![[personal profile]](https://www.dreamwidth.org/img/silk/identity/user.png){kind=small}
liveonearthp94 new topic introduced to continue next time
auto dom, auto rec, co-dom, x-linked already covered
this all considered to be "simple" genetics
non-Mendelian, complex traits are the most common
aka quantitative traits, or continuous variation of the phenotype
"multifactorial"
seen before as variable expressivity and reduced penetrance
multiple genes cause a trait: polygenic inheritance
environmental influences
combination of all that-->reality
inheritance difficult/impossible to track but "it runs in the family"
race = amalgamation of physical traits, too complex to id genes
awesome family tree showing musical genius in Bach's family
he had 19 children with two women! holy shit.
how much can you separate genetics from environment??? not much.
twin studies useful but diff to use in practical way
human intelligence = unresolveable question
POLYGENIC INHERITANCE IN WHEAT GRAIN COLOR
3 independent genes: A, B, C
ABC red, abc white, wheat is diploid
AABBCC is very red, aabbcc is very white grained
AaBbCc x AaBbCc --> results complex, see p95
genotypic ratio: 1:2:1:2:4:2:1:2:1:2:4:2:4:8:4:2:4:2:1:2:1:2:4:2:1:2:1
phenotypic ratio (with co-dominance): 1:6:15:20:15:6:1
**the greater the number of genes in a polygenic system the more continuous the variation
*HERITABILITY of a trait = relative contribution of genes vs envir, an est of pop phenotypic variation that is due to genotypic variation, completx mathematical calculation, heritability score of 1 = genetic, 0 = not genetic
*DNA MARKER SEQUENCE
single nucleotide polymorphisms (SNPs) correlate with conditions
id genes for susceptibility to develop a dz
clinically useful
DNA assoc studies requires lab testing for susceptibilities
*empirical risk figures
AKA empirical risk tables
mathematical game that says what happens before is a meaningful indicator of the future
requires large statistical database
*p99 FAMILIAL PATTERNS: COMMON CHARACTERISTICS
*family risk higher than general pop
*family risk drops off sharply with incr distance to index case, high for 1st degree relatives
*risk to 1st deg roughly the square root of the pop risk
*recurrent risk when more than 1 family member affected
*many exhibit threshhold of expression
***prior hx of the dz (empiric risk) is useful way to determine approx recurrent risk
*when empiric data not available:
*est recurrent risk in 1st deg relative by taking square root of pop prevalence
METHODS
MODEL THE DZ
loosely establish basic pattern of inheritance using pedigree
develop rules as needed for deviations
DEVELOP EMPIRICAL RISK TABLES
rely on prior observations
WILL COVER A BUNCH OF CONDITIONS IN THE 2ND HOUR
vast majority of human conditions
ADOLESCENT IDIOPATHIC SCOLIOSIS
OMIM 181800 (aut dom with reduced penetrance)
multifactorial
*penetrance is approx 60% ("fudge factor")
**common (1/30 in pts 10-16yoa)
prog: good, depends on degree of curvature
heritability approx 80%, also assoc with X link
v high concordance on monozygous twins
both parents affected-->40% of kids
one parent-->29%
no parents-->7% females and 2% males
CONGENITAL DISLOCATION OF THE HIP (ACETABULAR DYSPLASIA)
OMIM 147000
multifactoral
1/1000 not uncommon
loosely autosomal dominant with reduced penetrance
runs in families
severity ranges type I to type IV
NEURAL TUBE DEFECTS incl SPINA BIFIDA
OMIM 182940
*multifactorial
embryonic failure to close neural tube
1/1000 persons
2nd mc birth defect after heart
recurrent risk 4% in sibs
PYLORIC STENOSIS
aka Infantile Hypertrophic Pyloric Stenosis
OMIM 179010
multifactorial *hypertrophy and hyperplasia of pylorus (mm)
*not uncommon 1/400, more in males (*sex influenced)
threshhold trait demonstrated
CLEFT LIP AND PALATE
OMIM 119540
multfactorial
development failure of fusion
not uncommon 1/700
aut dom with variable expressivity/severity
CLUB FOOT incl TALIPES EQUINOVARUS
OMIM 119800
*talipes
*equinovarus
aut dom with reduced penetrance 40%
DIABETES MELLITUS
OMIM 222100 type I
OMIM 125853 type II "thrifty genes"
hyperglycemia, altered ins secretion
common and incr
1/3 americans born after 2000 will develop
children of type 2 diabetic have 33% chance of developing it or near
**odds of inheriting type 1 relatively low**
ESSENTIAL HYPERTENSION
OMIM 145400
multifactorial
high sytemic arterial BP
COURSE BUSINESS
week 9 starting at page 109
last 10-15 pages takes a lot of time
week 11 will be all review
exam is week 12 normal timeslot, will be proctored
sample Q's:
1) more genes involved in phenotype->pop variation gets smooth curve, more continuous
2) multifactorial trait: recurrent risk incr with higher severity of index case
3) incidence of multfactorial condition in fam with + is approx square root of pop incidence
4) type 2dm adult-->child develops condition ~33% of the time
5) disposition to complex multifactorial trais dt small molecular change, so what might be out come of prob with these substances?
a) angiotensinogen (or At-II receptors)-->HTN
b) leptin-->obesity? (not true but makes sense) alzheimers?
c) dopamine receptors-->ADHD, Parkinson's, AI, alcoholism** is his correct answer, substantiated
d) glucose receptor/transporters (glut4)-->IR
6) empirical risk table use to decide risk of scoliosis (p103 table)---17.7% female, 5.8% for male
7) aut dom not cause 50% affected in kids = reduced penetrance
8) tricky fam tree::: oddds of same condition 6 generations hence is near zero---or rather **about same as general pop
auto dom, auto rec, co-dom, x-linked already covered
this all considered to be "simple" genetics
non-Mendelian, complex traits are the most common
aka quantitative traits, or continuous variation of the phenotype
"multifactorial"
seen before as variable expressivity and reduced penetrance
multiple genes cause a trait: polygenic inheritance
environmental influences
combination of all that-->reality
inheritance difficult/impossible to track but "it runs in the family"
race = amalgamation of physical traits, too complex to id genes
awesome family tree showing musical genius in Bach's family
he had 19 children with two women! holy shit.
how much can you separate genetics from environment??? not much.
twin studies useful but diff to use in practical way
human intelligence = unresolveable question
POLYGENIC INHERITANCE IN WHEAT GRAIN COLOR
3 independent genes: A, B, C
ABC red, abc white, wheat is diploid
AABBCC is very red, aabbcc is very white grained
AaBbCc x AaBbCc --> results complex, see p95
genotypic ratio: 1:2:1:2:4:2:1:2:1:2:4:2:4:8:4:2:4:2:1:2:1:2:4:2:1:2:1
phenotypic ratio (with co-dominance): 1:6:15:20:15:6:1
**the greater the number of genes in a polygenic system the more continuous the variation
*HERITABILITY of a trait = relative contribution of genes vs envir, an est of pop phenotypic variation that is due to genotypic variation, completx mathematical calculation, heritability score of 1 = genetic, 0 = not genetic
*DNA MARKER SEQUENCE
single nucleotide polymorphisms (SNPs) correlate with conditions
id genes for susceptibility to develop a dz
clinically useful
DNA assoc studies requires lab testing for susceptibilities
*empirical risk figures
AKA empirical risk tables
mathematical game that says what happens before is a meaningful indicator of the future
requires large statistical database
*p99 FAMILIAL PATTERNS: COMMON CHARACTERISTICS
*family risk higher than general pop
*family risk drops off sharply with incr distance to index case, high for 1st degree relatives
*risk to 1st deg roughly the square root of the pop risk
*recurrent risk when more than 1 family member affected
*many exhibit threshhold of expression
***prior hx of the dz (empiric risk) is useful way to determine approx recurrent risk
*when empiric data not available:
*est recurrent risk in 1st deg relative by taking square root of pop prevalence
METHODS
MODEL THE DZ
loosely establish basic pattern of inheritance using pedigree
develop rules as needed for deviations
DEVELOP EMPIRICAL RISK TABLES
rely on prior observations
WILL COVER A BUNCH OF CONDITIONS IN THE 2ND HOUR
vast majority of human conditions
ADOLESCENT IDIOPATHIC SCOLIOSIS
OMIM 181800 (aut dom with reduced penetrance)
multifactorial
*penetrance is approx 60% ("fudge factor")
**common (1/30 in pts 10-16yoa)
prog: good, depends on degree of curvature
heritability approx 80%, also assoc with X link
v high concordance on monozygous twins
both parents affected-->40% of kids
one parent-->29%
no parents-->7% females and 2% males
CONGENITAL DISLOCATION OF THE HIP (ACETABULAR DYSPLASIA)
OMIM 147000
multifactoral
1/1000 not uncommon
loosely autosomal dominant with reduced penetrance
runs in families
severity ranges type I to type IV
NEURAL TUBE DEFECTS incl SPINA BIFIDA
OMIM 182940
*multifactorial
embryonic failure to close neural tube
1/1000 persons
2nd mc birth defect after heart
recurrent risk 4% in sibs
PYLORIC STENOSIS
aka Infantile Hypertrophic Pyloric Stenosis
OMIM 179010
multifactorial *hypertrophy and hyperplasia of pylorus (mm)
*not uncommon 1/400, more in males (*sex influenced)
threshhold trait demonstrated
CLEFT LIP AND PALATE
OMIM 119540
multfactorial
development failure of fusion
not uncommon 1/700
aut dom with variable expressivity/severity
CLUB FOOT incl TALIPES EQUINOVARUS
OMIM 119800
*talipes
*equinovarus
aut dom with reduced penetrance 40%
DIABETES MELLITUS
OMIM 222100 type I
OMIM 125853 type II "thrifty genes"
hyperglycemia, altered ins secretion
common and incr
1/3 americans born after 2000 will develop
children of type 2 diabetic have 33% chance of developing it or near
**odds of inheriting type 1 relatively low**
ESSENTIAL HYPERTENSION
OMIM 145400
multifactorial
high sytemic arterial BP
COURSE BUSINESS
week 9 starting at page 109
last 10-15 pages takes a lot of time
week 11 will be all review
exam is week 12 normal timeslot, will be proctored
sample Q's:
1) more genes involved in phenotype->pop variation gets smooth curve, more continuous
2) multifactorial trait: recurrent risk incr with higher severity of index case
3) incidence of multfactorial condition in fam with + is approx square root of pop incidence
4) type 2dm adult-->child develops condition ~33% of the time
5) disposition to complex multifactorial trais dt small molecular change, so what might be out come of prob with these substances?
a) angiotensinogen (or At-II receptors)-->HTN
b) leptin-->obesity? (not true but makes sense) alzheimers?
c) dopamine receptors-->ADHD, Parkinson's, AI, alcoholism** is his correct answer, substantiated
d) glucose receptor/transporters (glut4)-->IR
6) empirical risk table use to decide risk of scoliosis (p103 table)---17.7% female, 5.8% for male
7) aut dom not cause 50% affected in kids = reduced penetrance
8) tricky fam tree::: oddds of same condition 6 generations hence is near zero---or rather **about same as general pop
