Medical Genetics

Front 1

DNA stores genetic information as:

Back 1

a linear sequence of two types of nucleotide, the purines & pyrimidines linked by a sugar-phosphate backbone

Front 2

Human chromosome structure:

Back 2

1) Primary coiling of double helix
2) Secondary coiling around histone 'beads' forming nucleosomes
3) Tertiary coiling form chromatin fibers that form loops on a scaffold of non-histone acidic proteins
4) Tertiary coiling is further wound in a tight coil to make solenoid model of chromosome

Front 3

Describe 'gene' and 'locus':

Back 3

'gene' - A part of the DNA molecule of a chromosome that directs the synthesis of a specific polypeptide chain.
'locus' - Site of gene on chromosome

Front 4

What constitutes a normal karyotype?

Back 4

karyogram showing each chromosome pair in descending order of size

Front 5

Structure and organization of genes?

Back 5

Generally larger genes have greater number and size of exons. Individual introns can be larger than coding sequence and some contain sequences for other genes.

Front 6

Describe flow of information from gene to protein?

Back 6

Translation transmits gentic info from mRNA to protein. mRNA is transported from nucleus to cytoplasm and associates w/ ribosomes for protein synthesis.

Front 7

Basic description of structure of human genome?

Back 7

23 chromosome pairs, 22 autosomal pairs and 1 sex-determining pair.

60-70% of human genome consists of single or low copy number DNA sequences. 30-40% consists of either moderately or highly repetitive DNA sequences that are not transcribed consisting of mainly satellite DNA and interspersed DNA sequences.

Front 8

Describe sequence of cell cycle (G1, S, G2, M)

Back 8

Period between auccessive mitoses is interphase (G1, S, G2) lasting 16-24 hrs.

G1 (Gap) - chromosomes become thin & extended, variable in length and responsible for variation in generation time between different cell populations. Cells which stop dividing (neurons) usually arrest in this phase and said to have entered a non-cyclic stage (G0).

S (synthesis) - DNA replication, chromatin of each chromosome is replicated giving X-shaped configuration.

G2 - short phase where chromosomes begin to condense in preparation for next mitotic division

M (mitosis) - chromatid pairs separate and disperse into seperate daughter cells. Consists of Prophase, Prometaphase, Metaphase, Anaphase, Telophase.

Front 9

Summarize mitotic events through the five stages.

Back 9

Prophase - chromosomes condense, mitotic spindle begins to form, two centrioles form in each cell with radiating microtubules toward opposite poles of cell.

Prometaphase - nuclear membrane begins to disintegrate, chromosomes spread around cell becoming attached at its centromere to microtubule of mitotic spindle.

Metaphase - chromosomes become aligned on equatorial plane, where each chromosome is attached to centriole by microtubule forming mature spindle.

Anaphase - centromere of each chromosome divides longitudinally and two daughter chromatids seperate to opposite poles of cell

Telophase - two groups of daughter chromasomes become enveloped in a new nuclear membrane (formation of nuclei). Cytokinesis results in formation of two new daughter cells containing a complete diploid chromosome complement.

Front 10

Significance of meiosis and main achievements?

Back 10

Meiosis occurs during final stage of gamate formation and differs from mitosis in (3) ways:
1) Mitosis results in each daughter cell having diploid chromosomes (46) whereas meiosis results in haploid chromosomes (23)
2) Mitosis takes place in somatic cells and early cell division in gamete formation while meiosis occurs only in final division of gamete maturation.
3) Mitosis occurs in single one-step process, meiosis can be considered as two cell divisions known as meiosis I and meiosis II (ea. having prophase, metaphase, anaphase, telophase)

Front 11

What is the significance of recombination (crossing over) in prophase I?

Back 11

Homologous chromosomes pair and, w/ exception of X and Y chromosomes in male meiosis, exchange of homologous segments occurs between non-sister chromatids. This exchange occurs as a result of recombination (crossing over).

During Prophase I in males, pairing occurs between homologous segments of X and Y chromosomes at the tip of their short arms, w/ this portion being known as pseudoautosomal region.

Front 12

How does meiosis introduce diversity into the genotype?

Back 12

During prophase of Meiosis I, bivalents (homologous chromosomes in synapsis) seperate w/ each gamete recieving a selection of parental chromosomes.

Recombination (crossing over) results in each chromatid recieving a portion of DNA derived from both parental homologous chromosomes. This dispersion of DNA into different gametesis sometimes referred to as 'gene suffling'.

Front 13

What is the significance of recombination (crossing over) in prophase I?

Back 13

Homologous chromosomes pair and, w/ exception of X and Y chromosomes in male meiosis, exchange of homologous segments occurs between non-sister chromatids. This exchange occurs as a result of recombination (crossing over).

During Prophase I in males, pairing occurs between homologous segments of X and Y chromosomes at the tip of their short arms, w/ this portion being known as pseudoautosomal region.

Front 14

Autosomal dominant trait?

Back 14

gene on one of non-sex chromosomes that manifests in heterozygous state, person w/ both mutant and normal allele

Front 15

Autosomal recessive trait?

Back 15

gene on one of non-sex chromosomes manifests in homozygous state

Front 16

X-linked dominant trait?

Back 16

gene carried on X chromosome manifests in heterozygous female and male w/ mutant allele on single X chromosome

Front 17

X-linked recessive trait?

Back 17

gene carried on X chromosome, usually manifests only in males, expressed in hemizygous males

Heterozygous females are carriers
Homozygous females manifest features of X-linked recessive trait

Front 18

Allele?

Back 18

alternative form of gene found at same locus on homologous chromosomes

Front 19

Genotype?

Back 19

genetic consitution of individual

Front 20

Phenotype?

Back 20

appearance (physical, biochemical, physiological) of individual that results from interaction of environment and genotype

Front 21

Zygosity?

Back 21

refers to similarity of genes for a trait (homozygous, heterozygous, hemizygous or nullizygous)

Front 22

Genetic locus vs. allelic heterogeneity?

Back 22

Locus is the specific location of a gene or DNA sequence on a chromosome

vs.

Allelic heterogeneity is the phenomenon where different mutations at the same locus cause the same disorder. (ex. B-thalassemia different mutations in B-globin gene)

Front 23

Penetrance?

Back 23

The proportion of heterozygotes for a dominant gene who express a trait, even if mildly.

Front 24

Variable expression?

Back 24

variation in severity of phenotypic features seen in persons w/ autosomal dominant disorders

Front 25

How is disease liability transmitted for autosomal dominant disease?

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Autosomal Dominant Disease:
1) affects both males and females in equal proportions
2) transmitted from one generation to next
3) all forms of transmision between sexes (male to male, female to female, male to female, female to male)

Front 26

How is the classic pattern of inheritance disrupted by: incomplete penetrance, variable expressivity, variable age-of-onset

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Incomplete penetrance (reduced penetrance): individuals who must possess the abnormal gene, by pedigree must be obligate heterozygotes, show no manifestations of condition.

Delayed age-of-onset: many autosomal dominant disorders do not present until well into adult life.

Variable expressivity: clinical features in autosomal dominant disorders can show variation from person to person, even in the same family.

Front 27

How disease liability is transmitted for autosomal recessive diseases?

Back 27

Only homozygous individuals manifest recessive disorders. Heterozygous individuals are carriers. It is not possible to trace autosomal recessive traits or disorders through a family, as all affected individuals are usuallly in a single sibship (brothers & sisters) = 'horizontal' transmission

Front 28

Huntington's disease: Mode of inheritance?

Back 28

Autosomal dominant

Front 29

Cystic fibrosis: Mode of inheritance?

Back 29

Autosomal recessive

Front 30

Hemophilia: Mode of Inheritance?

Back 30

X-linked recessive

Front 31

Myotonic dystrophy: Mode of inheritance?

Back 31

Autosomal dominant

Front 32

Marfan's syndrome: Mode of inheritance?

Back 32

Autosomal dominant

Front 33

Phenylketonuria: Mode of inheritance?

Back 33

Autosomal recessive

Front 34

G6PD deficiency: Mode of inheritance?

Back 34

X-linked recessive

Front 35

Familial hypercholesterolemia: Mode of inheritance?

Back 35

Autosomal dominant

Front 36

Tay Sach's: Mode of inheritance?

Back 36

Autosomal recessive

Front 37

Duchenne muscular dystrophy: Mode of inheritance?

Back 37

X-linked recessive

Front 38

Osteogenesis imperfecta: Mode of inheritance?

Back 38

Autosomal dominant

Front 39

Sickle cell anemia: Mode of inheritance?

Back 39

Autosomal recessive

Front 40

Achondroplasia: Mode of inheritance?

Back 40

Autosomal dominant

Front 41

Thalassemia: Mode of inheritance?

Back 41

Autosomal recessive

Front 42

Leber hereditary optic neuropathy and non-Mendelian pattern of inheritance?

Back 42

mitochondrially inherited (mother only) degeneration of retinal ganglion cells and axons leading to acute loss of vision.

Affects predominantly males as LHON is only transmitted through mitochondrial genome (not nuclear).

Front 43

Mitochondrial Encephalomyopathy Lactic Acidosis and Stroke-Like Episodes (MELAS) and non-Mendelian pattern of inheritance?

Back 43

mitochondrially inherited (mother only) disorder w/ stoke-like episodes. May manifest as headaches, vomiting, or visual disturbances.

Front 44

Prader Willi Syndrome and non-Mendelian inheritance w/ imprinting defects?

Back 44

Imprinting: gene or region of chromosome showing different expression depending on parent of origin.

Deletion on paternally inherited, long arm of chromosome 15 causes Prader-Willi syndrome.

Deletion on maternally inherited, long arm of chromosome 15 causes Angelman syndrome.

Front 45

Achondroplasia: Mode of inheritance?

Back 45

Autosomal dominant

Front 46

Thalassemia: Mode of inheritance?

Back 46

Autosomal recessive

Front 47

Leber hereditary optic neuropathy and non-Mendelian pattern of inheritance?

Back 47

mitochondrially inherited (mother only) degeneration of retinal ganglion cells and axons leading to acute loss of vision.

Affects predominantly males as LHON is only transmitted through mitochondrial genome (not nuclear).

Front 48

Mitochondrial Encephalomyopathy Lactic Acidosis and Stroke-Like Episodes (MELAS) and non-Mendelian pattern of inheritance?

Back 48

mitochondrially inherited (mother only) disorder w/ stoke-like episodes. May manifest as headaches, vomiting, or visual disturbances.

Front 49

Prader Willi Syndrome and non-Mendelian inheritance w/ imprinting defects?

Back 49

Imprinting: gene or region of chromosome showing different expression depending on parent of origin.

Deletion on paternally inherited, long arm of chromosome 15 causes Prader-Willi syndrome.

Deletion on maternally inherited, long arm of chromosome 15 causes Angelman syndrome.

Front 50

Angelman syndrome and non-Mendelian inheritance w/ imprinting defects?

Back 50

Imprinting: gene or region of chromosome showing different expression depending on parent of origin.

Deletion on paternally inherited, long arm of chromosome 15 causes Prader-Willi syndrome.

Deletion on maternally inherited, long arm of chromosome 15 causes Angelman syndrome.

Front 51

Uniparental disomy and non-Mendelian inheritance?

Back 51

Individuals normally inherit one pair of homologous chromosomes from each parent.

Uniparental disomy is when two copies of the same homolog from one parent, through error in meiosis II, is inherited.

Front 52

Huntington's disease (triplet repeat mutation) and non-Mendelian inheritance w/ anticipation?

Back 52

Anticipation: onset of disease occurs at an earlier age in offspring than in parents, or disease occurs w/ increasing severity in subsequent generations.

Huntington disease gene in paternal meiosis accounts for increased risk of juvenile Huntington disease when gene transmitted by father.

Front 53

Myotonic dystrophy (triplet repeat mutation) and non-Mendelian inheritance w/ anticipation?

Back 53

Anticipation: onset of disease occurs at an earlier age in offspring than in parents, or disease occurs w/ increasing severity in subsequent generations.

Myotonic dystrophy gene in maternal meiosis accounts for severe neonatal form of myotonic dystrophy when gene transmitted by mother.

Front 54

Fragile X syndrome (triplet repeat mutation) and non-Mendelian inheritance w/ anticiptation?

Back 54

Anticipation: onset of disease occurs at an earlier age in offspring than in parents, or disease occurs w/ increasing severity in subsequent generations.

Fragile X syndrome is associated w/ the expansion of trinucleotide gene sequence on X chromosome resulting in failure to express a protein required for normal neural development.

Front 55

Digenic inheritance and non-Mendelian inheritance?

Back 55

Digenic inheritance refers to a disorder due to additive effects of heterozygous mutations at two different gene loci.

Front 56

Hardy Weinberg equilibrium and gene (allele) and genotype frequencies?

Back 56

Relative gene (allele) and genotype frequencies will remain constant regardless of how many generations are studied. The actual numbers of individuals with a particular gene or genotype will change as populations increase or decrease but their relative frequencies remain constant. This is known as Hardy Weinberg equilibrium.

Front 57

Factor that can affect Hardy Weinberg equilibrium?

Back 57

1) Non-random mating
2) Mutation
3) Selection
4) Small population size
5) Gene flow (migration)

Front 58

How can mutations change gene frequencies?

Back 58

Hardy Weinberg principle is based on the assumption that no new mutations occur. High mutation rates of a particular locus results in steady increase of mutant alleles in population. This effect is usually balanced by the loss of mutant alleles due to reduced fitness of affected individuals

Front 59

How can selection change gene frequencies?

Back 59

Deleterious characteristics likely have a negative selection w/ affected individuals having reduced reproductive fitness. In the absence of new mutations this reduction in fitness leads to gradual reduction in frequency of mutant gene, and hence disturbance of Hardy Wienberg equilibrium and gene frequencies.

Front 60

Heterozygote advantage?

Back 60

Heterozygotes show slight increase in biological fitness compared w/ unaffected homozygotes. Individuals heterozygous for sickle-cell disease are relatively immune to infection w/ plasmodium falciparum malaria b/c RBC's sickle and rapidly destroyed when invaded by parasite.

Front 61

How can alleles causing serious disorders be relatively frequent?

Back 61

Allele frequency can increase due to small populations and chance resulting in marked changes in allele frequency. Known as random genetic drift.

Front 62

How does genetic drift and founder effect influence allele frequency in different populations?

Back 62

Genetic drift: Allele frequency can increase due to small populations and chance resulting in marked changes in allele frequency.

Founder effect: certain genetic disorders can be common in populations where all individuals being descended from a relatively small numher of ancestors, one or few of whom had a particular disease.

Front 63

What's the probability of an individual being a homozygote for autosomal recessive trait in a general pedigree?

Back 63

Autosomal recessive genes are located on non-sex chromosomes that manifest in homozygous state. Thus, it's a 25% chance or 1 in 4 chance of having the autosomal recessive trait.

Front 64

What's the probability of an individual being a homozygote for an autosomal recessive trait in pedigrees exhibiting consanguinity?

Back 64

Consanguinity is the marriage between blood relatives w/ at least one common ancestor no more remote than a great-great-grandparent. Consanguinity leads to a relative increase in frequency of affected homozygotes and relative decrease in frequency of heterozygotes.

Front 65

Common laboratory techniques used for karyotyping (FISH, CGH, array CGH)

What is FISH?

Back 65

FISH combines conventional cytogenetics w/ molecular genetic technology. A portion of single-stranded DNA (a probe) can anneal w/ its complementary sequence on a metaphase chromosome, interphase nucleus or extended chromatin fiber. Fluorescent in-situ hybridization (FISH) labels a DNA probe w/ fluorochrome which hybridizes w/ the patients sample, allowing the region to be visualized.

Front 66

Common laboratory techniques used for karyotyping (FISH, CGH, array CGH)

What is CGH?

Back 66

Comparative genomic hybridization (CGH) detects regions of allele loss and gene amplification. Originally developed for obtaining quality metaphase preparations from solid tumors.

Tumor or 'test' DNA is labeled w/ green paint, control DNA w/ red paint and the two samples mixed to hybridize competitively to normal metaphase chromosomes, and an image is captured. If the test sample contains more DNA from particular chromosome regions than control sample, that region is identified by an increase in green to red ratio. Similarly a deletion in the test sample is identified by a reduction in green to red ratio.

CGH's lack of precise localization of genes involved in tumor development explains why 'array CGH' will likely supersede 'metaphase CGH'.

Front 67

Common laboratory techniques used for karyotyping (FISH, CGH, array CGH)

What is array CGH?

Back 67

Cytogenic techniques are traditionally based on microscopic analysis where as 'array CGH' replaces metaphase chromosomes w/ large numbers of DNa sequences bound to glass slides. DNA target sequences can be mapped clones (yeast artificial chromosome [YAC], bacterial artificial chromosome [BAC], P1-derived artificial chromosome [PAC] or cosmid) or oligonucleotides. Robotics spot DNA target sequences on slides to create microarray, in which each DNA target has a unique location. Following hybridization and washing to remove unbound DNA, relative levels of fluorescence are measured using computer software.

Used to detect any type of gain or loss, including detection of subtelomeric deletions in patients w/ unexplained intellectual impairment.

Array CGH is faster and more sensitive than metaphase CGH.

Front 68

Balanced vs. unbalanced chromosome rearrangements?

Back 68

In balanced chromosome rearrangement the chromosome complement is complete, with no loss or gain of genetic material. Balanced rearramgements are generally harmless except in rare cases in which one of the breakpoints damage an important functional gene. Carriers of balanced rearrangements are at risk of producing children w/ unbalanced chromosomal complements.

Unbalanced chromosome rearramgements contain an incorrect amount of chromosome material and clinical effects are usually serious.

Front 69

Reciprocal translocation? Balanced or unbalanced?

Back 69

Translocation refers to the transfer of genetic material from one chromosome to another.

Reciprocal translocation is formed when a break occurs in each of two chromosomes w/ the segements being exchanged to form two new derivative chromosomes.

Can be balanced or unbalanced (resulting in Robertsonian translocation). Balanced reciprocal translocation carriers have increased risks of creating gametes w/ inbalanced chromosome translocations leading to miscarriages or children w/ abnormalities.

Front 70

Robertsonian translocation?
Balanced or unbalanced?

Back 70

Translocation refers to the transfer of genetic material from one chromosome to another.

Robertsonian translocation is a reciprocal translocation in which the breakpoints are located at, or close to, the centromeres of two acrocentric (one chromosomal arm is much shorter than the other) chromosomes. The short arms of each chromosome are lost, this being no clinical importance as they contain genes for ribosomal RNa, which there are multiple copies on various other acrocentric chromosomes.

Total chromosome number is reduced to 45. As there is no loss or gain of important genetic material, this is a functionally balanced rearrangement.

Front 71

Chromosomal deletions?
Balanced or unbalanced?

Back 71

A deletion involves loss of part of a chromosome and results in monosomy for that segment of the chromosome. Larger deletions are usually incompatible w/ life, generally loss of >2% of total haploid genome will have lethal outcomes.

Assumably unbalanced???

Front 72

Chromosomal inversions?
Balanced or unbalanced?

Back 72

An inversion is a two-break rearrangement involving a single chromosome in which a segment is reversed in position (inverted). If the inverted segment involves the centromere it is termed a pericentric inversion. If it involves only one arm of the chromosome it is known as a paracentric inversion.

Inversions are balanced rearrangements that rarely cause problems in carriers unless one of the breakpoints disrupts an important gene.

Some pericentric inversions may not cause clinical problems in the balanced carrier but can lead to chromosomal imbalance in offspring with clinical consequences.

Front 73

Ring chromosomes?
Balanced or unbalanced?

Back 73

A ring chromosome is formed when a break occurs on each arm of a chromosome leaving two 'sticky' ends on the central portion that reunite as a ring.

The two distal chromosomal fragments are lost, thus if the involved chromosome is an autosome, the effects are usually serious.

Ring chromosomes are often unstable in mitosis, resulting in ring chromosomes in only a proportion of cells w/ other cells usually being monosomic b/c of absence of ring chromosome.

Balanced or unbalanced???

Front 74

Isochromosomes?
Balanced or unbalanced?

Back 74

Isochromosomes show loss of one arm w/ duplication of the other. Most probable explanation of isochromosome is the centromere has divided transversely rather than longitudinally.

Balanced or unbalanced???

Front 75

How can balanced rearrangements give rise to unbalanced rearrangements in the next generation?

Back 75

Pericentric inversions can produce unbalanced gamates if a cross-over occurs within the inversion segment during Meiosis I, when an inversion loop forms as the chromosomes attempt to maintain homologous pairing at synapsis. A cross-over within the loop will result in two complementary recombinant chromosomes, one w/ duplication of the distal non-inverted segment and deletion of the other end of the chromosome, and the other having the opposite arrangement.

Front 76

Clinical features of Trisomy 21?

Back 76

Newborn period:
Hypotonia, sleepy, excess nuchal skin

Craniofacial:
Brachycephaly, epicanthic folds, protruding tongue, small ears, upward sloping palpebral fissures

Limbs:
Single palmar crease, small middle phalanx of fifth finger, wide gap between first and second toes

Cardia:
Atrial and ventricular septal defects, common atrioventricular canal, patent ductus arteriosus

Other:
Anal atresia, duodenal atresia, Hirschsprung disease, short stature, strabismus (eyes not properly aligned)

Front 77

Clinical features of Trisomy 13 (Patau Syndrome) and Trisomy 18 (Edwards Syndrome)?

Back 77

Trisomy 13 may show severe cleft lip and palate abnormalities.

Trisomy 18 may show prominent occiput and tightly clenched hands.

Both show very poor prognosis, with most infants dying within first days or weeks of life. In the even of survival there is severe learning disabilities and cardiac abnormalities.

Front 78

Clinical features of Triploidy?

Back 78

Triploidy is relatively common spontaneous abortions, but rarely seen in live births. Such infants show severe intrauterine growth retardationw/ relative preservation of head growth at the expense of a small think trunk. Syndactyly of third and fourth fingers and/or second and third toes is common.

Front 79

Clinical features of Turner Syndrome (45,X)?

Back 79

Presentation at any time from birth to adult life. generalized edema (hydrops) or swelling localized to neck (nuchal cyst or thickened nuchal pad), puffy extremities, increased carrying angles at elbows, short fourth metacarpals, widely spaced nipples and coarctation of aorta, short stature and ovarian failur

Front 80

Clinical features of Klinefelter Syndrome (47,XXY)?

Back 80

Childhood:
male clumsiness or mild learning ddfficulities, overall IQ 10-20 points lower than unaffected siblings and controls, self-obsessed in their behavior

Adults:
slightly taller than average, long lower limbs, 30% show gynecomastia, all infertile w/ soft testes, increased incidence of leg ulcers, osteoporosis and carcinoma of breast in adult life

Front 81

What is fetal aneuploidy?

Back 81

Numerical abnormalities involving the loss or gain of one or more chromosomes.

The loss results in monosomy.
The gain of one or two homologous chromosomes is referred to as trisomy and tetrasomy.

Front 82

Relationship between maternal age and fetal aneuploidy?

Back 82

The risk for fetal aneuploidy such as Down Syndrome increases significantly w/ maternal age.

From an incidence of 1 in 1500 at 20 yrs. of age to 1 in 30 at 45 yrs. of age.

Front 83

Types of chromosomal abnormalities that can give rise to Down Syndrome and risk for recurrence?

Back 83

Maternal chromosome abnormalities as a result of non-disjunction in maternal Meiosis I accounts for 90% of Trisomy 21 cases. Robertsonian translocations account for 4% of cases.

Advanced maternal age and maternal chromosome origin have a close association to Trisomy 13 and Trisomy 18.

Unbalanced rearrangements account for 10% of Trisomy 13 cases, particularly robersonian translocations.

Trisomy 21 recurrence risk is related to maternal age and usually of the order 1 in 200 to 1 in 100. Translocation cases risks vary around 1-3% for male carriers and 10-15% for females where as carriers of 21q21q translocation have a 100% recurrence risk.

Front 84

Clinical application of single locus Fluorescent in situ Hybridization (FISH)?

Back 84

Single locus FISH can detect microdeletions involving a loss of only a few genes at closely adjacent loci, resulting in 'contiguous gene syndromes'.

Front 85

絞首刑

Back 85

교수형
death[execution] by hanging, hanging, [ +head + punishment]

Front 86

What is Chorionic villus biopsy?

Back 86

Chorionic villus tissue is sampled under ultrasonographic quidance by transcervical and more commonly transabdominal aspiration.

The fetal tissue is derived from the outer cell layer of the blastocyst (trophoblast).

Direct chromosomal or cultured analysis can be performed with direct chromosomal analysis giving results in 24hr.

Advantages being CVS offers first-trimester prenatal diagnosis however carries a 1-2% miscarriage risk and evidence this technique may cause limb abnormalities if performed prior to 9-10 weeks gestation. For this reason CVS is performed before 11 weeks gestation.

Front 87

What is Maternal serum screening?

Back 87

Maternal blood samples are screened at 16 weeks gestation to screen for neural tube defects (NTD's) and Down syndrome. Up to 75% of NTD's and 60-70% of Down syndrome cases can be detected.

Front 88

Define mutation?

Back 88

A change in genetic material, either of a single, or in number or structure of chromosomes. A mutation occuring in gamates is inherited; mutations in somatic cells are not inherited (somatic mutation)

Front 89

How can mutations be classified?

Back 89

Mutations can range from single base substitutions through insertions and deletions of single or multiple bases to loss or gain of entire chromosomes.

Base substitutions are most prevalent and missense mutations account for nearly half of all mutations.

A single base-pair substitution resulting in coding for a different amino acid and the synthesis of an altered protein is termed missense mutation.

Front 90

Importance of spontaneous mutagenic events?

Back 90

Spontaneous mutations arise de novo, apparently not due to environmental factors such as mutagens.

They are chance errors in chromosomal division or DNA replication.

Front 91

Mutations caused by physical mutagens?

Back 91

Pysical or chemical mutagens may result in formation of DNA adducts, chromosome breaks or aneuploidy.

Front 92

Define polymorphism?

Back 92

Polymorphism is the occurrence in a population of two or more genetically determined forms (alleles, sequence variants) in such frequencies that the rarest of them could not be maintained by mutation alone.

Balanced and transient polymorphism exist.

In balanced polymorphism two or more different forms are balanced by the selective advantage of the heterozygote and reduced fitness of homozygote. The high incidence of sickle-cell allele in areas w/ malaria is an example of balanced.

The sickle-cell allele is likely to decline in populations that are no longer exposed to malaria and thus transient.

Front 93

Types of polymorphism within the genome?

Back 93

Single nucleotide polymorphisms (SNP's) and variable number tandem repeat (VNTR's) are the two main types of polymorphism within the genome.

Front 94

How is PCR used to genotype STR polymorphisms?

Back 94

Short tandem repeat polymorphism (STRP) occurs when homologous STR loci differ in the number of repeats between individuals. Identifying repeats of a specific sequence at specific locations in the genome allows for a genetic profile of an individual. PCR is used to amplify small samples so that STR polymorphisms can be detected.

Front 95

How are SNP's genotyped?

Back 95

Restriction fragment length polymorphisms (RFLP's) can detect any SNP.

DNA microarrays have led to a dense SNP map of the human genome and is considered the new high-throughput method.

Front 96

What is haplotype?

Back 96

Haplotype conventionally refers to particular alleles present at the four genes of the HLA complex (genes on chromosome 6 responsible for determining cell-surface antigens important in organ transplant) on chromosome 6.

Haplotype is also used to describe DNA sequence variants on a particular chromosome adjacent to or closely flanking a locus of interest.

Front 97

How are SNP's genotyped?

Back 97

Restriction fragment length polymorphisms (RFLP's) can detect any SNP.

DNA microarrays have led to a dense SNP map of the human genome and is considered the new high-throughput method.

Front 98

What is haplotype?

Back 98

Haplotype conventionally refers to particular alleles present at the four genes of the HLA complex (genes on chromosome 6 responsible for determining cell-surface antigens important in organ transplant) on chromosome 6.

Haplotype is also used to describe DNA sequence variants on a particular chromosome adjacent to or closely flanking a locus of interest.

Front 99

Common types of DNA damage leading to mutations?

Back 99

Natural or artificial ionizing radiation and chemical or physical mutagens.

Any ionizing radiation, regardless of dose, can result in a mutation.

Chemical mutagens may cause DNA adducts (piece of DNA covalently bonded [cancer causing] to a chemical), chromosome breaks or aneuploidy.

Front 100

Describe these DNA repair mechanisms:
* proofreading
* excision repair
* mismatch repair

Back 100

In eukaryotes only polymerases dealing w/ elongation have proofreading ability which is 3' to 5' exonuclease activity.

Nucleotide excision repair (NER) removes thymine dimers and large chemical adducts.

Mismatch repair (MMR) corrects mismatched bases introduced during DNA replication.

Front 101

Consequences of mutations in DNA repair genes?

Back 101

Translesion DNA synthesis is a cells attempt at tolerating DNA damage where the DNA replication machinery bypasses sites of DNA damage, allowing normal DNA replication and gene expression to proceed downstream.

Cells also signal for cell cycle arrest to provide increased time for DNA repair. If DNA damage is unrepairable, the cell may initiate apoptosis.

Front 102

Hereditary DNA repair disorders as a consequence of mutations in DNA repair genes?

Back 102

Disorders as a result of 'Nucleotide excision repair' (NER) gene mutations:
Xeroderma pigmentosum
Cockayne's syndrome

Disorders as a result of 'Mismatch repair' (MMR) gene mutations:
nonpolyposis colorectal cancer

Front 103

Functional basis of substitution mutations (silent, missense, nonsense, splice site, promoter)?

Back 103

A substitution is the replacement of a single nucleotide. Substitutions can be 'silent, missense, nonsense, splice site, or promoter' type substitution mutations.

Silent substitutions commonly code for the same amino acid, particularly in third position of codon b/c of degeneracy of genetic code.

Missense substitutions alter amino acids and may affect protein function or stability.

Nonsense substitutions code for stop codons and loss of function or expression due to degradation of mRNA occurs.

Splice site substitutions code for aberrant (straying from natural) splicing resulting in exon skipping or intron retention.

Promoter substitutions alter gene expression.

Front 104

Functional basis of insertion/deletion mutations (in-frame, frameshift)?

Back 104

Insertion mutations add one or more nucleotides into a gene.

Deletion mutations involve the loss of one or more nucleotides.

Multiple of 3 (codon) cause 'in-frame' insertion or deletion mutations and may affect protein function or stability.

Non multiple of 3 cause 'framshift' insertion or deletion mutations and likely result in premature termination w/ loss of function or expression.

Front 105

Functional basis of amplification of repeat sequence and genomic instability?

Back 105

Amplification of repeat sequence are considered 'insertion mutations' and result in trinucleotide repeat sequences which become more unstable as it expands in size.

Triplet repeats below a certain length for ea. disorder are stably transmitted in mitosis and meiosis whereas above a certain repeat number for ea. disorder they are likely transmitted unstably w/ increase or decrease in repeat number.

Front 106

Human diseases caused by missense, nonsense, in-frame, frameshift, splice-site and amplification of repeat sequence mutations?

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Nonsense mutations: Cystic fibrosis, Duchenne muscular dystrophy, Beta thalassaemia, Hurler syndrome

Missense mutations: Sickle-cell disease, mutation of SOD1 (superoxide dismutase) can lead to ALS

Frameshift mutations: Tay-Sachs disease, some types of familial hypercholesterolemia

Splice-site mutations: some cases of b-thalassemia, TTP (thrombotic thrombocytopenic purpura)

Amplification of repeat sequence mutations: Huntingtons, Myotonic dystrophy type 1, Fragile X site A, Kennedy disease

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What is an oncogene and how does it transform cells?

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Oncogene is a gene affecting cell growth or development that can cause cancer (altered forms of normal genes)

Oncogenes act in three main ways in the process of signal transduction:
1) through phosphorylation of serine, threonine and tyrosine residues of proteins by the transfer of phosphate groups from ATP. (leads to alteration of the configuration activating the kinase activity of proteins and generating docking sites for target proteins, reulting in signal transduction)
2) The RAS family of proto-oncogenes are GTPases and function as molecular switches through the guanosine diphosphate-guanosine triphosphate (GDP-GTP) cycle as intermediates relaying the transduction signal from membrane-associated tyrosine kinases to serine threonine kinases.
3) Proteins located in the nucleus that control progress through cell cycle, DNA replication and expression of genes

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Role of tumor suppressor and mutator genes?

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Tumor suppressor genes suppress inappropriate cell proliferation. The loss-of-function results in development of malignancy.

Mutator genes is the equivalent in yeast to DNA proof-reading enzymes that cause hereditary non-polyposis colorectal cancer.