Homozygotes express different severity of phenotypes
:frowning_face: Anchondroplasia 軟骨發育不全
:silhouettes:Gene : FGFR3 gene = receptor for Fibroblast Growth Factor
:frowning_face: Familial Hypercholeterolemia
:frowning_face: Marfan Syndrome
:silhouettes:Gene : FBN1 gene = fibrillin > extracellular matrix glycoprotein
fibrillin下降; TGF-beta上升 > 對心血管有害
治療：losartin (高血壓藥)
:frowning_face: Neruofibromatosis
Sex-limited phenotype
:frowning_face: Male-limited precocious puberty
autosomally transmitted, but express only in male
:silhouettes:Gene : LHCGR gene = receptor for LH, HCG
LH
2 more items...
HCG
2 more items...
:mag:特徵：只有單一性別患病
incomplete(reduced) penetrance
:question: 意義： penetrance =/ 100%
:frowning_face: Erythermalgia 末端紅痛症
:frowning_face: Split-hand deformity
:mag:特徵：上下皆患病，自己沒病
:mag: 特徵：每一代都有人患病
Autosomal Recessive (AR)
:question: Recessive Phenotype意義：occurs when a phenotype is expressed in
only in homozygotes
; lack of wild-type allele
Quasidominant 假顯性
:question:意義：seems due to a dominant inheritance, in fact, mating of a person who has recessive disorder and one with asymptomatic carrier
Aa x aa
X-linked Inheritance
X-linked Dominant
:mag: 特徵：lack male-to-male transmission, 有病father的兒子全沒病;女兒全有帶原or發病
:question: 意義：heterozygous female express the phenotype
:frowning_face: Hypertrichosis
:frowning_face: Rett Syndrome
mental retardation, lethal in male during prenatal period
:silhouettes:Gene : MECP2 gene
X-linked Recessive
:question: 意義：heterozygous female does't express the phenotype
:mag: 特徵：爺爺有，叔叔伯伯姑姑爸爸都沒有，我卻有!
:frowning_face: Hemophilia A 血友病
:frowning_face: Muscular Distrophy
Duchenne Muscular Distrophy(DMD)
Deletion 造成frameshift
Becker Muscular Distrophy(BMD)
Deletion, 但沒有frameshift
absent of dystrophin from the muscle fiber
:mag: 特徵：幾乎是male發病
incomplete dominant
幾乎；因為x-inactivation
Pseudoautosomal inheritance
:question: 意義：the mutated gene located on the PARS of X
:mag: 特徵：有病father的兒子竟然有病，若是Dominant inheritance, 違背"不會male-to-male"
:frowning_face: Dyschondrosteosis 軟骨生成障礙綜合症
:silhouettes:Gene : SHOX gene
short stature, deformity of the forearms
X-dominant, pseuidoautosomal
Mitochondrial Inheritance (nonclassical pattern of Single-gene inheritance)
Factors that may complicate Inheritance Pattern
New mutation
:mag: 特徵：沒有家族病史，卻有人患病
Germline Mosaicism
:frowning_face: Osteogenesis imperfecta 玻璃娃娃
:mag: 特徵：AD, 沒有家族病史，新一代卻幾乎換病
Delayed Age of Onset
Reduced Penetrance
Variable Expression
causes
environmental effect
different mutations at the disease locus
modifier gene
:frowning_face: Osteogenesis imperfecta 玻璃娃
Pleiotropy & Heterogeneity
Pleiotropy
:question: 意義：gene that exert effects on multiple aspect of physiology or anatomy
Heterogeneity
:question: 意義：a number of phenotype that are similar but are actually determined by different genes
2 Types of Heterogeneity
Allelic Heterogeneity
different mutation or gene at same locus
Locus Heterogeneity
different mutation or gene at different loci
Anticipation
trinucleotide repeats
expansion of repeats
:frowning_face: Fragile-X
Genomic Imprinting
both sets of haploid chromosome come from same origin
Androgenetic (paternally-derived)
Gynogenetic (maternally-derived)
:frowning_face: PWS/AS
uniparental
Heterodisomy
(1) disomic + monosomic germ cell (2)post-zygotic deletion
Isodisomy
(1) nullisomic + monosomic germ cell (2)post-zygotic duplication
5 Major Types of Genetic Disease
Single gene disorder(Mendelian disorder)
Chromosomal disorder
Multifactorial disorder
Mitochondrial disorder
Somatic cell genetic disorder
Complex Inheritance of Multifactorial Disorders
2 types of traits
Qualitative traits
Familial aggregation in Qualitative traits
:question: Why
Familial Aggregation
? : the more closely related to the affected individual, the more likely one will share the relevant allele
2 approached to measure & assess
Relative Risk Ratio (λr)
definition
:pencil2:λr = (Prevalence of the disease in the relatives of the affected person) /(Prevalence of the disease in the general population)
Case-control study
definition
CASE: the frequency with of disease found in the families of the affected person
CONTROL: the frequency of disease in the families of a suitable control
suitable control: similar age, ethnicity, shared environment; mostly the "Spouse" of the case
eg. yes/not
Quantitative traits
eg. height, weight, blood pressure, serum HDL concentration
Genetic factors contribute to Quantitative traits
2 approaches to measure the genetic contribution
Familial Correlation (r)
eg. child's serum choleterol level vs. that of the parents
-1<=r<=+1
Heritability (H^2)
definition
The faction of the total
phenotypic varience
of a quantitative trait that is due to
allelic variation
0<=H^2<=1
H^2 = 0
Genetic variation contribute nothing to the phenotypic change
H^2 = 1
Genetic variation is totally responsible for the phenotypic variance
:pencil2:H^2 = (variance in DZ pairs - variance in MZ pairs) /(vairiance in DZ pairs)
2 types of factors
Gene Factors
Other factors
Environmental influences
Somatic Mutation
Aging
Differences in X-inactivation
Relative Contribution of the 2 Factors
Family Studies
Twin Studies
eg.
同時同地扶養的DZ,一個罹病：genetic factors > other factors
分開扶養的MZ,兩個罹病：other factors > genetic factors
Limitation
MZ twins don't have precisely identical gene
Environmental exposure may not be the same for the both
Ascertainment bias
not population-based ascertainment
Examples
:frowning_face: Type I DM 第一型糖尿病
:silhouettes: DR3/DR4 heterozygote
:frowning_face: Alzheimer Disease 阿茲海默症
病因
Senile plaques
Neurofibrillary tangles
:silhouettes: ApoE(ε4 allele), APP, PS1, PS2
:frowning_face: Cerebral Venous Thrombosis 腦靜脈竇栓塞
3 Factors
Factor V Leiden
:silhouettes: Prothrombin gene
Oral contraceptives 口服避孕藥
遺傳諮詢的優先考量族群
venous thrombosis under 50yr old
relatives with venous thrombosis under 50yr old
venous thrombosis in unusual sites(hepatic, mesenteric,...)
recurrent venous thrombosis
family history
Venous thrombosis in women taking oral contraceptives
Congenital Malformation
:frowning_face: Neural Tube Defect (NTD)
folic acid deficiency (<200ug/L)
Advice: 400~800ug/day
:silhouettes: MTHFR = 5,10-methylene-tetrahydrofolate reductase
:frowning_face: Retinitis Pigmentosa 視網膜色素變性
:silhouettes:Gene : peripherin, Rom1 = photoreceptor membrane protein
Heterozygous for both mutation onset the disease
photoreceptor death, loss of vision