Pedigree, Mendelian inheritance, Genome organization Flashcards
(332 cards)
1
Q
Proband
A
“index case,” the affected member through whom a family with a genetic disorder is brought to attention
2
Q
consanguinous matings
A
couples that have >1 known ancestor in common
3
Q
mendelian disorders
A
a disorder caused by a single gene (oversimplification)
4
Q
Phenotype
A
the observable expression of a genotype as a morphological, clinical, cellular or biochemical trait
5
Q
Genotype
A
the set of alleles that make up his or her genetic constitution
6
Q
Mendelian inheritance
A
the transmission of inherited characters from generation to generation through the transmission of genes
7
Q
genes come in ____, with one from each ____
A
pairs, parent
8
Q
genes come in different ____, which result in different observed ______
A
alleles, phenotypes
9
Q
Mendel’s first law
A
Law of segregation: at meiosis, alleles separate from each other such that each gamete receives one copy from each allele pair
10
Q
Mendel’s second law
A
Law of independent assortment: at meiosis, the segregation of each pair of alleles is independent
11
Q
Dominant
A
expressed when only one chromosome of a pair carries the mutant allele (in a heterozygous state)
12
Q
recessive
A
expressed when both paired chromosomes carry a mutant allele at a locus (expressed in a homozygous or compound heterozygous state)
13
Q
codominant
A
when both traits (alleles) are expressed in a heterozygous state
14
Q
How many chromosomes do humans have?
A
46
15
Q
each chromosome is believed to consists of a _______ continuous _____ _____ _____
A
single, DNA double helix
16
Q
Retroposed gene
A
a gene without introns
17
Q
______ + ______=phenotype
A
genotype, environment
18
Q
Is chromosome 19 gene rich or gene poor?
A
gene rich
19
Q
are genes 13, 18, 21 gene rich or gene poor
A
gene poor
20
Q
Euchromatic
A
more relaxed regions of DNA
21
Q
Heterochromatic
A
more condensed regions of DNA
22
Q
Minisatellites
A
tandemly repeated 10-100bp blocks of DNA, VNTR(variable number of tandem repeats)
23
Q
Microsatellites
A
di, tri, tetra nucleotide repeats, 5X10^4 per genome, STRPs (short tandem repeat polymorphisms)
24
Q
______ are PCR detectable markers that are easy to store and are widely distributed, 1/1000bps
A
Single Nucleotide Polymorphisms (SNPs)
25
Copy Number variations
variations in segments of genome from 200bp-2Mp, can range from one copy to many, array comparative genome hybridization
26
Many human genes are members of _____ _____
gene families
27
Gene families are composed of genes with ______ _______ ______. Do they carry out similar or distinct functions?
high sequence similarity. They carry out both similar and distinct functions
28
Gene families arise through _____ _____, a mechanism of evolutionary change
gene duplication
29
Limitation of Nextgen DNA sequencing
no mammalian genome has been completely sequenced and assembled, it relies on short read sequences, complex, highly duplicated regions are typically unexamined and can be implicated in diseases (1q21)
30
Limitations of Genome wide association studies (GWAS)
"missing heritability" for complex diseases: many large scale studies implicate loci 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
31
bivalents
maternal and paternal homologs of each chromosome that pair along their entire lengths
32
synaptonemal complex
a proteinaceous structure which promotes inter-homolog interactions
33
Chiasmata
Crossovers between homologs
34
When does the synaptonemal complex disassemble? What holds the bivalents together?
at the end of prophase I, and the bivalents are held together by the chisamata only
35
What is the most error prone step of meiosis
Meiosis 1-chromosome nondisjunction at this stage is the most frequent mutational mechanism in humans
36
Genetic consequences of meiosis
1) reduction in chromosome number from diploid to haploid, 2) random segregation of homologous chromosomes, 3) random shuffling of genetic material due to crossover events
37
Metacentric
the centromere of chromosome is located in the middle of the chromosome such that 2 chromosome arms are apprx. equal in length
38
Submetacentric
the centromere is slightly removed from center
39
Acrocentric
the centromere is near one end of the chromosome
40
Aneuploidy
condition where wells contain an abnormal chromosome number
41
nondisjunction
missegregation of chromosomes at metaphase in either mitosis or meiosis such that daughter cells receive extra or fewer than the normal number of chromosomes
42
Monosomy
when a cell lacks one copy of a chromosome
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trisomy
when a cell has an extra copy of an entire chromosome
44
Are monosomies compatible with life?
No. Except for Turner's syndrome (monosomy for X chromosome)
45
Are trisomies compatible with life
yes, although some result in spontaneous abortion
46
What phase is the implicated most commonly in trisomy 21
maternal meiosis 1
47
Trisomy 18
Edward's syndrome-intrauterine growth retardation, characteristic faces, severe intellectual disability, characteristic hand positioning, valvular heart disease, posterior fossa CNS maldevelopment, diaphragmatic hernias, renal anomalies
48
Trisomy 13
Patau syndrome, characteristic facies, intellectual disability, holoprosencephaly, facial clefts, polydactyly, renal abnormalities
49
XXY
Kleinfelter syndrome. Tall stature, hypogonadism, elevated frequency of gynecomastia, commonly sterile, language impairment
50
X0
Turner syndrome- short stature, webbed neck, edema of hands and feet, narrow hips, broad chest, renal and cardio anomalies, gonadal dysgenesis
51
Mosaicism
presence of at least 2 genetically different cells in a tissue arising from a single zygote
52
heteroploid
a chromosome complement with any chromosome number other than 46
53
eupoloid
An exact multiple of the haploid chromosome number
54
What are the 2 basic types of structural chromosome rearrangements?
Balanced and unbalanced
55
Chromosome inversion
when one chromosome undergoes two double strand breaks of the DNA backbone and the intervening sequence is inverted prior to the rejoining of the broken ends
56
Paracentric inversion
a chromosome inversion that excludes the centromere
57
Pericentric inversions
a chromosome inversion that includes the centromere
58
Reciprocal translocation
Results from the breakage and rejoining of non-homologous chromosomes, with a reciprocal exchange of the broken segments
59
Robertsonian translocation
the fusion of 2 afrocentric chromosomes within their centromeric regions, resulting in the loss of both short arms (containing rDNA repeats). Reduction in chromosome number but are balanced rearrangements
60
Deletion
Loss of genetic info that can arise by simple chromosome breakage and rejoining, unequal crossing over between misaligned homologous chromosomes or sister chromatids, or by abnormal segregation of a balanced translocation or inversion
61
Duplication
gain of genetic information, which is generally less harmful than deletion, but can lead to abnormalities. Can also result from unequal crossing over or by abnormal segregation during meiosis in a carrier of a translocation or inversion
62
Ring chromosome
a chromosome fragment that circularizes and acquires kinetochore activity for stable transmission to daughter cells. Sample karyotype: 46, XY, r(13)(p11q34)
63
Isochromosome
A chromosome in which one arm is missing and the other duplicated in a mirror-image fashion, possibly occurring through an exchange involving one arm of a chromosome and its homolog at the proximal edge of the arm, adjacent to the centromere
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Continuous gene syndromes
abnormal phenotypes caused by over-expressoin of loss (haploinsufficiency) of neighboring genes
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Imprinting
Allele-specific methylation of CpG dinucleotides on the promotor region of imprinted genes
66
Characteristics of imprinted genes
1. they tend to be clustered, 2. These clusters contain both maternally and paternally imprinted genes, 3. The imprinted genes encode both proteins and non-coding RNAs
67
What is a common finding in childhood B-cell acute lymphoblastic leukemia (ALL)?
high hyper-diploidy revealed by chromosome and FISH analyses
68
What is diagnostic for chronic myelogenous leukemia (CML)?
t(9;22)
69
What can CML be treated with?
tyrosine kinase inhibitors
70
What is diagnostic for a specific acute promyeloid leukemia (PML)?
t(15;17)
71
What can PML be treated with?
Retinoic Acid
72
FISH: Centromere Probe-name and function, example
cen, used for Enumeration – leukemias, ex: Cen 4, 8, 10, 17, 21
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FISH: Locus Specific-name and used for, examples
LSI, Deletion, leukemias, p53
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FISH
fluorescent in-situ hybridization. Uses labelled probes to detect and localize the presence or absence of specific DNA sequences on chromosomes
75
Chromosomal Microarray (CMA)
Compares patient DNA to control to detect gains and losses using fluorescent hybridization
76
Can CMA detect balanced rearrangements?
No
77
What test is used for children with children with developmental delays?
CMA
78
What are FISH panels used for?
for initial differential diagnosis, and as a means to monitor treatments or disease progression
79
How many regions are interrogated in a single CMA?
180,000
80
Database of Genomic Variants
contains published literature as well as the mapping of the variants and known disease regions.
81
Name the 3 ways to get Down Syndrome
(95%) Trisomy 21 from nondisjunction, (3-4%) Unbalanced translocation between chromosome and another acrocentric chromosome, (1-2%) Mosaic Tri
82
What are the 1st semester screening tests for Down Syndrome? What is the detection rate?
Detection rate 82-87%. US measurement of nuchal folds, Beta-hCG, PAPP-A (pregnancy-assocaited plasma protein A)
83
What does 2nd trimester screening consist of? What is the detection rate?
80% detection rate. Quad screen: Beta-hCG, AFP (alpha-fetoprotein), unconjugated estradiol, inhibin level
84
What is the detection rate of 1st trimester + second trimester?
95%
85
How can the suspicion of Down Syndrome be confirmed?
Chromosome analysis via amniocentesis or CVS
86
Comment on the growth parameters of DS babies
growth parameters are usually normal
87
Common facial features of DS
midface hypoplasia, upslanting palpebral fissures, epicanthal folds, small ears, large appearing tongue
88
Comment on the muscle tone and joints of babies with DS
low muscle tone, increased joint mobility
89
hand features of DS
short fingers, transverse plamar crease, Vth finger incurving (clinodactyly), increased space between toes 1 and 2
90
Cardiac issues with DS
all types of anomalies can be present, but AV canal is most common. EKG as a newborn recommended.
91
GI issues with DS
Structural: esophageal and duodenal atresia, Hirschsprung's.
Functional: feeding problems, constipation, GERD, celiac disease
92
Opthalmic issues with DS
blocked tear ducts, myopia, lazy eye, nystagmus, cataracts
93
ENT issues with DS
chronic ear infectons, deafness (neuro and conductive), chronic nasal congestion, enlarged tonsils and adenoids-apnea
94
Endocrine issues (autoimmune) with DS
thyroid disease (hypothyroidism-congenital or acquired), insulin dependent diabetes, alopecia atreata, reduced fertility
95
Do individuals with DS experience puberty normally?
yes
96
orthopedic problems with DS
hip problems, joint subluxation, atlantoaxial subluxation
97
Hematological issues with DS
myeloproliferative disorder in newborn, increased risk of leukemia, iron deficient anemia
98
Developmental issues with DS
hypotonia affects gross motor development, mild to moderate intellectual disability, speech problems
99
Neurological problems associated with DS
hypotonia mild-severe, seizures, infantile spasms
100
Psychiatric issues with DS
depression, early AD, 1/10 Autistic
101
How does a newborn with PW present?
hypotonia, dysmorphic features, undescended testicles
102
What test can be used to diagnose PW?
FISH, methylation testing
103
Describe feeding of PW
early on failure to thrive, difficult feeding, preschool age they develop hyperphagia and gain weight
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hyperphagia
Excessive hunger, characteristic of PW
105
Describe the developmental delay of PW
mild-moderate to intellectual disability
106
Opthalmic problems associated with PW
strabismus and nystagmus
107
What causes PW?
missing information on paternal chromosome 15q11-q13
108
List the ways PW may occur
1. Paternal deletion, 2.UPD of maternal allele, 3. Imprinting error-"virtual" maternal UPD
109
What common orthopedic issues exist for PW patients
scoliosis
110
What else can cause problems on chromosome 15?
linkage disequilibrium between patients with autism and polymorphisms on the GABAa-b3 locus
111
What is the most common cytogenetic abnormality in patients with autism?
Maternal mutation 15q11-q13
112
Phenotype of Angleman's Syndrome
mildly dysmorphoc facial features, hypotonia as a chilf that turns to spasticity, intellectual disability, seizures, autism
113
4 Characteristics of epigenetic phenomena
1) Different gene expression pattern/phenotype, identical genome, 2) Inheritance thru cell division, even through generations, 3) Like a switch ON/OFF, 4) Erasable (therapeutic?)
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Waddington's epigenetic landscape
Each cell state is a "low energy" state
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3 examples of epigenetic phenomena
1) sweden famine/feast (diabetes/CV issues), 2) Father smoking during slow growth period (BMI). 3) High and low methyl donor diet (AGOUTI gene: coat color and feeding habits)
116
Why is erasure and resetting of methylation patterns of imprinted genes during gametogenesis essential?
Embryos with no active copies or 2 active copies of imprinted genes would be produced at high frequencies
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DNA methylation lock DNA in what state?
repressed
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Where does DNA methylation occur
only on cytosines of CpG
119
Does DNA methylation affect the base pairing of 5-meC with G?
NO
120
_______, _______, and _____ are examples of epigentetic phenomena
x inactivation, imprinting, and herterochromatin domains
121
Examples of non-nuclear inheritance
cytosolic epigenetic inheritance in cancer
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How could methylation lead to cancer?
Normally, a tumor suppressor gene (TSG) is ON. If it gets methylated and turns off, this can lead to cancer
123
Population genetics
quantitative study of the distribution of genetic variation in populations and how the frequencies of genes and genotypes are maintained or change.
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What evolutionary forces affect allele frequencies?
natural selection, genetic drift, mutation and gene flow
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Polymorphism
A genetic variant (mutation) which is common (>1%) in the populations
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Founder effects
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
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Genetic drift
random fluctuation of allele frequencies, usually in small populations
128
Selection:
active selection of favorable alleles over non-favorable ones
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fitness
a measure of the chance an allele will be transmitted to the next generation (Scale is 0-1).
130
Hardy-Weinberg principle
describes the frequency of two alleles in a population in terms of allele frequency and genotype frequency
131
Hardy-Weinberg assumptions
random mating, no mutation, no selection for/against any allele, no migration/drift, large population
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Stratification
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 higher incidence social stratification favoring mating of AAs with other AAs, than is predicted by HWE)
133
Assortive mating
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.
134
Eye characteristics of Turner syndrome
Inner canthal folds, blue sclerae, ptosis
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ENT of someone with Turner syndrome
prominent auricles, low set ears, high narrow palate, small mandible
136
Neck of Turner syndrome
low posterior hairline, webbing
137
Chest of someone with Turner Syndrome
broad, shield like chest, wide spaced nipples, pectus excavatum
138
Skeleton of someone with Turner syndrome
cubitus valgus, short 5th metacarpal/metatarsal, made lung deformity, scoliosis
139
What are the heart conditions common to Turner syndrome?
(Prenatal) cystic hygroma, (newborn) neck webbing
| bicuspid aortic valve, coartation of the aorta, systemic hypertension, EKG abnormalities
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what other systems are affected by Turner syndrome?
Lymphatics, urinary, vision and hearing
141
Sexual probs-turner syndrome:
infertility, sexual development, no menstruation
142
Common pitfalls in disclosure of Turner Syndrome
secret keeping, difficulty communicating an infertility diagnosis, perceived negative experiences with physicians
143
What is at the root of Gaucher's disease?
not making enough of the enzyme "glucocerebrosidase"to break down the lipid "glucocerebroside" so it accumulates in the lysozomes of macrophages
144
How many RBCs are produced (and destroyed) every second?
2.4 million new red blood cells
145
How long is an RBC in circulation?
120 days
146
What happens to old RBCs?
they are recycled by macrophages
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How are RBCs broken down?
90% removed from the circulation by the phagocytic macrophages in liver, spleen and lymph nodes.
2. 10% hemolyze in the circulation. Fragments of engulfed by macrophages.
148
Where are the chemical components of the RBC broken down?
within vacuoles of the macrophages due to the action of lysosomal enzymes
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Hemoglobin is degraded into ______, ________, and ______
globin, heme, iron
150
macrophages convert ____ into ____ and then ____ that is released into the blood where it forms a complex with blood albumin (bound bilirubin).
heme, bilverdin, bilirubin
151
In the liver cells (hepatocytes) ______ reacts with glucuronic acid to form ______.
Bound bilirubin, conjugated bilirubin
152
Most of the _______ is secreted into the small intestine with the bile. In the large bowel, bacteria convert _____ into the yellow-brown pigment (urobilinogen)
conjugated bilirubin, bilirubin
153
_____ is removed from heme molecules in the phagocytes. In the plasma, it binds to the protein ______ and is carried to the bone marrow where the iron can be used to synthesize new hemoglobin.
Iron, transferrin
154
What % of the RBC membrane is lipid?
30%
155
Where are the typical Gaucher cells stored?
mainly in liver, spleen and bone marrow.
156
What is the most common first symptom of Gaucher's disease and what can it be attributed to?
A swollen stomach. This is because the spleen has swollen.
157
Why is anemia common?
When the spleen enlarges, sometimes to 25 times its normal size, it weeds out too many blood cells, including good ones.
158
Difference between Type I, II, and III Gaucher's disease
type 2 and 3 have neurological symptoms
159
How can gaucher's disease be diagnosed?
1. blood test to check glucocerebrosidase levels, 2. Genetic testing: N370S, L444P, 84gg and IVS2
160
What type of mendeilan disease is Gaucher's?
Autosomal recessive
161
Imiglucerase (Cerezyme)
recombinant DNA-produced analogue of human β-glucocerebrosidase. It is given intravenously after reconstitution as a treatment for Type 1 Gaucher's disease
162
Miglustat
inhibitor of the enzyme glucosylceramide synthase, reduced the substrate to treat Gaucher's disease
163
Taliglucerase alfa
recombinant glucocerebrosidase enzyme produced in a slurry of carrot cells.
164
Characteristics of diseases demonstrating multifactorial inheritance
1. cluster in families, 2. do not follow simple Mendelian inheritance, 3. Likely due to variants in multiple genes and non-genetic factors interacting, 4. No simple relationship b/w genetic variant and trait
165
Heterogeneity (allele and locus)
allele-cystic fibrosis, locus-alzheimer's disease
166
Phenocopies
tahildomide-induced limb malformation
167
define heterogeneity at an allele or locus
the "same" disease can be caused by different alleles at one location or by alleles at different locations in the genome
168
Define phenocopy
disease traits that manifest like the disease, but have a different cause other than primary genetics.
169
Multifactorial inheritance
indicated when there is an increased risk to relatives, but there is no consistent pattern of inheritance within families
170
Heritability
the proportion of total variance in a trait that is due to variation in genes.
171
A ____ heritability implies that differences among individuals with respect to a trait such as blood pressure in a population can be attributed to differences in the genetic make-up.
high
172
A ____ heritability does not imply that non-genetic factors are not important
high
173
What are the most common polymorphic DNA markers?
Microsatellites, SNPs, and CNVs
174
Each SNP occurs in local context (_______) of surrounding SNPs
haplotype
175
haplotype
Groups of SNPs that can be inherited
176
haplotype block
Alleles that are in linkage disequilibrium, and therefor are inherited together. Smaller in african populations
177
How often do CNVs contribute to human disease?
It is uncertain
178
Are candidate gene association studies hypothesis driven or hypothesis free? Consequence?
Hypothesis driven, false positives. Hypotheses are often wrong
179
What are candidate gene association studies most powerful for?
common risk alleles with small to moderate effects
| i.e. “complex”, polygenic traits
180
Do candidate gene association studies depend on Linkage disequilibrium
yes
181
How does candidate gene association work?
1. Genotype marker in candidate gene in cases and in controls
2. Compare allele frequencies in cases versus controls
182
Advantages of candidate gene association studies
simple, reasonable number of controls (hundreds), simple stats
183
Genetic linkage studies: hypothesis driven or no?
hypothesis free!
184
What do genetic linkage studies do?
Search genome for segments disproportionately co-inherited along with disease through “multiplex families” (families with multiple cases of a disease)
185
What does a genetic linkage study assume?
affected relatives share the disease (not phenocopies)
186
What is a disadvantage of genetic linkage study?
less powerful for complex traits
187
What types of traits does a genetic linkage study work best for?
Mendelian traits (uncommon alleles with strong effects)
188
What is the unit of genetic distance in linkage studies?
centiMorgan (cM)
| 1 cM = 1% recombination between two loci per meiosis
189
What is the statistical measure of genetic linkage analysis?
LOD (log of odds) score
190
Significance level of LODs for Mendelian and polygenic traits
LOD >3.0 for Mendelian trait
| LOD >3.3 for Polygenic trait
191
What does GWAS stand for?
Genome wide association study
192
How are GWAS different from candidate gene association studies?
GWAS tests hundreds of thousands or millions of markers (SNPs) across entire genome
193
What is a disadvantage of GWAS?
must use more than a thousand cases and 1000 controls
194
What is GWAS most effective for?
Most effective for common alleles with small to moderate effect sizes
195
What are exomes and what % of the genome do they make up?
Gene coding regions; ~ 3 Mb (1% of genome)
196
What are the 3 steps of sexual differentiation?
1. establishment of genetic sex thru X and Y chromosomes, 2. Formation of sex specific gonads (testes and ovaries), 3. development of internal and external reproductive organs
197
Genetic sex is determined by______
the presence or absence of Y chromosome
198
All diploid somatic cells in both males and females have a single ______ __ ______regardless of the total number of X and Y chromosomes present.
active x chromosome
199
X inactivation is normally _____ so that females are _____ for expression of their x chromosomes.
random, mosaic
200
How is the x chromosome inactivated?
DNA methylation and modification of histone proteins
201
XIST gene
encodes noncoding RNA, which is expressed in the nucleus where it associates in cis as a part of an XIST RNA/barr body complex
202
What percentage of genes on the X chromosome escape inactivation? Where are they located?
10-15%, many are located on Xp
203
Where do the X and Y chromosomes pair for recombination during meiosis?
pseudoautosomal region
204
Nonrandom X inactivation. How might this present clinically?
when an X chromosomes is abnormal or there is an X-autosome translocation. Might present as a female with an x linked recessive phenotype
205
Gonadal sex is determined by
expression of genes that induce the development of testes (SRY)
206
SRY
principal determinant of testicular differentiation. Without SRY--> ovaries
207
Germ cells develop in 2 stages:
1. sexually independent pregonadal stage where they migrate from yolk sac->developing gonads
2. gonadal dependent stage-they mature
208
Mutations at autosomal loci on chromosomes ___, ___, and ___ can lead to sex reversal in the presence of ____ gene
9, 11, 17, SRY
209
WT gene
directs differentiation of the mesonephros and genital ridge (precede gonadal development)
210
Loss of ____ gene can lead to adrenal hypoplasia and gonadal agenesis
SF1
211
DAX1 is a nuclear hormone receptor. It's presence leads to the development of ____ even in the presence of ___, a disorder called ____
ovaries, SRY, Dosage Sensitive Sex Reversal (DSS)
212
Anatomic sex is determined by:
the action of growth factors and sex steroid hormones
213
Testes contain two non-germ cells:
1. Sertoli cells (MIF), 2. Leydig cells (testosterone)
214
What do sertoli cells produce?
Mullerian Inhibitory factor
215
What do leydig cells produce?
testosterone
216
What does MIF do?
Prevents formation of the mullein duct derivatives (would be fallopian tubes, uterus, and upper vagina)
217
What does testosterone stimulate the development of? What does it become?
Wolffian (mesonephric) duct, becomes epidydimal duct and ductus deferens.
218
In the absence of testosterone, what structure degenerates in women?
wolffian (mesonephric duct)
219
The male external genitalia develop in response to what?
testosterone
220
In many androgen sensitive tissues, testosterone must be converted to ____
dihydrotestosterone
221
The genital tubercle becomes what in M/F?
M: glans and shaft of penis
F: glans and shaft of clitoris
222
The definitive urogenital becomes what in M/F?
M: penile urethra
F: vestibule of vagina
223
The urethral fold becomes what in M/F?
M: Penis surrounding penile urethra
F: Labia miora
224
Labioscrotal fold becomes what in M/F?
M: Scrotum
F: Labia majora
225
Sex reversal
whe gonadal sex is the opposite of what is predicted from karyotype (genetic sex)
226
XX males
translocation of Y chromosome material (SRY) to another chromosome. Translocation to an autosome is most common.
227
XY females
insertion of SRY gene on a chromosome
228
pseudohermaphroditism
abnormal development of genital sex. External phenotype and sex assignment can be different than genetic sex.
229
How can pseudohermaphroditism occur for males and females?
masculinized females-exposure to androgens during development
males-failure to produce or respond to testosterone
230
Loss-of-Function Mutations:
Caused by genetic mutations that eliminate (or reduce) the function of the protein.
231
Of the four major mechanisms, which is the most common genetic mechanism leading to human genetic disease?
loss of function mutation
232
Examples of loss of function mutations:
Duchenne Muscular dystrophy (loss of protein), alpha-thalassemia (reduction of protein), Turner syndrome (loss of entire chromosome), hereditary retinoblastoma (loss of a TSG). Also: Hereditary neuropathy with liability to pressure palsies (HNPP), Osteogenesis imperfecta type I. MANY METABOLIC DISORDERS
233
Gain of function mutations
caused by genetic mutations (often missense or sometimes promoter mutations) that enhance one or more normal functions of a protein (e.g. increased protein expression, increased half- life, decreased degradation, increased activity)
234
Examples of gain of function mutations
Hemoglobin Kempsey, Achrondroplasia, Alzheimer, Charcot-Marie-Tooth
235
Novel property mutations
Caused by genetic mutations (often missense) that confer a novel property on the protein, without necessarily altering its normal functions. Although the introduction of a novel property has sometimes been advantageous from an evolutionary standpoint, the majority of such changes result in a novel protein property that reduces fitness (i.e. can lead to disease).
236
Are novel property mutations common or uncommon?
uncommon
237
Examples of novel property mutations
Sickle cell anemia, Huntington disease
238
Ectopic or Heterochronic expression mutations are seen in what kind of conditions?
Cancers. Also hereditary persistance of fetal Hb
239
Ectopic or Heterochronic expression mutations
Caused by genetic mutations that alter regulatory regions of a gene and alter either the timing (wrong time = heterochronic) or location (wrong place = ectopic) of expression.
240
Unstable Repeat Sequences
These genes contain tri, or tetra-nucleotide repeats that make the genes susceptible to slipped mispairing during DNA replication. The repeat numbers for each allele are prone to change from parent to offspring. An expansion of repeat numbers can lead to disease.
241
Example of unstable repeat sequence disease
Huntington disease
242
Genetic anticipation
the observation that disease severity worsening in subsequent generations.
243
What explains genetic anticipation?
tri/tetra nucleotide repeat number expansions occurring from parent to offspring. The offspring inheriting an expanded disease allele is more likely to present earlier and progress faster
244
Consequences of expansion of noncoding repeats and loss of function:
- Impaired transcription
- Mutant RNA not made
- Mutant protein not made
245
Consequences of expansion of noncoding repeats conferring novel properties
- RNA has novel property (abnormal RNA binds and soaks up RNA-binding proteinsàaffects other gene products)
- Mutant RNA is made
- Mutant protein not made
246
Consequences of expansion of codons in exons
- Novel property on expressed protein
- Mutant RNA is made
- protein is made and is toxic
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Where do the majority of mutant alleles exist for a given autosomal recessive disease?
Carriers
248
Allelic heterogeneity
existence of multiple mutant alleles for a single gene
249
Compound heterozygote
one who carries 2 different mutant alleles on the same gene
250
What enzyme is missing in PKU?
phenylalanine hydroxylase
251
What happens in PKU?
high levels of Phe accumulate and damage CNS
252
Describe the risks for a pregnant PKU woman
miscarriage, baby might have deformities, mental retardation, growth impairment REGARDLESS OF BABY'S GENOTYPE
253
What is the treatment for PKU?
Diet low in phenylalanine
254
What tests can screen for PKU?
Guthrie test (bacteria will grow in presence of Phe when they normally would't), Mass spectrometry.
255
Why is timing important for PKU screening?
Can screen at birth, but have to be careful because levels might be normal. PKU levels will increase in the first few days
256
How can you imagine a1-antitrypsin?
A lung protector
257
What are some characteristics of a1-antitrypsin deficiency? (ATD)
- late onset
- common among norther Europeans
- 20X risk of emphysema, high risk of cirrhosis and liver cancer
- smoking makes it much worse
258
What does a1-antitrypsin do on a molecular level?
Inhibits elastase, which is a protease that breaks down lung tissue. When a1-antitrypsin is not present in sufficient amounts, emphysema results.
259
Why can a1-antitrypsin deficiency cause cirrhosis?
because misfolded a1-antitrypsin aggregates in the liver where it is produced
260
Which mutant allele of a1-antitrypsin deficiency is most severe? Why?
Z allele so most severe and most common. Improperly folded protein sticks in the liver (potential for cirrhosis)
261
Which mutant allele is less severe? why?
S allele, makes a protein unstable but is not misfiled so no liver disease.
262
What gene is mutated in Tay-Sachs?
HEXA
263
What gene is mutated in Sandhoff disease?
HEXB
264
What gene is mutated in AB-variant of Tay Sachs?
GM2AP
265
What are the substrates involved in Tay-sachs?
GM2 gangliosides
266
What are the substrates involved in Sandhoff disease?
globosides
267
What does the enzyme test for tay-sachs show?
HEXA defective, HEXB normal
268
What does the enzyme test show for Sandhoff disease?
HEXA and HEXB both defective
269
What does the enzyme test show for AB-variant of tay sachs
Normal HEXA and HEXB
270
What group is at a high risk for tay-sachs?
central/eastern europeans and Ashkenazi Jews
271
What causes tay sachs?
HEXA mutation=defective hexosaminidaseA, can't degrade ganglioside=progressive CNS destruction
272
What type of hemoglobin is present in embryos?
Zeta2epsilon2
273
Hb in fetal development
a2y2 (HbF)
274
Adult Hb
a2B2 (HbA) and a2d2 (HbA2)
275
What Hb's are present in an adult?
HbA, HbA2, and HbF
276
Locus control region
upstream of the coding regions for the alpha and B globin clusters. Controls timing and levels of the globin proteins
277
Sickle cell anemia results from a switch between ___ and ___ in codon ____ of exon____
Glu, Val, 6, 1
278
In low O2, HbS is ______ soluble than HbA
less
279
Hemoglobin C Disease results from a change from ___ to ___ in exon ___ and codon ___
Glu, Lys, 1, 6
280
In low O2, HbC is ____ soluble than HbA and tends to ______ causing _____
less, crystalize, lysis
281
How can sickle cell anemia be diagnosed?
PCR using MstII to tell between HbA and HbS (cannot tell between HbA and C)
282
How many total copies of the alpha globin gene do people have
4 (2 on each chromosome)
283
How many total copies of beta globin gene do people have?
2 (1 on each chromosome)
284
What is the genotype for a silent carrier of a-thalassemia? What % a-globin level?
aa/a-
| 75%
285
What is the genotype for a-thalassemia 1 trait? What % a-globin level? Where is it common?
aa/--
50%
common in SE asia
286
What is the genotype for a-thalassemia 2 trait? What % a-globin level? Where is it common?
a-/a-
50%
Africa, mediterranean, asia
287
What is the genotype for HbH disease? What % a-globin level? What forms?
a-/--
25%
B4 clusters form
288
hydrops fetais
--/-- y4 clusters, results in fetal death
289
locus heterogeneity
mutation in more than one locus that causes the same clinical condition
290
trinucleotide repeat disorders work by a _____ ______ mechanism
slipped mispairing
291
______ and _______ ________ _____ are characteristics of trinucleotide repeat disorders
anticipation, parental transmission bias
292
Are trinucleotide repeat disorders AD, AR, or X linked?
They can be autosomal dominant, autosomal recessive, or x linked
293
Parental transmission bias
trinucleotide expansion more prone to occu in gametogenesis of male or female
294
Where do mtDNA disorders typically cause dysfunction
repiratory chain
295
How many genes are coded for in the mitochondrial genome?
37
296
Pharmacogenetics
Study of differences in drug response due to allelic variation in genes affecting drug metabolism, efficacy, toxicity
297
Pharmacogenetics is variable due to _____
individual genes
298
Pharmacogenomics
the genomic approach to pharmacogenetics, concerned with assessment of common genetic variants in the aggregate for their impact on the outcome of drug therapy.
299
Pharmacogenomics has a variable response due to _______
multiple loci across the genome
300
What are the two major elements of response to drugs?
Pharmacokinetics and pharmacodynamis
301
Pharmacokinetics
ADME: Absorption, Distribution, Metabolism, and Excretion of drugs
302
Pharmacodynamics
Describes the relationship between the concentration of a drug at its site of action, observed biological effects.
303
Drug metabolism: Phase I
polar group added (exposed)-->solubilize
304
Drug metabolism: Phase II
conjugation rxn (sugar/acetyl group)-->detoxify
305
Where are the gene products of CYP450 complex active?
liver, intestinal epithelium
306
What are the 3 main families of CYP450 complex
CYP1, CYP2, CYP3
307
Most CYPs function to _______ drugs. Is this always the case?
inactivate, not always the case, sometimes they are needed for activation
308
What converts codeine to morphine?
CYP2D6
309
What inactivates 40% of common drugs?
CYP3A4
310
What types of mutations are expected for a poor metabolizer?
Frameshift, splicing, nonsense, missence (some)
311
What types of mutations are expected for an ultrafast metabolizer?
increased copy number, missense (some)
312
10 % of females are affected in which x linked recessive disorder?
hemophilia a
313
1/3 of females are affected by what trinucleotide repeat, x linked disorder
Fragile X, but much less severely
314
Cooley's thalassemia is another name for what?
B thalassemis major
315
What might be observed for a patient with B thalassemia
osteopenia, dense marrow expansion, enlarged spleen, short stature
316
homoglobin S variant: (ethnic group)
15 % African Americans carriers
317
hemoglobin E varient: (region)
7% SE asians
318
Treatment for Multiple Endocrine Neoplasia (MEN)
Thyroid removal after early testing
319
Treatment for Aplha-1AT
recombinant enzymen therapy
320
Treatment for Fabry disease
recombinant a-galactose (stabilizes the protein so it can fold correctly) intreacellular protein
321
Treatment for hemophilia A
replace factor VIII
322
informative result
definitively diagnoses or excludes the disease
323
non-informative
result is normal, but not possible to exclude disease risk
324
genetic heterogeneity
multiple genes (when mutated) are associated with the same phenotype
325
example of genetic heterogeneity
HCM
326
a SNP occurs every ____/_____ bp
1/1000
327
Number of base pairs in human genome
3X10^9
328
More AT or GC rich regions?
AT rich, 54%
329
what % of genome is protein coding?
1.5%
330
what % of genome is genes?
20-25%
331
Number of human genes
20-30k
332
gene duplication
major mechanism of evolutionary change. When it duplicates, it frees up one copy to very while the other copy continues to carry out function
