Lesson 6 - Genetic Basis Of Human Diseases Flashcards
A scientific discipline that bridges the gap between classical genetics and the microscopic world of chromosomes
Cytogenetics
By studying the structure and number of chromosomes in an individual’s cells, cytogenetics helps us understand the link between ____ and various ____.
Chromosomal abnormalities; genetic conditions
(3) Cytogenetic Techniques
Karyotyping
FISH (Fluorescence in situ Hybirdization)
CGH (Comparative Genetic Hybridization)
What cytogenetic technique?
Analyzing the number and structure of chromosomes
Karyotyping
What cytogenetic technique?
targeting specific DNA sequences
FISH (Fluorescence in situ Hybridization)
What cytogenetic technique?
detecting chromosomal gains or losses
CGH (Comparative Genomic Hybridization)
Cells are cultured and then artificially arrested in mitosis during ____ (or ____)
Metaphase; prometaphase
The most commonly used banding and staining method is the ____ (___)
GTG Banding; G-bands trypsin Giemsa
GTG banding is also known as
G Banding
XX meaning
Female
XY meaning
Male
[##] meaning
Number [#] of cells
cen meaning
Centromere
del meaning
Deletion
der meaning
Derivative
dup meaning
Duplication
ins meaning
Insertion
inv meaning
Inversion
ish meaning
Metaphase FISH
nuc ish meaning
Interphase FISH
mar meaning
Marker
mos meaning
Mosaic
p meaning
Short arm
q meaning
Long arm
r meaning
Ring chromosome
t meaning
Translocation
ter meaning
Terminal
/ meaning
Slash
+ meaning
Gain of
— meaning
Loss of
Normal female Karyotype
46, XX
Normal male karyotype
46, XY
Number of cells in each clone, typically inside brackets Mosaicism in Klinefelter syndrome with 12 normal cells and 10 cells with an extra X chromosome
46, XY[12]/47, XXY[10]
Male with deletion of chromosome 5 short arm
46, XY, del(5p)
Female with structurally rearranged chromosome 2 that resulted from a translocation between chromosomes 2 (short arm) and 7 (long arm)
46, XX, der(2), t(2p12;7q13)
Male with interstitial duplication in the long arm of chromosome 15 in the Prader-Willi/Angelman syndrome region
46, XY, dup(15)(q11-q13)
Male with an insertion within chromosome 3
A piece between q21q26 has reinserted on p13
46, XY, ins(3)(p13q21q26)
Male with pericentric inversion of chromosome 2 with breakpoints at bands p21 and q31
46, XY, inv(2)(p21q31)
Female with deletion in the Williams syndrome region detected by in situ hybridization
46, XX.ish del(7)(q11.23q11.23)
Interphase in situ hybridization showing 3 signals for the X centromeric region
nuc ish(DXZ1 x 3)
Male with extra, unidentified chromosome material
47, XY, +mar
Turner syndrome mosaicism (analysis of 30 cells showed that 14 cells were 45,X and 16 cells were 46,XX)
mos 45,X[14]/46, XX[16]
Male with deletion on the short arm of chromosome 5, band p12 (short nomenclature)
46,XY, del(5)(p12)
Male with a deletion on the long arm of chromosome 5, band 14
46, XY, del(5)(p14)
Female with 1 normal X chromosome and a ring X chromosome
46, X, r(X)(p21q27)
Interchange of material between chromosome 2 and 8 with breakpoints at bands 2q33 and 8q24.1
t(2;8)(q33;q24.1)
Male with a deletion of chromosome 5 between p12 and the end of the short arm (long nomenclature)
46, XY, del(5)(p12-pter)
Separate lines or clones
Mosaicism for monosomy X and a male cell line
45, X / 46, XY
Female with trisomy 21
47, XX, +21
Male with monosomy 21
45, XY, -21
identifying chromosomal abnormalities in fetuses
Prenatal Diagnosis
(3) Clinical applications of cytogenetics
Prenatal diagnosis
Cancer diagnosis
Genetic counseling
detecting chromosomal rearrangements in tumors
Cancer diagnosis
informing couples about the risk of passing chromosomal disorders
Genetic counseling
Far more common that is widely appreciated
Genetic disorders
Genetic disorders
Lifetime frequence is estimated to be ____ per ____
670;1000
Less extreme genotypic errors permit _____ and ____
Full embroyonic development; live birth
Estimated that ___% of spontaneous abortuses early in gestation demonstrate chromosomal abnormality
50
About ___% of all newborn infants possess a gross chromosomal abnormality
1
Serious disease with a significant genetic component develops in approximately __% of individuals younger than age ___ years
5; 25
Cause the disease or predispose to disease
Disorders related to mutations in single genes with large effects
Highly penetrant
Disorders related to mutations in single genes with large effects
Caused by single gene mutations and usually follow the classic Mendelian pattern of inheritance
Disorders related to mutations in single genes with large effects
Generally rare unless maintained in a population by strong selective forces
Disorders related to mutations in single genes with large effects
Chromosomal disorders arise from ____ or ___ in the autonomies and sex chromosomes
Structural; numerical alteration
Chromosomal disorders are ___ but associated with ___
Uncommon; high penetrance
Caused by interactions between multiple variant forms of genes and environmental factors
Complex multigenic disorders
Complex multigenic disorders are far more ___
Common
Variant gene confers small increase in disease risk, no susceptible gene is necessary to produce the disease
Polymorphisms
This is under polymorphisms
Complex multigenic disorders
Complex multigenic disorders occurs when several polymorphisms occur that in ____ or _____
Multigenic or polygenic diseases
Small effect and has low penetrance
Complex multigenic disorders
Environmental interactions are important in pathogenesis ~ multifactorial disorders (4)
Hypertension
Atherosclerosis
Diabetes mellitus
Autoimmune diseases
A permanent change in DNA
Mutations
Germ cells = ___
Inherited diseases
Somatic cells = ____
Cancers and some congenital malformations
Point mutations within coding sequences (3)
Silent mutations
Missense mutations
Nonsense mutations
Frameshift mutations (2)
Deletion
Insertion
(4) mutations
Point mutations within coding sequences
Mutations within noncoding sequences
Deletions and Insertions (Frameshift mutations)
Trinucleotide-repeat mutations
Genetic mutation where a single nucleotide base is changed, inserted or deleted from a sequence
Point mutation
Mutations in DNA that do not have an observable effect on the organism’s phenotype
Silent mutation
Silent mutations are a specific type of _____
Neutral mutation
Mutations that alter the meaning of the sequence of the encoded protein
Missense mutation
Type of missense mutation (2)
Conservative
Nonconservative
Type of missense mutation
Substituted amino acid is biochemically similar to the original and causes little change in function
Conservative
Type of missense mutation
Replaces the normal amino acid with a biochemically different one
Nonconservative
A point mutation may change amino acid codon to a chain terminator or stop codon
Nonsense mutation
Signals the cell to stop building protein which results in a shortened protein that may function improperly or not at all
Nonsense mutation
Interfere with binding of transcription factors and leads to marked reduction or lack of transcription
Mutations with noncoding sequences
Interfere with binding of transcription factors and leads to marked reduction or lack of transcription such as ____
Thalassemias
Mutations with noncoding sequences may lead to ___ of intervening sequences and results to form a mature ____ . Therefore translation cannot take place and the gene product is not ____.
Defective splicing; mRNA
Synthesized
involves the loss of one or more nucleotides (in multiple of threes of not) from a segment of DNA
Deletion
Permanent change in DNA sequence caused by the addition of nucleotides (in multiple of three or not)
Insertion mutation
Small deletions or insertions of base pairs involved is three or multiple of three
Non-frameshift mutation
The reading frame of non-frameshift mutation will remain ___ and an abnormal protein lacking or gaining one or more amino acids will be ____
Intact; synthesize
The number of affected coding bases is not a multiple of threes
Frameshift mutations
The frameshift mutation results in an altered reading frame if the DNA strand typically results in incorporation of a ___ number of incorrect amino acids followed by a premature ____ codon
Variable; stop
The frameshift mutation results in an altered reading frame if the DNA strand typically results in incorporation of a ___ number of incorrect amino acids followed by a premature ____ codon
Variable; stop
Characterized by amplification of a sequence of three nucleotides
Trinucleotide-Repeat mutations
Specific nucleotide sequence that undergoes amplication differs in various disorders, almost all affected sequences share the nucleotides ____ and ___
Guanine (G); cytosine (C)
These disorders are caused by expansion in the number of 3-bp repeats
Triple repeat expansion disorders
Triplet repeat expansion disorders include (4)
fragile X syndrome
myotonic dystrophy
Huntington disease
spinocerebellar ataxias
Triple repeat expansion disorder can result to loss of protein production when gene becomes ____
Hypermethylated
Triple Repeat Expansion Disorders
Some can cause disease through a mechanism other than decreased protein production like in Huntington disease, expansion causes the gene product to have a _____ effects on the ____
Toxic; neurons
For most triplet repeat disorders, there is a clinical correlation to the size of the expansion, with a greater expansion causing more severe symptoms and having an earlier age of disease onset
Anticipation
Thread-like structures found within the nucleus of a cell
Chromosome
Chromosome contains the ___ material
Hereditary
Humans have ___ chromosomes organized into ___ pairs
46; 23
Chromosome is an organized structure where the DNA is tightly packed with histones forming the ____
Chromatin
Each chromosome is made up of identical copies, called ____, held together by _____.
Sister chromatids; centromere
Tips of the chromosome are guarded by ____, which prevent from ____
Telomeres; fraying
Chromosomes are the foundation of ____, holding the information of our ____ and shaping the _____we inherit
Heredity
Ancestry; traits
The chromosome’s complex structure allows for the precise ____ and transmission of _____
Replication; genetic information
Chromosomal disorders variation (5)
Variation in chromosome number
Variation in chromosome size
Variation in the arrangement of chromosome segments
Variation in the number of chromosome segments
Variation in chromosome morphology
Any exact multiple of the haploid number of chromosomes (23)
Euploid
Type of polyploidy (1)
Triploidy
Types of aneuploidy
Monosomy
Trisomy
Euploid cells with more than the normal diploid number of 46 (2n) chromosomes: 3n, 4n
Euploid
Those with 3 haploid sets of chromosomes (3n)
Triploidy
An error occurs in meiosis or mitosis and a cell acquires a chromosome complement that is not the exact multiple of 23
Aneuploidy
Occur when only 1, instead of the normal 2, of a given chromosome is present
Monosomy
In humans, most autosomal monosomies appear to be ____ early in development, and survival is possible in mosaic forms except in ____
Lethal
Turner syndrome (45,X)
Results from complete or partial monosomy of the X chromosome
Turner Syndrome 45,X
Turner syndrome characterized primarily by ____ in phenotypic females
Hypogonadism
the failure of chromosomes to disjoin normally during meiosis
Nondisjunction
Characterized by the presence of 3 chromosomes, instead of the normal 2, of any particular chromosome
Trisomy
Monosomy is the most common sex chromosome abnormality in ____, affecting about ___ in ____ live-born females
Females
1; 2500
Most common form of aneuploidy
Trisomy
Trisomy 21
Down syndrome
Trisomy 18
Edwards syndrome
Trisomy 13
Patau syndrome
47, XXY
Klinefelter syndrome
Most common of the chromosomal disorders and is a major cause of mental retardation
Down Syndrome or Trisomy 21
Approximately 1% of Down syndrome patients are ____
Mosaics
Male hypogonadism that occurs when there are two or more X chromosomes and one or more Y chromosomes
Klinefelter syndrome
Loss of a portion of a chromosome
Deletions
Most are ____ but rarely terminal deletions may occur
Interstitial
Formation of a ring chromosome by a break in each arm, loss of the terminal segments and union of the centric segment
Ring chromosome
The presence of extra genetic material from the same chromosome
Duplication
breaks are in the 2 opposite arms of the chromosome and include the centromere
Pericentric inversions
Occur when a piece of a chromosome broken at 2 points is incorporated into a break in another part of a chromosome
Insertion
Occur when a piece of a chromosome broken at 2 points is incorporated into a break in another part of a chromosome
Insertion
Consist of 2 copies of the same chromosome arm joined through a single centromere and forming mirror images of one another
Isochromosome
Involve the transfer of material from one chromosome to another
Translocation
Result of breaks in nonhomologous chromosomes with reciprocal exchange of the broken segments
Balanced Reciprocal Translocation
Translocation between two acrocentric chromosomes
Robertsonian Translocation or Centric Fusion
Robertsonian Translocation or Centric Fusion significance also lies in the production of ____
Abnormal progeny
refers to traits that are caused by a combination of inherited, environmental, and stochastic factors
Multifactorial inheritance
refers to traits that result from the additive effects of multiple genes
Polygenic inheritance
Example of Triplenucleotide-Repeat Disorder (7)
Dentatorubral-pallidoluysian atrophy
Fragile-X syndrome
Friedreich’s ataxia
Hungtington’s disease
Myotonic dystrophy
Spinobulbar muscular atrophy
Spinocerebellar ataxia
Example of trisomy syndrome (3)
Trisomy 13 (Patau syndrome)
Trisomy 18 (Edwards syndrome
Trisomy 8 (mosaicism)
