Unit 2 Flashcards
(151 cards)
1
Q
Penetrance
A
-The fraction of individuals with a trait (disease) genotype who show manifestations of the disease. If all persons carrying a mutation have the trait, the condition is 100% penetrant. If some mutation carriers do not show signs of the trait, penetrance is incomplete (
2
Q
Expressivity
A
The degree to which a trait is expressed in an individual (is a measure of severity). Expressivity is analogous to a light dimmer (the light is ‘on’ but the brightness (expressivity) exists along a spectrum (of severity)). The variation in phenotype is explained (in part) by sex influence, environmental factors, stochastic effects, and modifier genes
3
Q
Sex influence and sex limitation
A
Phenotypic expression in some conditions is dependent on the individual’s sex (e.g. gout is more common in males than premenopausal females). Sex limitation occurs if only one sex can express a phenotype (e.g. unicornuate uterus).
4
Q
Stochastic Effects on Mendelian gene patterns
A
Stochastic (random) effects can influence the expression of
phenotypes. This concept pays homage to the fact that some phenotypes may be influenced by chance events/processes absent any obvious genetic/environmental factor.
5
Q
Modifier genes and Mendelian inheritance
A
Genetic factors outside of the genetic locus causing a disease can be important for the expression of Mendelian diseases.
6
Q
Phenocopies
A
Diseases (traits) that are due to non-genetic factors. Example: A thyroid cancer due to radiation exposure cannot always be distinguished from a thyroid cancer due to mutations in RET gene.
7
Q
Pleiotropy
A
Used to describe multiple different phenotypic effects due to mutation(s) in a single gene. Often used, when the phenotypes are seemingly unrelated and/or in multiple different tissues. Example: Neurofibromatosis Type I leads to: café au lait spots (skin), neurofibromas (peripheral nervous tissue), hammartomas in the eyes (ocular), abnormal freckling (skin again), and learning difficulties (central nervous system).
8
Q
Polymorphism:
A
A genetic variant (mutation) which is common (>1%) in the populations
9
Q
Founder effects:
A
a high frequency of a mutant allele in a population founded by a small ancestral
group when one or more of the original founders was a carrier of the mutant allele
10
Q
Genetic drift:
A
random fluctuation of allele frequencies, usually in small populations
11
Q
Estimating Autosomal dominant mutation rates (direct method)
A
For autosomal dominant conditions with 100% penetrance one can simply count
the number of new cases that occur with no family history. For example, if 12 disease cases are
identified in 100,000 children and 10 of the 12 cases have a negative family history, then the
mutation rate is 10/100,000 children. Since each child actually as 2 alleles for each gene the
theoretical gene ‘mutation-rate’ (μ) is 10/200,000, or 1/20,000 alleles
12
Q
Estimating autosomal dominant mutation rates (indirect method)
A
For an autosomal dominant condition where the reproductive fitness (f) is zero
(i.e. affected persons do not survive to reproduce and/or are infertile) then all cases represent new
mutations. Since each child inherits 2 genes (each could mutate) then the incidence (I) of disease
is really twice the mutation rate I = 2μ.
13
Q
Mutation rate estimation for nonzero fitness
A
Autosomal dominant: μ= 1/2 F (1-f) Autosomal recessive μ= F (1-f) X-linked recessive μ= 1/3 F (1-f) mu= mutation rate f=fitness F=frequency of disease
14
Q
Hardy-Weinberg equation
A
p^2+ 2pq + q^2= 1.
In rare conditions q is small, making q^2
very small so 2pq»_space; q^2. This means that
most copies of the minor allele are found in
heterozygotes.
15
Q
Idealized Assumptions in Hardy-Weinberg Equilibrium (HWE):
A
Large population mating randomly
Allele frequencies remain constant over time because:
o No appreciable rate of new mutation
o No selection for/against any allele
o No appreciable immigration/emigration of persons from population with different allele
frequencies
16
Q
Stratification (Non-random mating)
A
refers to populations containing 2 or more subgroups which tend preferentially mate
within their own subgroup. Mate selection is not dependent on the trait/disease or interest.
(Example: sickle cell anemia in African Americans (AAs) has hig
17
Q
Assortive mating
A
refers to when the choice of mate is dependent (in part) on a particular trait (or
sometimes a disease). This occurs because people tend to choose mates who resemble
themselves for (language, intelligence, height, skin color, etc.). This has been observed for
congenital short stature (previously called ‘dwarfism’), blindness, and deafness.
18
Q
Consanguinity,
A
occurs when persons marry closely-related blood relatives. This, non-random,
mating practice increases matings between carriers of autosomal recessive diseases, thereby
increasing the number of cases of autosomal recessive diseases in the population.2
19
Q
Mendel’s law of segregation
A
Law of Segregation:
At meiosis each allele (2) of a single gene separates/segregates into different gametes –> 50/50 ratio
Basically, all the alleles split up into different gametes
20
Q
Mendel’s law of independent assortment
A
Law of Independent Assortment:
At meiosis the segregation of each pair of alleles in >= 2 genes is independent –> each 50/50 ratio
Separate genes for separate traits are passed along to offspring independently of one another – they’re ‘independently assorted’
21
Q
X-linked recessive inheritance pattern
A
X-linked recessive:
- if you’re female, will not display phenotype, but will be a carrier
- if you’re male, and your mother is a carrier, you have a chance of getting it. If your father is a carrier, you will not get it
22
Q
X-linked dominant inheritance
A
- if the father has it – all daughters will definitely display phenotype. Sons will not.
- if the mother has it – daughters & sons may get it
23
Q
Three “threats” to mendelian inheritance
A
Penetrance:
Affected/unaffected
(lightswitch)
Expressivity:
Severity
(Dimmer)
Pleiotropy:
Localized or multi-system?
(Lights on in several rooms of house, or just one?
24
Q
Size of human genome
A
- 3 x 10^9 bp
25
Prevalence of new mutations in an individual
~30 new mutations occur in every individual
26
Prevalence of a SNP between two individuals
Average of 1 SNP every 1000 bp between any two randomly chosen human genomes.
**Detectable by PCR--> easy to score, widely distributable
27
Indels: Minisatellites
tandemly repeated 10-100 bp blocks of DNA
| VNTR (variable number of tandem repeats)
28
Indels: Microsatellites
-di-, tri-, tetra-nucleotide repeats
->5 x 104 per genome
STRPs (Short Tandem Repeat Polymorphisms)
29
CNV's
- variation in segments of genome from 200 bp – 2 Mb
- can range from one additional copy to many
- array comparative genomic hybridization (array CGH)
30
Gene Poor chromosomes
Chr 13, 18, 21 (aneuploidy)
31
Unstable regions of the genome
1q21; chr 5q13 (SMA);chr 22q (Digeorge)
32
GC/AT rich portions of genome
38%/54%, respectively. Clustering allows bands to appear on karyotypes
33
Status of sequencing of the euchromatic genome
99% of the euchromatic genome is sequenced & is accurate to an error rate of 1 event per 100,000 bp
Many (>200) sequence gaps remain in eurochromatic DNA
Many of the remaining gaps are associated with segmental duplications
34
Frequency of categories of genomic DNA sequences
1) 1.5% is translated (protein coding)
2) 20-25% is represented by genes (exons, introns, flanking sequences involved in regulating gene expression)
3) 50% “single copy” sequences
4) 40-50% classes of “repetitive DNA”
Sequences that are repeated hundreds to millions of times
35
Human specific pentanucleotide tandem repeat
found in heterochromatic regions on chr 1, 9, 16, Y: Hotspots for human-specific evolutionary change
36
Dispersed repetitive elements
Alu (short, ~300 bps, ~500k copies)
L1 (long, ~6 kb, ~100k copies)
-Often retrotransposed (insertional inactivation possible)
-Repeats may facilitate aberrant recombination leading to disease
37
Number of human genes
25k-30k; includes protein coding genes, RNA encoding genes, and pseudogenes
38
Gene Families
. A gene family is composed of genes with high sequence similarity (e.g. >85-90%) that may carry out similar but distinct functions. Some are clustered, some are dispersed. Gene families arise through gene duplication, a major mechanism underlying evolutionary change.
(when a gene duplicates it frees up one copy to vary while the other copy continues to carry out a critical function)
39
CNV's
- Possible prevalent because gene duplication has evolutionary advantage
- CNV loci may cover 12% of genome
- CNVV regions are often enriched for human specific gene duplications, genome sequence gaps, and human disease
40
CNV regions associated with disease
1q21.1(everything, see other card); 9p13.3-9q21.1(Alfi's syndrome); 5q13.3 (SMA)
41
DUF1220/NBPF sequences
deletions or repeats of these sequences in the 1q21 region are associated with disease.
Deletions-->microcephaly, SZD
Duplications-->Macrocephaly, ASD
42
Limitations of Nextgen sequencing
Complex, highly duplicated regions are typically unexamined
Such regions are implicated in numerous diseases, e.g. 1q21
Relies on short read sequences, no mammalian genome has been completely sequenced
43
Limitations of GWAS
–“Missing heritability” for complex diseases: Many large-scale studies implicate loci (e.g. SNPs) that account for only a small fraction of the expected genetic contribution
– Many regions of the genomes are unexamined by available “genome-wide” screening technologies: is this where the “missing heritability” lies?
44
Triploidy
Three of every chromosome (69XXX, 69 XXY, 69 XYY)
| Formed when one 2n gamete joins a 1n gamete
45
Trisomy
Three copies of one chromosome. (47 XX +21)
46
Monosomy
45, X (Turner Syndrome)
47
Mosaicism
47, XXX/46,XX
48
Trisomy 18
Edwards Syndrome--> intrauterine growth retardation, characteristic faces, severe intellectual disabilities, characteristic hand positioning, congenital malformations (valvular heart disease, posterior fossa CNA maldevelopment, diaphragmatic hernia, renal abnormalities)
Perinatal fatality~90%
49
Trisomy 13
Patau Syndrome - Characteristic faces, severe intellectual disability, congenital malformations (holoprosencephaly, facial clefts, polydactyly, renal abnormalities_
50
Polyploidy
Having a multiple of all of the chromosomes greater than 23 (Triploid=69, tetraploid= 92--occurs when DNA replication occurs without cell division)
51
Aneuploidy
Incomplete set (Trisomy or monosomy)
52
Tissue samples for Constitutional cytogenetic studies
Prenatal: Amniotic fluid or chorionic villus
Postnatal: peripheral blood or skin biopsy
53
Tissue samples for cancer cytogenetic studies
bone marrow, solid tumor, peripheral blood, lymph node, CNS
54
Genetic cause of Trisomy 21
Majority result of maternal meiosis I nondisjunction errors; ~4% are associated with a parental balanced translocation
55
45,X
Turner Syndrome
- Prenatal lymphedema/cystic hygroma
- Congenital malformations – heart disease (coarctation of aorta), gonadal dysgenesis, short stature, webbed neck
- 25% have mosaicism, thought to contribute to survival
- Most severe phenotypes-- tiny ring or tiny marker chromosome
56
Cytogenetics of structural abnormalities
Structural abnormality must be >5000 kb to be visible on a karyotype
57
Balanced Translocations
No loss or gain of genetic material
No phenotypic effect for heterozygote carrier
Exception: breakpoint in a gene, disrupting function
58
Robertsonian Translocation
fusion of two acrocentric chromosomes within their centromeric regions, resulting in the loss of both short arms (these short arms contain rDNA repeats, so the loss of these is not deleterious)
a. Phenotypically normal, but their offspring may have phenotypic mutations
75% are 13/15 RT's
59
Reciprocal Translocation (Alternate segregation)
From quadrivalent state:
(A) got very lucky; both unbroken chromosomes got transferred to gamete
or
(B)chromosomes get transferred that end up containing complete genetic information
60
Reciprocal translocation (Adjacent 1)
From quadrivalent state:
- Abnormal segregation
- Adjacent, or next door, non-homologous centromeres go to same pole
- Most common form of mal-segregation when translocated segments are relatively small
- results in trisomy and monosomy for some segments
61
Human Acrocentric chromosomes
13,14,15,21,22
62
Robertsonian translocations leading to Downs or Patau
any RT with a 21 chromosome can lead to trisomy (normal 21 plus RT "analog") (similar with chr 13)
63
Benign Pericentric Inversions
- 9qh, 16qh,1qh,yqh (constitutive heterochromatin)
- G-positive band of 9
- Pericentric region of 2 and 3
- usually familial
- not associated with SAB's, infertility, recombinant offspirng
64
Meiotic outcomes in Pericentric carriers
25% normal, unrearranged
25% rearranged, balanced
50% unbalanced-2 complementary recombinants
65
rec(8) infants
- Partial trisomy and monosomy of 8 derived from an inv(8) carrier
- VSD (ventriculoseptal defect), hypertelorism, thin upper lip, wide face
66
Outcomes of meiosis from Paracentric carriers
-~50% dicentric or acentric chromosomes
67
Deletion or Duplication 21q11 syndrome
- Disturbances of neural crest cell migration--> cleft lip/palate defects, thymus defects (T-cell dysfunction, parathyroid defects (hypocalcemia)
- Critical protein=TBX-1
68
Epigenetic variation
- mitotically and meiotically heritable variations in gene expression that are not caused by changes in DNA sequence.
- Reversible, post-translational modifications of histones and DNA methylation are examples of epigenetic mechanisms that alter chromatin structure, thereby affecting gene expression.
69
MeCP2
Protein that binds methylated DNA and facilitates deacytelation and methylation of adjacent histones
70
Imprinting
sex-dependent epigenetic modulation of regulatory regions such as promoter sequences.
- DNA methylation marks are established in the gamete and stably maintained in somatic cells after fertilization
- Methylation is reversible so it can be reset during gametogenesis
71
Maintenance of methylation markers in somatic cells
-Maintenance methyltransferase
72
Genetic cause of Prader Willi
del (15q11-15q13) on paternal chromosome (70%)
- maternal uniparental disomy (28%)
- 2% imprinting center defect on paternal allele
73
Genetic cause of Angelman syndrome
- del (15q11-15q13) on maternal chromosome (70%)
- paternal uniparental disomy (4%)
- mutation in imprinting center on maternal allele (8%)
- Mutation of UBE3A on maternal chromosome (8%)
74
Symptomes of Prader Willi
-short stature, hypogonadism, mild ID, excessive eating
75
Symptomes of Angelman
short stature, severe ID, seizures, spasticity
76
Genomic susceptibility to 15q11-13 deletions
Large genomic duplications of HERC2 lead to misalignment, which cause repeats flanking the locus
77
Uniparental disomy leading to Prader Willi
For example, the maternal gamete could be disomic for Chr 15 (have 2 copies of Chr 15) & paternal gamete is normal. Conceptus will be trisomic, which is normally incompatible with life. However, a mitotic nondisjunction early in gestation rescues lethality. Fetus is viable, but has maternal imprinting only --> no expression of PWS gene, since it is methylated in maternal homologue. Individual will have Prader-Willi Syndrome.
78
Acute lymphocytic leukemia prognosis (precursor B)
Low Hypodiploidy or near triploidy-->poor prognosis
| Hyperdiploidy (>50)-->good prognosis
79
Function of FISH
Specific, cloned DNA sequences can enumerate number of a specific chromosome OR identify
translocation
80
Types of FISH probes (5)
Centromere-use for enumeration (ALL panel, prenatal dx)
Locus Specific- deletion/duplication (p53, cancer)
Dual fusion, fusion - translocation (BCR:ABL, PML:RARalpha--> cancer)
Break apart - translocation rearrangement (MLL-->cancer)
Whole Chromosome paint (identifying markers, translocations)
81
BCR/ABL
(9,22) translocation leads to novel protein
Detected using Dual Fusion FISH probe
Recurrent in myeloid and lymphoid leukemia
82
ETV6/RUNX1
t(12,21) (p13;q22) in ALL can only be detected by FISH
83
Two common causes of specific types of AML
t(9;22)-->BCR/ABL fusion. 0.7% frequency. chronic myelogenous leukemia (CML), treatment with tyrosine kinase inhibitor (Gleevec)
t(15;17)--> PML/RARalpha fusion 4.1% frequency. specific Acute promyeloid leukemia (APML) --> treatment with retinoic acid changes the conformation of the novel protein (its receptor) to enable differentiation leading to remission. Auer rods characteristic.
84
DS cancer predisposition
DS infants and children have 20-100 fold
Elevated risk for developing ALL or AML
500 x more likely to get AMKL (Acute
Megakaryo-Blastic leukemia
85
How does CMA work?
CMA analysis: single-stranded DNA oligomers are placed onto slide or bead. Sample DNA (from peripheral blood) is amplified, labeled, hybridized onto slide/bead, and then the arrays are viewed via an optical scanner. Patient DNA is labeled green, and reference DNA is labeled red. If the two are displayed in equal intensities, spot will be yellow. If spot is more red or more green, displays a deletion or duplication of patient DNA respectively.
86
What is CMA good at detecting?
- CMA detects gains and losses only (but even microscopic ones!) --> no balanced translocations
- Limited ability to detect mosaicism (10-15%)
- Runs of homozygosity
87
CMA reports
Determine Size and location of deletions/duplications (most >200 Kbp) = further investigation in databases
- Common CNV/s not reported
- Genes/functions discussed and known phenotypes
88
Algorithm for testing kids with learning disorders
1. CMA analysis, report
a. Consult database of genomic variance
2. If 3 or more oligo clones are deleted or duplicated, and they are not part of CNV, patient & parental chromosomes will be studied with FISH
a. Parents with a balanced translocation, but no phenotype, are at risk for having offspring with an unbalanced karyotype
89
Features of Prader Willi
Early childhood hypotonia, almond eyes, undescended testicles, lighter pigmentation than siblings
Early failure to thrive and feeding difficulties which reverse during preschool age turning to hyperphagia and weight gain
mild/moderate developmental delay
Opthalmologic problems (strabismus/nystagmus)
Obstructive sleep apnea (contradindication to use of growth hormone
90
Developmental and Behavioral Prader Willi
Cognitive disability
Behavioral issues: tantrums, throw things, break things, have problems with picking at their skin (obsessive-compulsive quality to their behaviors)
91
Other 15q disorders
Maternal deletion in region--> angelman
Interstitial 15q duplications (paternally inhereted)-->NOTHING
Interstitial 15q duplications --> autism, hypotonia, ID, seizures
Supernumerary marker chromosomes: inverted duplicated isodicentric 15q, or IDIC 15(isodicentric isochrome)--> autism, non dysmorphic, often hypotonic, seizures common
**Connection with autism may relate to GABA A gene
92
Prader Willi Diagnosis
1) Methylation analysis (to establish disease)
| 2) FISH or microarray- to figure out the type of mutation
93
Genetic causes of Down Syndrome
-Trisomy 21 (95%)
-Unbalanced translocation between 21 and another acrocentric chromosome (2-3%)
Mosaic Tri 21 (1-2%)=> milder phenotype
94
Pharmacogenetics
- the study of differences in drug response due to allelic variation in genes affecting drug metabolism, efficacy, and toxicity
- variable response due to individual genes
- genes are selected for study a priori due to knowledge of their role in drug metabolism
95
Pharmacogenomics
- the genomic approach to pharmacogenetics – is concerned with the assessment of common genetic variants in the aggregate for their impact on the outcome of drug therapy
- variable response due to multiple loci across the genome
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Pharmacokinetics
-the rate at which the body absorbs, transports, metabolizes, or excretes drugs or their metabolites
-whether or how much the drug reaches the target
Describes absorption, distribution, metabolism and excretion of drugs (commonly referred to as ADME)
97
Pharmacodynamics
- the response of the drug binding to its targets and downstream targets, such a receptors, enzymes, or metabolic pathways
- when the drug successfully reaches its target
98
Phase I and II drug metabolism (pharmacokinetics)
Phase I: attach a polar group onto the compound to make it more soluble; usually a hydroxylation step
Phase II: attach a sugar/acetyl group to detoxify the drug and make it easier to excrete
99
CYP3A(4)
```
-genetically, is less important than other drug metabolism genes because the population distribution of activity is continuous and unimodal
Substrates:
o Cyclosporine (immunosuppressant)
Inhibitors:
o Ketoconazole
o Grapefruit juice
Inducers
o Rifampin
CYP3A4 participates in metabolism of 40% of administered drugs
```
100
CYP2D6
```
Substrates:
-Tricyclic antidepressants
-Opioids: codeine (cleaves to morphine)
Inhibitors:
-Quinidine, fluoxetine, paroxetine
```
101
CYP2C9 and VKORC1
Substrate:
| Warfarin
102
NAT
N-acetyltransferase
| Substrate: Isoniazid for TB
103
TMPT
6-mercaptopurine, 6-thioguanine
-1 in every 300-400 children do not have this enzyme – if you give these children with ALL (leukemia) the standard chemotherapeutic dose, you will kill the child due to immunosuppression
104
G6PD
-Most common disease-producing enzyme defect in the world – 400 million ppl worldwide
-10% of African-American males are G6PD deficient
-Deficient individuals are susceptible to hemolytic anemia after drug exposures
Substrates
-Sulfonamide
-Dapsone
Mxn: x-linked enzyme
105
If point mutations are more likely to occur in the paternal germline, what impact would that have on the clinical counseling of a family in which a single affected male child has one of the X-linked recessive diseases most frequently caused by point mutations, such as hemophilia B, LeschNyhan syndrome, or ornithine transcarbamylase deficiency?
The mother is more likely to be a heterozygote by virtue of her getting an x-chromosome from her more mutation prone father
– If male and female mutation rates are equal in an Xlinked genetic lethal condition, you would expect two thirds of the mothers of an isolated affected male to be carriers.
– However, if point mutations are much more likely in the male germline, she will have a >90% chance of being a carrier
106
Klinefelter Syndrome
47 XXY --> Childhood learning disabilities , delayed speech and language, tendency to being quiet, tall stature, small testes, less facial hair, infertility, hypospadias, gynecomastia
1/500-1/1000 boys
107
Jacob's syndrome
47 XYY--> learning disability, speech delay, developmental delay, behavioral difficulties, autism spectrum, tall stature
1/1000 boys
108
Triple X syndrome
47, XXX --> tall stature, my have increased risk of learning disability, delayed speech, delayed motor milestones, seizures, kidney abnormalities
1/1000 newborn girls
109
Genetic regulation of sex differentiation
- ovaries and testes result from a common, bi-potential gonad (both gene-directed processes)
- Gonadal development then determines secondary sex characteristics
110
Embryology of human reproductive organs (4th week)
Primordial germ cells form in wall of yok sac
111
Embryology of reproductive organs (5th week)
coelomic epithelium becomes genital ridge
112
6th week of human reproductive development
- Primordial germ cells migrate to undifferentiated gonad
| - epithelial cells of gonadal ridge proliferate and form primitive sex cords
113
7th week of reproductive development (men)
Differentiation of genital ridge into Sertoli cells (-->sperm) and Leydig cells (interstitial cells)
114
8th week of reproductive development (men)
Leydig cells produce testosterone
Sertoli cells produce Anti-Mullerian Hormone (AMH)
Primitive sex cords differentiate into testis cords and rete testis (--> seminiferous tubules)
115
7-8th week of reproductive development in women
In the absence of SRY and in presence of XX:
primitive sex cords dissociate into irregulary clusters
Medullary (primitive) cords regress and cortical (secondary) cords are formed
116
Initial 2 pairs of genital ducts that form in males and females
Mesonephric (wolffian) duct
| Paramesonephric (Mullerian) duct
117
SRY and Sox9
Responsible for production of AMH, causes regression of paramesonephric duct
118
FGF9
Essential for testes differentiation
119
SF1/NR5A1
Stimulate differentiation of Sertoli/Leydig
120
Mesonephric duct products
Epididymis, seminal vesicles, vas deferens
121
Paramesonephric duct and other things formed due to influence of estrogens
uterus, cervix, broad ligament, fallopian tubes, upper 1/3 of vagina
122
WNT4 protein
responsible for differentiation of ovaries, inhibited by SOX9
123
DHH
Upregulted by WNT4, downregulates SOX9
124
RSP01
Coactivator of WNT pathways
125
External genitalia formation (both genders)
-At 3 weeks, cells migrate and form genital tubercle and genital swellings
-Both males and females originate from urogenital sinus
Dihydrotestosterone exposure-->penis, scotum, urethral opening
Estrogen from maternal&placental sources-->clitoris, labia majora/minora, lower 2/3 of vagina
126
Clinical algorithm for DSD
1) physical exam (Prader Stages)
2) FISH studies for sex chromosome and karyotype
3) Hormone studies (LH, FSH, testosterone, dihydrotestosterone, AMH)
4) Ultrasound study of gonads and uterus
5) surgical consult with urology
127
Primary sex determination
Sex is primarily determined from the GONADS (which are in turn determined by chromosomes)
As a general rule, presence of Y--> male
X in absence of Y --> female
128
Androgen Insensitivity Syndrome
X-linked, AR
| Mutation causes abnormality of androgen receptor. Phenotypes range from milde to full sex reversal
129
5-alpha reductase deficiency
decreased ability of body to convert testosterone to dihydrotestosterone
Phenotype: undervirilized male with increased virilization at time of puberty
130
SRY gene disorders
- deletions or absence of gene results in full sex reversal and phenotypically normal female.
- Ectopic presence of SRY in 46,XX leads to phenotypically normal male
- Mutations in SRY lead to decreased AMH production and under virilization
131
Denys-Drash and Frasier Syndrome
- Sex reversal with 46, XY
- Due to mutations in WT1 gene (transcription factor for SRY)
- Both cause kidney disease
- Increased risk for wilms tumor
132
Congenital Adrenal Hyperplasia
Ambiguous genitalia in 46, XX
- 21 Hydroxylase deficiency
- Complicated by salt wasting in first few years of life and times of metabolic stress
133
phenocopy
Environmentally caused phenotype that mimics the genetic version of a trait
Ex. thalidomide induced limb malformation vs. rare genetic
134
Definition of heritability
How much of the spread or differences among people (measured as statistical variance) is due to genetics
It doesn't tell you whether there is a genetic component, but can provide an idea of how easy it will be to find a genetic component
135
lambda s (measure of risk of disease in relatives)
risk of disease in siblings of affected/risk of disease in general population
136
Allelic heterogeneity
Different alleles in different genes can result in different phenotypes or the same phenotype
ex. CF- many alleles have very similar clinical progression, but they can also be grouped based on severity of lung and pancreatic involvement
Other ex. PKU! (enzyme can vary form 20-50% activity)
137
CTFR phenotype/genotype
ΔF508/ ΔF508 leads to a severe pancreatic phenotype (stronger correlate)
Different CTFR genotypes also correlate with severity of lung deficiency, but it's a pretty weak correlation
138
significance tests for linkage analysis
chi square, fisher, exact test
If testing multiple variants, must apply multiple-testing correction
In GWAS, p must be
139
SNP's
bi-allelic
1/50-300 bp
used for association, occurrence different between ethnic goups
-Each occurs in a local haplotype
140
Haplotype
Local context of surrounding SNP's
141
CNV's
bi-allelic, multi-allelic, or unique
include common genomic deletions
Huge in size, also differ between populations
Most are not common for human disease
142
Odds Ratio
Risk of disease if carrying a given gene variant/Risk of disease if not carrying a given gene variant
143
Haplotype blocks
Recombination is not truly random, so very close polymorphism genotypes carried on the same chromosome cluster into ~10-50 kb haplotype blocks in which SNP alleles are in linkage disequilibrium (LD; marker alleles within blocks tend to be co-inherited, because recombination within blocks is uncommon)
144
Unit of genetic distance/recombination
centimorgan (cM)
| 1% recombination between 2 loci per meiosis
145
Statistical measure of linkage
LOD (Log of Odds)
Lod= log(likelihood of data if loci linked at x (cM)/likelihood of data if loci unlinked)
>3.0 is considered proof of linkage/gene localization
146
GWAS
tests hundreds of thousands of SNP's across the genome
search for significantly different allele
Still need to match cases and controls ethnically, but can accurately measure and correct for population stratification
You know the number of tests performed genome-wide (solves both problems)
147
Autosomal recessive pedigree
Parents of affected child are obligate carriers
| Unaffected siblings have 2/3 chance of being a carrier
148
Compound heterozygote
an individual who carries two different mutant alleles (Ex. BetaS/BetaC alleles, may show some characteristics of sickle cell and hemoglobin C disease mutant, but symptoms won't be as bad as someone with 2 sickle cell alleles (?))
149
Alpha1-Antitrypsin (SerpinA1)
Suicide inhibitor of serine protease Elastase
150
Two molecular causes of PKU
defect of Phenylalanine hydroxylase (PAH)
--98% of cases
Defects in BH4 cofactor --1-2% of cases
BH4 is also involved in 5-HT and DA synthesis
151
Newborn Screening for PKU
Mass spec for [F]/[Y], offered 1-2 days postnatally and 10-14 (aiming for the sweet spot where maternal enzyme is gone but damage hasn't really occurred yet.
