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Genetics > Pedigree, Mendelian inheritance, Genome organization > Flashcards

Pedigree, Mendelian inheritance, Genome organization Flashcards

1
Q

Proband

A

“index case,” the affected member through whom a family with a genetic disorder is brought to attention

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2
Q

consanguinous matings

A

couples that have >1 known ancestor in common

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3
Q

mendelian disorders

A

a disorder caused by a single gene (oversimplification)

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4
Q

Phenotype

A

the observable expression of a genotype as a morphological, clinical, cellular or biochemical trait

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5
Q

Genotype

A

the set of alleles that make up his or her genetic constitution

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6
Q

Mendelian inheritance

A

the transmission of inherited characters from generation to generation through the transmission of genes

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7
Q

genes come in ____, with one from each ____

A

pairs, parent

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8
Q

genes come in different ____, which result in different observed ______

A

alleles, phenotypes

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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

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10
Q

Mendel’s second law

A

Law of independent assortment: at meiosis, the segregation of each pair of alleles is independent

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11
Q

Dominant

A

expressed when only one chromosome of a pair carries the mutant allele (in a heterozygous state)

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12
Q

recessive

A

expressed when both paired chromosomes carry a mutant allele at a locus (expressed in a homozygous or compound heterozygous state)

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13
Q

codominant

A

when both traits (alleles) are expressed in a heterozygous state

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14
Q

How many chromosomes do humans have?

A

46

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15
Q

each chromosome is believed to consists of a _______ continuous _____ _____ _____

A

single, DNA double helix

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16
Q

Retroposed gene

A

a gene without introns

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17
Q

______ + ______=phenotype

A

genotype, environment

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18
Q

Is chromosome 19 gene rich or gene poor?

A

gene rich

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19
Q

are genes 13, 18, 21 gene rich or gene poor

A

gene poor

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20
Q

Euchromatic

A

more relaxed regions of DNA

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21
Q

Heterochromatic

A

more condensed regions of DNA

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22
Q

Minisatellites

A

tandemly repeated 10-100bp blocks of DNA, VNTR(variable number of tandem repeats)

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23
Q

Microsatellites

A

di, tri, tetra nucleotide repeats, 5X10^4 per genome, STRPs (short tandem repeat polymorphisms)

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24
Q

______ are PCR detectable markers that are easy to store and are widely distributed, 1/1000bps

A

Single Nucleotide Polymorphisms (SNPs)

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25
Q

Copy Number variations

A

variations in segments of genome from 200bp-2Mp, can range from one copy to many, array comparative genome hybridization

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26
Q

Many human genes are members of _____ _____

A

gene families

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27
Q

Gene families are composed of genes with ______ _______ ______. Do they carry out similar or distinct functions?

A

high sequence similarity. They carry out both similar and distinct functions

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28
Q

Gene families arise through _____ _____, a mechanism of evolutionary change

A

gene duplication

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29
Q

Limitation of Nextgen DNA sequencing

A

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)

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30
Q

Limitations of Genome wide association studies (GWAS)

A

“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

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31
Q

bivalents

A

maternal and paternal homologs of each chromosome that pair along their entire lengths

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32
Q

synaptonemal complex

A

a proteinaceous structure which promotes inter-homolog interactions

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33
Q

Chiasmata

A

Crossovers between homologs

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34
Q

When does the synaptonemal complex disassemble? What holds the bivalents together?

A

at the end of prophase I, and the bivalents are held together by the chisamata only

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35
Q

What is the most error prone step of meiosis

A

Meiosis 1-chromosome nondisjunction at this stage is the most frequent mutational mechanism in humans

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36
Q

Genetic consequences of meiosis

A

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

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37
Q

Metacentric

A

the centromere of chromosome is located in the middle of the chromosome such that 2 chromosome arms are apprx. equal in length

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38
Q

Submetacentric

A

the centromere is slightly removed from center

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39
Q

Acrocentric

A

the centromere is near one end of the chromosome

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40
Q

Aneuploidy

A

condition where wells contain an abnormal chromosome number

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41
Q

nondisjunction

A

missegregation of chromosomes at metaphase in either mitosis or meiosis such that daughter cells receive extra or fewer than the normal number of chromosomes

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42
Q

Monosomy

A

when a cell lacks one copy of a chromosome

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43
Q

trisomy

A

when a cell has an extra copy of an entire chromosome

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44
Q

Are monosomies compatible with life?

A

No. Except for Turner’s syndrome (monosomy for X chromosome)

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45
Q

Are trisomies compatible with life

A

yes, although some result in spontaneous abortion

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46
Q

What phase is the implicated most commonly in trisomy 21

A

maternal meiosis 1

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47
Q

Trisomy 18

A

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

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48
Q

Trisomy 13

A

Patau syndrome, characteristic facies, intellectual disability, holoprosencephaly, facial clefts, polydactyly, renal abnormalities

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49
Q

XXY

A

Kleinfelter syndrome. Tall stature, hypogonadism, elevated frequency of gynecomastia, commonly sterile, language impairment

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50
Q

X0

A

Turner syndrome- short stature, webbed neck, edema of hands and feet, narrow hips, broad chest, renal and cardio anomalies, gonadal dysgenesis

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51
Q

Mosaicism

A

presence of at least 2 genetically different cells in a tissue arising from a single zygote

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52
Q

heteroploid

A

a chromosome complement with any chromosome number other than 46

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53
Q

eupoloid

A

An exact multiple of the haploid chromosome number

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54
Q

What are the 2 basic types of structural chromosome rearrangements?

A

Balanced and unbalanced

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55
Q

Chromosome inversion

A

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

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56
Q

Paracentric inversion

A

a chromosome inversion that excludes the centromere

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57
Q

Pericentric inversions

A

a chromosome inversion that includes the centromere

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58
Q

Reciprocal translocation

A

Results from the breakage and rejoining of non-homologous chromosomes, with a reciprocal exchange of the broken segments

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59
Q

Robertsonian translocation

A

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

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60
Q

Deletion

A

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

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61
Q

Duplication

A

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

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62
Q

Ring chromosome

A

a chromosome fragment that circularizes and acquires kinetochore activity for stable transmission to daughter cells. Sample karyotype: 46, XY, r(13)(p11q34)

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63
Q

Isochromosome

A

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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64
Q

Continuous gene syndromes

A

abnormal phenotypes caused by over-expressoin of loss (haploinsufficiency) of neighboring genes

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65
Q

Imprinting

A

Allele-specific methylation of CpG dinucleotides on the promotor region of imprinted genes

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66
Q

Characteristics of imprinted genes

A
  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
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67
Q

What is a common finding in childhood B-cell acute lymphoblastic leukemia (ALL)?

A

high hyper-diploidy revealed by chromosome and FISH analyses

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68
Q

What is diagnostic for chronic myelogenous leukemia (CML)?

A

t(9;22)

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69
Q

What can CML be treated with?

A

tyrosine kinase inhibitors

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70
Q

What is diagnostic for a specific acute promyeloid leukemia (PML)?

A

t(15;17)

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71
Q

What can PML be treated with?

A

Retinoic Acid

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72
Q

FISH: Centromere Probe-name and function, example

A

cen, used for Enumeration – leukemias, ex: Cen 4, 8, 10, 17, 21

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73
Q

FISH: Locus Specific-name and used for, examples

A

LSI, Deletion, leukemias, p53

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74
Q

FISH

A

fluorescent in-situ hybridization. Uses labelled probes to detect and localize the presence or absence of specific DNA sequences on chromosomes

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75
Q

Chromosomal Microarray (CMA)

A

Compares patient DNA to control to detect gains and losses using fluorescent hybridization

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76
Q

Can CMA detect balanced rearrangements?

A

No

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77
Q

What test is used for children with children with developmental delays?

A

CMA

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78
Q

What are FISH panels used for?

A

for initial differential diagnosis, and as a means to monitor treatments or disease progression

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79
Q

How many regions are interrogated in a single CMA?

A

180,000

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80
Q

Database of Genomic Variants

A

contains published literature as well as the mapping of the variants and known disease regions.

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81
Q

Name the 3 ways to get Down Syndrome

A

(95%) Trisomy 21 from nondisjunction, (3-4%) Unbalanced translocation between chromosome and another acrocentric chromosome, (1-2%) Mosaic Tri

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82
Q

What are the 1st semester screening tests for Down Syndrome? What is the detection rate?

A

Detection rate 82-87%. US measurement of nuchal folds, Beta-hCG, PAPP-A (pregnancy-assocaited plasma protein A)

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83
Q

What does 2nd trimester screening consist of? What is the detection rate?

A

80% detection rate. Quad screen: Beta-hCG, AFP (alpha-fetoprotein), unconjugated estradiol, inhibin level

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84
Q

What is the detection rate of 1st trimester + second trimester?

A

95%

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85
Q

How can the suspicion of Down Syndrome be confirmed?

A

Chromosome analysis via amniocentesis or CVS

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86
Q

Comment on the growth parameters of DS babies

A

growth parameters are usually normal

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87
Q

Common facial features of DS

A

midface hypoplasia, upslanting palpebral fissures, epicanthal folds, small ears, large appearing tongue

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88
Q

Comment on the muscle tone and joints of babies with DS

A

low muscle tone, increased joint mobility

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89
Q

hand features of DS

A

short fingers, transverse plamar crease, Vth finger incurving (clinodactyly), increased space between toes 1 and 2

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90
Q

Cardiac issues with DS

A

all types of anomalies can be present, but AV canal is most common. EKG as a newborn recommended.

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91
Q

GI issues with DS

A

Structural: esophageal and duodenal atresia, Hirschsprung’s.
Functional: feeding problems, constipation, GERD, celiac disease

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92
Q

Opthalmic issues with DS

A

blocked tear ducts, myopia, lazy eye, nystagmus, cataracts

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93
Q

ENT issues with DS

A

chronic ear infectons, deafness (neuro and conductive), chronic nasal congestion, enlarged tonsils and adenoids-apnea

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94
Q

Endocrine issues (autoimmune) with DS

A

thyroid disease (hypothyroidism-congenital or acquired), insulin dependent diabetes, alopecia atreata, reduced fertility

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95
Q

Do individuals with DS experience puberty normally?

A

yes

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96
Q

orthopedic problems with DS

A

hip problems, joint subluxation, atlantoaxial subluxation

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97
Q

Hematological issues with DS

A

myeloproliferative disorder in newborn, increased risk of leukemia, iron deficient anemia

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98
Q

Developmental issues with DS

A

hypotonia affects gross motor development, mild to moderate intellectual disability, speech problems

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99
Q

Neurological problems associated with DS

A

hypotonia mild-severe, seizures, infantile spasms

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100
Q

Psychiatric issues with DS

A

depression, early AD, 1/10 Autistic

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101
Q

How does a newborn with PW present?

A

hypotonia, dysmorphic features, undescended testicles

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102
Q

What test can be used to diagnose PW?

A

FISH, methylation testing

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103
Q

Describe feeding of PW

A

early on failure to thrive, difficult feeding, preschool age they develop hyperphagia and gain weight

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104
Q

hyperphagia

A

Excessive hunger, characteristic of PW

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105
Q

Describe the developmental delay of PW

A

mild-moderate to intellectual disability

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106
Q

Opthalmic problems associated with PW

A

strabismus and nystagmus

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107
Q

What causes PW?

A

missing information on paternal chromosome 15q11-q13

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108
Q

List the ways PW may occur

A
  1. Paternal deletion, 2.UPD of maternal allele, 3. Imprinting error-“virtual” maternal UPD
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109
Q

What common orthopedic issues exist for PW patients

A

scoliosis

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110
Q

What else can cause problems on chromosome 15?

A

linkage disequilibrium between patients with autism and polymorphisms on the GABAa-b3 locus

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111
Q

What is the most common cytogenetic abnormality in patients with autism?

A

Maternal mutation 15q11-q13

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112
Q

Phenotype of Angleman’s Syndrome

A

mildly dysmorphoc facial features, hypotonia as a chilf that turns to spasticity, intellectual disability, seizures, autism

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113
Q

4 Characteristics of epigenetic phenomena

A

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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114
Q

Waddington’s epigenetic landscape

A

Each cell state is a “low energy” state

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115
Q

3 examples of epigenetic phenomena

A

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)

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116
Q

Why is erasure and resetting of methylation patterns of imprinted genes during gametogenesis essential?

A

Embryos with no active copies or 2 active copies of imprinted genes would be produced at high frequencies

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117
Q

DNA methylation lock DNA in what state?

A

repressed

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118
Q

Where does DNA methylation occur

A

only on cytosines of CpG

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119
Q

Does DNA methylation affect the base pairing of 5-meC with G?

A

NO

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120
Q

_______, _______, and _____ are examples of epigentetic phenomena

A

x inactivation, imprinting, and herterochromatin domains

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121
Q

Examples of non-nuclear inheritance

A

cytosolic epigenetic inheritance in cancer

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122
Q

How could methylation lead to cancer?

A

Normally, a tumor suppressor gene (TSG) is ON. If it gets methylated and turns off, this can lead to cancer

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123
Q

Population genetics

A

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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124
Q

What evolutionary forces affect allele frequencies?

A

natural selection, genetic drift, mutation and gene flow

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125
Q

Polymorphism

A

A genetic variant (mutation) which is common (>1%) in the populations

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126
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

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127
Q

Genetic drift

A

random fluctuation of allele frequencies, usually in small populations

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128
Q

Selection:

A

active selection of favorable alleles over non-favorable ones

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129
Q

fitness

A

a measure of the chance an allele will be transmitted to the next generation (Scale is 0-1).

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130
Q

Hardy-Weinberg principle

A

describes the frequency of two alleles in a population in terms of allele frequency and genotype frequency

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131
Q

Hardy-Weinberg assumptions

A

random mating, no mutation, no selection for/against any allele, no migration/drift, large population

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132
Q

Stratification

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 higher incidence social stratification favoring mating of AAs with other AAs, than is predicted by HWE)

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133
Q

Assortive mating

A

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
Q

Eye characteristics of Turner syndrome

A

Inner canthal folds, blue sclerae, ptosis

135
Q

ENT of someone with Turner syndrome

A

prominent auricles, low set ears, high narrow palate, small mandible

136
Q

Neck of Turner syndrome

A

low posterior hairline, webbing

137
Q

Chest of someone with Turner Syndrome

A

broad, shield like chest, wide spaced nipples, pectus excavatum

138
Q

Skeleton of someone with Turner syndrome

A

cubitus valgus, short 5th metacarpal/metatarsal, made lung deformity, scoliosis

139
Q

What are the heart conditions common to Turner syndrome?

A

(Prenatal) cystic hygroma, (newborn) neck webbing

bicuspid aortic valve, coartation of the aorta, systemic hypertension, EKG abnormalities

140
Q

what other systems are affected by Turner syndrome?

A

Lymphatics, urinary, vision and hearing

141
Q

Sexual probs-turner syndrome:

A

infertility, sexual development, no menstruation

142
Q

Common pitfalls in disclosure of Turner Syndrome

A

secret keeping, difficulty communicating an infertility diagnosis, perceived negative experiences with physicians

143
Q

What is at the root of Gaucher’s disease?

A

not making enough of the enzyme “glucocerebrosidase”to break down the lipid “glucocerebroside” so it accumulates in the lysozomes of macrophages

144
Q

How many RBCs are produced (and destroyed) every second?

A

2.4 million new red blood cells

145
Q

How long is an RBC in circulation?

A

120 days

146
Q

What happens to old RBCs?

A

they are recycled by macrophages

147
Q

How are RBCs broken down?

A

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
Q

Where are the chemical components of the RBC broken down?

A

within vacuoles of the macrophages due to the action of lysosomal enzymes

149
Q

Hemoglobin is degraded into ______, ________, and ______

A

globin, heme, iron

150
Q

macrophages convert ____ into ____ and then ____ that is released into the blood where it forms a complex with blood albumin (bound bilirubin).

A

heme, bilverdin, bilirubin

151
Q

In the liver cells (hepatocytes) ______ reacts with glucuronic acid to form ______.

A

Bound bilirubin, conjugated bilirubin

152
Q

Most of the _______ is secreted into the small intestine with the bile. In the large bowel, bacteria convert _____ into the yellow-brown pigment (urobilinogen)

A

conjugated bilirubin, bilirubin

153
Q

_____ 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.

A

Iron, transferrin

154
Q

What % of the RBC membrane is lipid?

A

30%

155
Q

Where are the typical Gaucher cells stored?

A

mainly in liver, spleen and bone marrow.

156
Q

What is the most common first symptom of Gaucher’s disease and what can it be attributed to?

A

A swollen stomach. This is because the spleen has swollen.

157
Q

Why is anemia common?

A

When the spleen enlarges, sometimes to 25 times its normal size, it weeds out too many blood cells, including good ones.

158
Q

Difference between Type I, II, and III Gaucher’s disease

A

type 2 and 3 have neurological symptoms

159
Q

How can gaucher’s disease be diagnosed?

A
  1. blood test to check glucocerebrosidase levels, 2. Genetic testing: N370S, L444P, 84gg and IVS2
160
Q

What type of mendeilan disease is Gaucher’s?

A

Autosomal recessive

161
Q

Imiglucerase (Cerezyme)

A

recombinant DNA-produced analogue of human β-glucocerebrosidase. It is given intravenously after reconstitution as a treatment for Type 1 Gaucher’s disease

162
Q

Miglustat

A

inhibitor of the enzyme glucosylceramide synthase, reduced the substrate to treat Gaucher’s disease

163
Q

Taliglucerase alfa

A

recombinant glucocerebrosidase enzyme produced in a slurry of carrot cells.

164
Q

Characteristics of diseases demonstrating multifactorial inheritance

A
  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
Q

Heterogeneity (allele and locus)

A

allele-cystic fibrosis, locus-alzheimer’s disease

166
Q

Phenocopies

A

tahildomide-induced limb malformation

167
Q

define heterogeneity at an allele or locus

A

the “same” disease can be caused by different alleles at one location or by alleles at different locations in the genome

168
Q

Define phenocopy

A

disease traits that manifest like the disease, but have a different cause other than primary genetics.

169
Q

Multifactorial inheritance

A

indicated when there is an increased risk to relatives, but there is no consistent pattern of inheritance within families

170
Q

Heritability

A

the proportion of total variance in a trait that is due to variation in genes.

171
Q

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.

A

high

172
Q

A ____ heritability does not imply that non-genetic factors are not important

A

high

173
Q

What are the most common polymorphic DNA markers?

A

Microsatellites, SNPs, and CNVs

174
Q

Each SNP occurs in local context (_______) of surrounding SNPs

A

haplotype

175
Q

haplotype

A

Groups of SNPs that can be inherited

176
Q

haplotype block

A

Alleles that are in linkage disequilibrium, and therefor are inherited together. Smaller in african populations

177
Q

How often do CNVs contribute to human disease?

A

It is uncertain

178
Q

Are candidate gene association studies hypothesis driven or hypothesis free? Consequence?

A

Hypothesis driven, false positives. Hypotheses are often wrong

179
Q

What are candidate gene association studies most powerful for?

A

common risk alleles with small to moderate effects

i.e. “complex”, polygenic traits

180
Q

Do candidate gene association studies depend on Linkage disequilibrium

A

yes

181
Q

How does candidate gene association work?

A
  1. Genotype marker in candidate gene in cases and in controls
  2. Compare allele frequencies in cases versus controls
182
Q

Advantages of candidate gene association studies

A

simple, reasonable number of controls (hundreds), simple stats

183
Q

Genetic linkage studies: hypothesis driven or no?

A

hypothesis free!

184
Q

What do genetic linkage studies do?

A

Search genome for segments disproportionately co-inherited along with disease through “multiplex families” (families with multiple cases of a disease)

185
Q

What does a genetic linkage study assume?

A

affected relatives share the disease (not phenocopies)

186
Q

What is a disadvantage of genetic linkage study?

A

less powerful for complex traits

187
Q

What types of traits does a genetic linkage study work best for?

A

Mendelian traits (uncommon alleles with strong effects)

188
Q

What is the unit of genetic distance in linkage studies?

A

centiMorgan (cM)

1 cM = 1% recombination between two loci per meiosis

189
Q

What is the statistical measure of genetic linkage analysis?

A

LOD (log of odds) score

190
Q

Significance level of LODs for Mendelian and polygenic traits

A

LOD >3.0 for Mendelian trait

LOD >3.3 for Polygenic trait

191
Q

What does GWAS stand for?

A

Genome wide association study

192
Q

How are GWAS different from candidate gene association studies?

A

GWAS tests hundreds of thousands or millions of markers (SNPs) across entire genome

193
Q

What is a disadvantage of GWAS?

A

must use more than a thousand cases and 1000 controls

194
Q

What is GWAS most effective for?

A

Most effective for common alleles with small to moderate effect sizes

195
Q

What are exomes and what % of the genome do they make up?

A

Gene coding regions; ~ 3 Mb (1% of genome)

196
Q

What are the 3 steps of sexual differentiation?

A
  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
Q

Genetic sex is determined by______

A

the presence or absence of Y chromosome

198
Q

All diploid somatic cells in both males and females have a single ______ __ ______regardless of the total number of X and Y chromosomes present.

A

active x chromosome

199
Q

X inactivation is normally _____ so that females are _____ for expression of their x chromosomes.

A

random, mosaic

200
Q

How is the x chromosome inactivated?

A

DNA methylation and modification of histone proteins

201
Q

XIST gene

A

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
Q

What percentage of genes on the X chromosome escape inactivation? Where are they located?

A

10-15%, many are located on Xp

203
Q

Where do the X and Y chromosomes pair for recombination during meiosis?

A

pseudoautosomal region

204
Q

Nonrandom X inactivation. How might this present clinically?

A

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
Q

Gonadal sex is determined by

A

expression of genes that induce the development of testes (SRY)

206
Q

SRY

A

principal determinant of testicular differentiation. Without SRY–> ovaries

207
Q

Germ cells develop in 2 stages:

A
  1. sexually independent pregonadal stage where they migrate from yolk sac->developing gonads
  2. gonadal dependent stage-they mature
208
Q

Mutations at autosomal loci on chromosomes ___, ___, and ___ can lead to sex reversal in the presence of ____ gene

A

9, 11, 17, SRY

209
Q

WT gene

A

directs differentiation of the mesonephros and genital ridge (precede gonadal development)

210
Q

Loss of ____ gene can lead to adrenal hypoplasia and gonadal agenesis

A

SF1

211
Q

DAX1 is a nuclear hormone receptor. It’s presence leads to the development of ____ even in the presence of ___, a disorder called ____

A

ovaries, SRY, Dosage Sensitive Sex Reversal (DSS)

212
Q

Anatomic sex is determined by:

A

the action of growth factors and sex steroid hormones

213
Q

Testes contain two non-germ cells:

A
  1. Sertoli cells (MIF), 2. Leydig cells (testosterone)
214
Q

What do sertoli cells produce?

A

Mullerian Inhibitory factor

215
Q

What do leydig cells produce?

A

testosterone

216
Q

What does MIF do?

A

Prevents formation of the mullein duct derivatives (would be fallopian tubes, uterus, and upper vagina)

217
Q

What does testosterone stimulate the development of? What does it become?

A

Wolffian (mesonephric) duct, becomes epidydimal duct and ductus deferens.

218
Q

In the absence of testosterone, what structure degenerates in women?

A

wolffian (mesonephric duct)

219
Q

The male external genitalia develop in response to what?

A

testosterone

220
Q

In many androgen sensitive tissues, testosterone must be converted to ____

A

dihydrotestosterone

221
Q

The genital tubercle becomes what in M/F?

A

M: glans and shaft of penis
F: glans and shaft of clitoris

222
Q

The definitive urogenital becomes what in M/F?

A

M: penile urethra
F: vestibule of vagina

223
Q

The urethral fold becomes what in M/F?

A

M: Penis surrounding penile urethra
F: Labia miora

224
Q

Labioscrotal fold becomes what in M/F?

A

M: Scrotum
F: Labia majora

225
Q

Sex reversal

A

whe gonadal sex is the opposite of what is predicted from karyotype (genetic sex)

226
Q

XX males

A

translocation of Y chromosome material (SRY) to another chromosome. Translocation to an autosome is most common.

227
Q

XY females

A

insertion of SRY gene on a chromosome

228
Q

pseudohermaphroditism

A

abnormal development of genital sex. External phenotype and sex assignment can be different than genetic sex.

229
Q

How can pseudohermaphroditism occur for males and females?

A

masculinized females-exposure to androgens during development
males-failure to produce or respond to testosterone

230
Q

Loss-of-Function Mutations:

A

Caused by genetic mutations that eliminate (or reduce) the function of the protein.

231
Q

Of the four major mechanisms, which is the most common genetic mechanism leading to human genetic disease?

A

loss of function mutation

232
Q

Examples of loss of function mutations:

A

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
Q

Gain of function mutations

A

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
Q

Examples of gain of function mutations

A

Hemoglobin Kempsey, Achrondroplasia, Alzheimer, Charcot-Marie-Tooth

235
Q

Novel property mutations

A

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
Q

Are novel property mutations common or uncommon?

A

uncommon

237
Q

Examples of novel property mutations

A

Sickle cell anemia, Huntington disease

238
Q

Ectopic or Heterochronic expression mutations are seen in what kind of conditions?

A

Cancers. Also hereditary persistance of fetal Hb

239
Q

Ectopic or Heterochronic expression mutations

A

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
Q

Unstable Repeat Sequences

A

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
Q

Example of unstable repeat sequence disease

A

Huntington disease

242
Q

Genetic anticipation

A

the observation that disease severity worsening in subsequent generations.

243
Q

What explains genetic anticipation?

A

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
Q

Consequences of expansion of noncoding repeats and loss of function:

A
  • Impaired transcription
  • Mutant RNA not made
  • Mutant protein not made
245
Q

Consequences of expansion of noncoding repeats conferring novel properties

A
  • RNA has novel property (abnormal RNA binds and soaks up RNA-binding proteinsàaffects other gene products)
  • Mutant RNA is made
  • Mutant protein not made
246
Q

Consequences of expansion of codons in exons

A
  • Novel property on expressed protein
  • Mutant RNA is made
  • protein is made and is toxic
247
Q

Where do the majority of mutant alleles exist for a given autosomal recessive disease?

A

Carriers

248
Q

Allelic heterogeneity

A

existence of multiple mutant alleles for a single gene

249
Q

Compound heterozygote

A

one who carries 2 different mutant alleles on the same gene

250
Q

What enzyme is missing in PKU?

A

phenylalanine hydroxylase

251
Q

What happens in PKU?

A

high levels of Phe accumulate and damage CNS

252
Q

Describe the risks for a pregnant PKU woman

A

miscarriage, baby might have deformities, mental retardation, growth impairment REGARDLESS OF BABY’S GENOTYPE

253
Q

What is the treatment for PKU?

A

Diet low in phenylalanine

254
Q

What tests can screen for PKU?

A

Guthrie test (bacteria will grow in presence of Phe when they normally would’t), Mass spectrometry.

255
Q

Why is timing important for PKU screening?

A

Can screen at birth, but have to be careful because levels might be normal. PKU levels will increase in the first few days

256
Q

How can you imagine a1-antitrypsin?

A

A lung protector

257
Q

What are some characteristics of a1-antitrypsin deficiency? (ATD)

A
  • late onset
  • common among norther Europeans
  • 20X risk of emphysema, high risk of cirrhosis and liver cancer
  • smoking makes it much worse
258
Q

What does a1-antitrypsin do on a molecular level?

A

Inhibits elastase, which is a protease that breaks down lung tissue. When a1-antitrypsin is not present in sufficient amounts, emphysema results.

259
Q

Why can a1-antitrypsin deficiency cause cirrhosis?

A

because misfolded a1-antitrypsin aggregates in the liver where it is produced

260
Q

Which mutant allele of a1-antitrypsin deficiency is most severe? Why?

A

Z allele so most severe and most common. Improperly folded protein sticks in the liver (potential for cirrhosis)

261
Q

Which mutant allele is less severe? why?

A

S allele, makes a protein unstable but is not misfiled so no liver disease.

262
Q

What gene is mutated in Tay-Sachs?

A

HEXA

263
Q

What gene is mutated in Sandhoff disease?

A

HEXB

264
Q

What gene is mutated in AB-variant of Tay Sachs?

A

GM2AP

265
Q

What are the substrates involved in Tay-sachs?

A

GM2 gangliosides

266
Q

What are the substrates involved in Sandhoff disease?

A

globosides

267
Q

What does the enzyme test for tay-sachs show?

A

HEXA defective, HEXB normal

268
Q

What does the enzyme test show for Sandhoff disease?

A

HEXA and HEXB both defective

269
Q

What does the enzyme test show for AB-variant of tay sachs

A

Normal HEXA and HEXB

270
Q

What group is at a high risk for tay-sachs?

A

central/eastern europeans and Ashkenazi Jews

271
Q

What causes tay sachs?

A

HEXA mutation=defective hexosaminidaseA, can’t degrade ganglioside=progressive CNS destruction

272
Q

What type of hemoglobin is present in embryos?

A

Zeta2epsilon2

273
Q

Hb in fetal development

A

a2y2 (HbF)

274
Q

Adult Hb

A

a2B2 (HbA) and a2d2 (HbA2)

275
Q

What Hb’s are present in an adult?

A

HbA, HbA2, and HbF

276
Q

Locus control region

A

upstream of the coding regions for the alpha and B globin clusters. Controls timing and levels of the globin proteins

277
Q

Sickle cell anemia results from a switch between ___ and ___ in codon ____ of exon____

A

Glu, Val, 6, 1

278
Q

In low O2, HbS is ______ soluble than HbA

A

less

279
Q

Hemoglobin C Disease results from a change from ___ to ___ in exon ___ and codon ___

A

Glu, Lys, 1, 6

280
Q

In low O2, HbC is ____ soluble than HbA and tends to ______ causing _____

A

less, crystalize, lysis

281
Q

How can sickle cell anemia be diagnosed?

A

PCR using MstII to tell between HbA and HbS (cannot tell between HbA and C)

282
Q

How many total copies of the alpha globin gene do people have

A

4 (2 on each chromosome)

283
Q

How many total copies of beta globin gene do people have?

A

2 (1 on each chromosome)

284
Q

What is the genotype for a silent carrier of a-thalassemia? What % a-globin level?

A

aa/a-

75%

285
Q

What is the genotype for a-thalassemia 1 trait? What % a-globin level? Where is it common?

A

aa/–
50%
common in SE asia

286
Q

What is the genotype for a-thalassemia 2 trait? What % a-globin level? Where is it common?

A

a-/a-
50%
Africa, mediterranean, asia

287
Q

What is the genotype for HbH disease? What % a-globin level? What forms?

A

a-/–
25%
B4 clusters form

288
Q

hydrops fetais

A

–/– y4 clusters, results in fetal death

289
Q

locus heterogeneity

A

mutation in more than one locus that causes the same clinical condition

290
Q

trinucleotide repeat disorders work by a _____ ______ mechanism

A

slipped mispairing

291
Q

______ and _______ ________ _____ are characteristics of trinucleotide repeat disorders

A

anticipation, parental transmission bias

292
Q

Are trinucleotide repeat disorders AD, AR, or X linked?

A

They can be autosomal dominant, autosomal recessive, or x linked

293
Q

Parental transmission bias

A

trinucleotide expansion more prone to occu in gametogenesis of male or female

294
Q

Where do mtDNA disorders typically cause dysfunction

A

repiratory chain

295
Q

How many genes are coded for in the mitochondrial genome?

A

37

296
Q

Pharmacogenetics

A

Study of differences in drug response due to allelic variation in genes affecting drug metabolism, efficacy, toxicity

297
Q

Pharmacogenetics is variable due to _____

A

individual genes

298
Q

Pharmacogenomics

A

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
Q

Pharmacogenomics has a variable response due to _______

A

multiple loci across the genome

300
Q

What are the two major elements of response to drugs?

A

Pharmacokinetics and pharmacodynamis

301
Q

Pharmacokinetics

A

ADME: Absorption, Distribution, Metabolism, and Excretion of drugs

302
Q

Pharmacodynamics

A

Describes the relationship between the concentration of a drug at its site of action, observed biological effects.

303
Q

Drug metabolism: Phase I

A

polar group added (exposed)–>solubilize

304
Q

Drug metabolism: Phase II

A

conjugation rxn (sugar/acetyl group)–>detoxify

305
Q

Where are the gene products of CYP450 complex active?

A

liver, intestinal epithelium

306
Q

What are the 3 main families of CYP450 complex

A

CYP1, CYP2, CYP3

307
Q

Most CYPs function to _______ drugs. Is this always the case?

A

inactivate, not always the case, sometimes they are needed for activation

308
Q

What converts codeine to morphine?

A

CYP2D6

309
Q

What inactivates 40% of common drugs?

A

CYP3A4

310
Q

What types of mutations are expected for a poor metabolizer?

A

Frameshift, splicing, nonsense, missence (some)

311
Q

What types of mutations are expected for an ultrafast metabolizer?

A

increased copy number, missense (some)

312
Q

10 % of females are affected in which x linked recessive disorder?

A

hemophilia a

313
Q

1/3 of females are affected by what trinucleotide repeat, x linked disorder

A

Fragile X, but much less severely

314
Q

Cooley’s thalassemia is another name for what?

A

B thalassemis major

315
Q

What might be observed for a patient with B thalassemia

A

osteopenia, dense marrow expansion, enlarged spleen, short stature

316
Q

homoglobin S variant: (ethnic group)

A

15 % African Americans carriers

317
Q

hemoglobin E varient: (region)

A

7% SE asians

318
Q

Treatment for Multiple Endocrine Neoplasia (MEN)

A

Thyroid removal after early testing

319
Q

Treatment for Aplha-1AT

A

recombinant enzymen therapy

320
Q

Treatment for Fabry disease

A

recombinant a-galactose (stabilizes the protein so it can fold correctly) intreacellular protein

321
Q

Treatment for hemophilia A

A

replace factor VIII

322
Q

informative result

A

definitively diagnoses or excludes the disease

323
Q

non-informative

A

result is normal, but not possible to exclude disease risk

324
Q

genetic heterogeneity

A

multiple genes (when mutated) are associated with the same phenotype

325
Q

example of genetic heterogeneity

A

HCM

326
Q

a SNP occurs every ____/_____ bp

A

1/1000

327
Q

Number of base pairs in human genome

A

3X10^9

328
Q

More AT or GC rich regions?

A

AT rich, 54%

329
Q

what % of genome is protein coding?

A

1.5%

330
Q

what % of genome is genes?

A

20-25%

331
Q

Number of human genes

A

20-30k

332
Q

gene duplication

A

major mechanism of evolutionary change. When it duplicates, it frees up one copy to very while the other copy continues to carry out function

Genetics (3 decks)

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