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M2M Unit II > Genetics > Flashcards

Flashcards in Genetics Deck (174):
1

What is an allele?

A certain version of a gene

2

Define Mendel's Law of Segregation

Alleles segregate (at meiosis) into the gametes

3

Define Mendel's Law of Independent Assortment

The segregation of each pair of alleles is independent

4

Define genotype

The DNA sequence (alleles) at a particular locus

5

Define homozygous genotype

2 identical alleles at a given locus

6

Define heterozygous genotype

2 different alleles at a given locus

7

Define hemizygous genotype

Refers mostly to males (XY), who have just a single copy of each X-chromosomal gene

8

Define phenotype

The observed/measured trait

9

Define dominance

A phenotype that is expressed (observed) in the heterozygous state

10

Define recessive

A phenotype that is expressed only in homozygotes or hemizygotes

11

Define semi-dominant

When the heterozygous phenotype is intermediate between the two homozygous phenotypes

12

Define penetrance

Some with a mutation can still be unaffected; ex. 80% penetrance indicates that 80% with the mutation are affected; Used with dominant and recessive mutations

13

Define expressivity

Severity of phenotype in those who Are affected

14

Define pleiotropy

Genes that have multiple effects in body; polysystemic versus monosystemic

15

What are three threats to Mendelian inheritance?

Penetrance, expressivity, & pleiotropy

16

Define environmental factors

Factors that are not genetic that affect the expression of Mendelian diseases

17

Define modifier genes

Genetic factors that influence a phenotype

18

Define stochastic effects

Stochastic (random) effects can influence the expression of phenotypes

19

Define phenocopy

Same phenotype as a genetic condition due to non-genetic factors

20

Define proband

The affected member through whom a family with a genetic disorder is brought to attention

21

Define consultand

The person who brings the family to attention (affected or unaffected)

22

Define locus

Segment of DNA occupying a particular position/location on a chromosome

23

Define compound heterozygote

Two recessive mutant alleles, but they're different

24

What is the difference between autosomal and sex-linked?

Autosomal affects males and females equally. Sex-linked means the mutation is on X chromosome

25

Define allelic heterogeneity

A single disorder, trait, or pattern of traits caused by different mutations within a gene

26

Define locus heterogeneity

A single disorder, trait, or pattern of traits caused by mutations in genes at different chromosomal loci

27

Define phenotypic heterogeneity

When different mutations in same gene cause different phenotypes

28

What are "threats" to Mendelian genetics?

Factors or characteristics of mutations that discourage phenotypes from following Mendelian rules or expectations.

29

What is the Mendel's First Law of Inheritance?

The Principle of Segregation: A gene pair separates, sending one allele to one gamete and the other to another gamete

30

What is Mendel's Second Law of Inheritance?

The Principle of Independent Assortment: Genes for different traits assort independently of one another in the formation of gametes

31

How many pairs of chromosomes make up the human genome?

23 pairs (one of which is a sex pair of chromosomes)

32

What is one chromosome made up of?

One single continuous double-helixed DNA strand

33

What is a typical gene? A retroposed genes?

A typical gene is intron-containing, while a retroposed gene is intronless

34

About what is the size range of chromosomes?

~50,000,000 bp - 250,000,0000 bp

35

What is a genetic map vs. a physical map in genomics?

Both maps are a collection of genetic markers and gene loci, but genetic map distances are based on the genetic linkage information measured in Centi-Morgans, while physical maps use actual physical distances measured in base pairs.

36

What is the Human Genome Sequence a record of?

Human evolutionary history

37

What is the average propensity of single nucleotide polymorphisms (SNP) in humans?

1 SNP every 1000 bp between any two randomly chose unrelated human genomes

38

What are the three gene-poor human chromosomes?

13, 18, 21 (viable)

39

Why are chromosomal banding patterns possible?

There is clustering (non-random distribution) of GC-rich and AT-rich regions

40

What are the two methods for sequencing the human genome?

1. Make clone libraries of genome, map them out, then sequence overlapping clones
2. Shotgun sequencing: break apart entire genome, sequence, then assemble it

41

Does genome sequencing sequence euchromatic or heterochromatic regions?

Euchromatic regions (accessible - heterochromatic regions usually just contain copies of genes)

42

What are DNA tandem repeats? aka "satellite DNAs"

Short sequences of DNA (2-5bps) that are repeated numerous times in a head-tail manner. Used as the basis for cytogenetic banding. Hotspots for human-specific evolutionary changes.

43

What are DNA alpha-satellite repeats?

A 171 bp repeat unit found near centromeric regions of all human chromosomes; may be important to chromosome segregation in mitosis & meiosis

44

What is non-allelic homologous recombination (NAHR)?

NAHR is a form of homologous recombination that occurs between two lengths of DNA that have high sequence similarity, but are not alleles.

45

What is retrotransposition?

The insertion of DNA sequences mediated by an RNA intermediate. In humans, carried out through reverse-transcriptase.

46

How do we measure changing number of copies?

Array CGH (comparative genomic hybridization)

47

What is a 'gene family' composed of?

Composed of genes with high sequence similarity that may carry out similar but distinct functions.

48

How are gene families the major mechanism behind evolutionary change?

When a gene duplicates it frees up one copy to vary while the other can continue carrying out its critical function

49

For what percentage of genes do we not know specific molecular function?

41%

50

What is the primary type of genome structural variation?

Copy number variations

51

What do duplications of the DUF1220 indicate?

Macrocephaly & autism

52

What do deletions of the DUF1220 indicate?

Microcephaly & schizophrenia

53

What is indicated by 'gene-rich' and 'gene-poor?'

A gene-rich region of DNA has multiple genes within in. A gene-poor region... self-explanatory.

54

What is the missing heritability problem?

Studies that look for genetic factors in complex diseases only truly discover a small percentage of factors. Many genetic contributions are yet to be discovered and sequenced.

55

Chromosomal abnormalities occuring during meiosis can result in what kinds of mutations?

germ line mutations

56

Chromosomal abnormalities occuring during mitosis can result in what kinds of mutations?

somatic mutations, germ line mutations - results in mosaicism

57

Define mosaicism

Cells with more than one chromosomal composition - not all cells are identical when they should be

58

What are the basic steps of meiosis and what is the haploid state at each step?

2N cell undergoes DNA replication -> 4N -> Homologs pair and separate -> 2N -> another round of segregation to result in 4 haploid (N) gamete cells

59

How are X and Y chromosomes paired up for meiosis when they are not identical homologs?

There are regions called pseudoautosomal regions that share homology so that they can be properly aligned.

60

Define epigenetics

Expression of genes from characteristics other than DNA sequences

61

What on the DNA can be methylated?

CpG sites; sites where a cytosine and guanine are separated by only one phosphate, cyosine is 5' to guanine; cytosine methylated at 5' position

62

Describe Waddington's Landscape as Epigenetic Visualization

A ball (ex. pleuripotent stem cell) sits at top of hill. It waits for signals so that it can decide which route to roll down for different gene expression.

63

Non-disjunction during Meiosis I results in what?

100% abnormal gametes

64

Non-disjunction during Meiosis II results in what?

50% abnormal gametes

65

How are chromosomes visualized? (striped)

Giemsa Staining; GC do not stain (Giemsa-light) and AT stain (Giemsa-dark)

66

What are the three chromosomal structural classifications?

Metacentric, submetacentric, acocentric

67

In what order are karyotypes listed?

Number of chromosomes; gender; findings

68

Define mosaicism

Two or more chromosome complements present within a single individual; commonly caused by nondisjunction in an early post-zygotic mitotic division

69

What is polyploid mosaicism?

Diploid/Triploid

70

What is aneuploid mosaicism?

Normal/Trisomy21

71

What are the two types of stuctural chromosomal abnormalities and their subcategories?

1) Balanced
-Inversions
-Reciprocal translocations
-Robertsonian translocations

2) Unbalanced
-Deletions
-Duplications
-Isochromosomes
-Marker (ring) chromosomes

72

What is reciprocal translocation?

Exchange of genetic material between two non-homologous chromosomes

73

What is a paracentric inversion?

An inversion excluding the centromere; occurs when one chromosome undergoes two DSBs of the backbone and the intervening sequence is inverted prior to the rejoining of the broken ends

74

What is a pericentric inversion?

An inversion including the centromere; occurs when one chromosome undergoes two DSBs of the backbone and the intervening sequence is inverted prior to the rejoining of the broken ends

75

How can inversions show no phenotype but produce abnormal gametes?

Although there is an inversion, all genetic material is still present. During the pairing of homologs in meiosis, a loop is introduced in the homolog containing the inversion

76

What is the risk that a carrier of a reciprocal translocation will produce offspring with balanced translocation?

5-10%

77

Reciprocal chromosome translocation leads to what kind of leukemia?

Chronic Myelogenous Leukemia; 95% of patients with CML have the Philadelphia chromosome and an abnormal chromosome 9

78

What is a Robertsonian Translocation?

Fusion between centromeric regions of two acrocentric chromosomes, with deletion of both short arms.

79

Define isochromosome

A chromosome in which one arm is missing and the other arm is duplicated in a mirror-like fashion

80

What chromosome is involved in the most common isochromosome?

Long arm of X chromosome

81

What percentage of the viable offspring of a carrier of isochromosome 21 are abnormal?

100%

82

How do aberrant recombination events lead to unbalanced chromosomal rearrangements?

Two chromosomes align slightly out of register with each other and one homolog contains a deletion while the other contains a duplication

83

What percentage of gametes in a Robertsonian translocation are normal?

5-10%

84

Define contiguous syndrome

Abnormal phenotype caused by over-expression or loss of neighboring genes

85

Define epigenetics

Mitotically and meiotically heritable variations in gene expression that are not caused by changes in DNA sequence, but by reversible post-translational modifications of histones or DNA methylation, for example

86

What is genetic imprinting?

Genes that are inherited in a transcriptionally active state from one parent and a transcriptionally inactive state from the other parent

87

About what percent of genes in the human genome are thought to be imprinted?

~1%

88

At what point are DNA methylation marks established?

In the gamete

89

Why does DNA methylation have to be reversed and reset?

So that during gametogenesis, the sex-appropriate marker can be placed

90

What are four characteristics of epigenetics?

1. Different gene expression patter/phenotype with an identical genome

2. Inheitance through cell division, even through generations

3. Like a switch: on/off

4. Erase-able (inter-convertible) - therapeutic potential

91

Describe Waddington's Landscape as epigenetic visualization

A ball sits at top of hill (pleuripotent stem cell). It can roll down the hill through multiple divets and paths. Hills represent the "activation energy" to go down that pathway. The ball waits for cues to differentiate into different types of cells.

92

Where can DNA methylation occur?

Only on cytosines of CpG; where C is just 5' to G

93

Do epigenetic mechanisms and inheritance occur inside or outside nucleus?

Both!

94

What gene can lead to cancer when aberrantly methylated with 5meC?

Tumor Suppressor Gene (TSG)

95

What constitutes a genetic test?

1. Analyzing an individual's genetic material to determine predisposition to a particular health
condition or to confirm a diagnosis of genetic disease.

2. Examining a sample of blood or other body fluid or tissue for biochemical, chromosomal, or genetic
markers that indicate the presence or absence of genetic disease.

96

What are 'informative' and 'non-informative' genetic test results?

Informative test results are when the results actually determine disease presence/absence and identification. Non-informative implies that more information is needed.

97

Explain how allelic heterogeneity can affect the sensitivity of genetic tests.

d

98

Explain how genetic heterogeneity can affect the sensitivity of genetic tests.

d

99

What is the basic approach of chromosomal analysis?

d

100

What is the basic approach of fluorescent in-situ hybridization (FISH)?

d

101

What is the basic approach of microarray analysis?

d

102

What is the basic approach of DNA sequencing?

d

103

What are the advantages of chromosomal analysis?

d

104

What are the advantages of fluorescent in-situ hybridization (FISH)?

d

105

What are the advantages of microarray analysis?

d

106

What are the advantages of DNA sequencing?

d

107

What are the limitations of chromosomal analysis?

d

108

What are the limitations of fluorescent in-situ hybridization (FISH)?

d

109

What are the limitations of microarray analysis?

d

110

What are the limitations of DNA sequencing?

d

111

What is the chance that an unaffected sibling is a carrier of an autosomal recessive allele?

2/3

112

In the p/q equation, what determines frequency of mutant allele?

q

113

In the p/q equation, what determines frequency of carriers of a mutant allele?

2pq

114

In the p/q equation, what determines frequency of an autosomal recessive disease (prevalence)?

q squared

115

Define allelic heterogeneity

Presence of multiple common mutant alleles of the same gene in a population

116

Define compound heterozygote

An individual who carries two different mutant alleles of the same gene (different alleles regardless)

117

Define incomplete dominance

When homozygotes are affected more severely than heterozygotes

118

Define slipped mispairing

Mispairing of bases in regions of repetitive DNA replication coupled with inadequate DNA repair systems

119

How do you calculate risk of disease in relatives in diseases of multifactorial inheritance?

gamma(s) = risk of disease in siblings of affected / risk of disease in general population

120

Define allelic heterogeneity

Different alleles in the same gene result in same trait, or different trait

121

Define locus heterogeneity

Variants in different genes result in very similar clinical presentations

122

Define phenocopy

Environmentally caused phenotype that mimics the genetic version of the trait

123

Define sexual dimorphism

The phenotypic differences between males & females

124

How does the female body choose which X chromosome to inactivated?

Random process; the inactive X chromosome expresses the XIST gene

125

What is nonrandom X chromosome inactivation?

Occurs when there is a structurally abnormal X chromosme; more of the normal Xs are turned on

126

What is skewed X inactivation?

When there is an imbalance in a good/bad X chromosome that's inactivated.

127

What does gonad determination depend on?

Chromosomes!

128

What is the "default" state: female or male?

Female

129

What determines secondary sex characteristics?

Gonadal development

130

In the embryology of reproductive organs, what occurs in the 5th week?

Coelomic epithelium becomes genital ridge

131

In the embryology of reproductive organs, what occurs in the 6th week?

Primordial germ cells migrate to the dorsal mesentary of the hindgut adn enter undifferentiated gonad; epithelial cells of gonadal ridge proliferate and form primitive sex cords

132

In the embryology of reproductive organs, what occurs in the 7th week in males?

The genital ridge is differentiated into Sertoli and Leydig cells

133

In the embryology of reproductive organs, what occurs in the 8th week in males?

Leydig cells begin producing testosterone and Sertoli cells produce AMH; primitive sex cords differentiate into testis cords & rete testis

134

In the embryology of reproductive organs, what occurs in the 7th-8th weeks in females?

In the absence of SRY & in presence of 2 X chromosomes, primitive sex cords dissociate into irregular clusters and go away; medullary cords regress and cortical cords are formed, which are destined to become follicular cells of the ovary.

135

What are the male genital ducts called? The female?

Male: Mesonephric (Wolffian)
Female: Paramesonephric (Mullerian)

136

What two genes are responsible for virilization and are on the Y chromosome?

SRY & SOX9 genes; produce AMH

137

What male gene is a chemotactic factor that causes tubules from mesonephric duct to penetrate gonadal ridge?

FGF9

138

What male gene stimulates differntiation of the Sertoli & Leydig cells?

SF1/NR5A1

139

What do the mesonephric (Wolffian) ducts elongate to form?

Epididymis, seminal vesicles, vas deferens

140

What protein is responsible for differentiation of the ovary/

WNT4 protein

141

What gene is a nuclear hormone receptor up-regulated by WNT4 that functions to downregulate SOX9?

DHH gene

142

What gene is a coactivator of the WNT pathway in female development?

RSPO1 gene

143

The paramesonephric (Mullerian) ducts form what?

Uterus, cervix, broad ligament, Fallopian tubes, upper 1/3 of vagina

144

At 3 weeks of embryonic development, what forms the genital tubercle and genital swellings?

Mesenchymal cells in the primitive streak

145

For finding disease genes, instead of sequencing entire genomes, how do we find genetic differences in individuals/families?

We genotype polymorphic DNA "markers" (any scoreable difference) at known genomic positions

146

What are three commonly used marker types when finding disease genes?

Microsatellites, single-nucleotide polymorphisms (SNPs), & copy-number variations (CNVs)

147

Define haplotype

Recombination breaks macro-patterns of polymorphic genotypes on the same chromosome into haplotypes: genes too close together to be separated during recombination.

148

Define linkage disequilibrium

When marker alleles within haplotype blocks tend to be co-inherited because recombination within blocks is uncommon

149

What is candidate gene DNA sequencing?

Studies gene directly and depends on biological hypothesis and positional hypothesis/information

150

When is candidate gene DNA sequencing most useful?

Sometimes successful in Mendelian disorders, but in complex disorders it is most useful when candidates are positive from GWAS

151

Are most hypotheses from candidate gene DNA sequencing right or wrong?

Wrong!

152

What are candidate gene association studies?

Most common type of 'genetic study."

153

When are candidate gene association studies most useful?

Most powerful for common risk alleles with small to moderate effects.

154

How do fatal flaws lead to false-positives in candidate gene association studies?

d

155

Define pharamcogenetics

The study of differences in drug response due to allelic variation in genes affecting drug metabolism, efficacy, and toxicity

156

Define pharmacogenomics

The genomic approach to pharmacogenetics, concerned with the assessment of common genetic variants in the aggregate for their impact on the outcome of drug therapy

157

What are pharmacokinetics & pharmacodynamics?

Describes absorption, distribution, metabolism, and excretion of drugs. Pharmacodynamics describes the relationship between the concentration of a drug at its site of action and the observed biological effects.

158

Contrast Phase I and Phase II drug metabolism steps

In Phase I, a polar group is added (exposed) in order to solubilize. In Phase II, conjugation reaction (sugar/acetyl group) to detoxify.

159

Describe the central role of the CYP450 enzyme system in drug metabolism

Its gene products are active in liver and intestinal epithelium. Account for ~90% of phase I for common drugs.

160

What are the three main families of the CYP450 complex?

CYP1, CYP2, CYP3

161

What is the function of most CYPs?

Inactivate drugs. Rarely needed for activation.

162

Which CYP gene is needed to activate codeine into morphine?

CYP2D6

163

What is the role of TPMT in terms of drug metabolization?

Just another way to metabolize

164

What is an important CYP3A substrate, inhibitors (2), and inducer?

CYP3A substrate: cyclosporine
Inhibitor: grapefruit juice & ketoconazole
Inducer: rifampin

165

What are two important substrates of CYP2D6? Three important inhibitors?

Substrates: Tricyclic antidepressants, codeine

Inhibitors: Fluoxetine, Quinidine, Paroxetine

166

What is an important substrate of CYP2C9?

Warfarin

167

What is an important substrate of the NAT gene?

Isoniazid for tuberculosis

168

What are two important substrates for TMPT?

6-mercaptopurine & 6-thioguanine; cannot give juvenile leukemia patients standard dose of these because it is fatal due to immunosuppression

169

What are two important substrates of G6PD? What is its mechanism?

Sulfonamide antibiotics & Dapsone. X-linked enzyme.

170

Those who are deficient in G6PD are susceptible to what after drug exposures?

Hemolytic anemia

171

If a patient has hemolytic anemia after a drug exposure, what are they most likely deficient in?

G6PD gene products

172

What is an important substrate of VKORC1 gene?

Warfarin

173

What is the medication Warfarin used for? What is its usual starting dose?

Blood thinner; 5mg

174

What is so complicated about prescribing warfarin?

It has a narrow therapeutic window intra-individually, but a very wide therapeutic range inter-individually. Under-dose = clot, over-dose = bleed