Pedigree/numerical chrom Flashcards
The pedigree (or family history) is ______
a graphical representation of the family tree
proband
The affected member through whom a family with a genetic disorder is brought to attention
consultand
the person who brings the family to attention (can be affected or unaffected)
consanguineous matings
Couples who have >1 known ancestors in common
Phenotype:
the observable expression (of a genotype) as a morphological, clinical, cellular, or biochemical trait
Genotype:
the set of
alleles that make up his or
her genetic constitution (usually we are talking about a single locus)
Two types of structural abnormalities:
Balanced
unbalanced
Balanced:
normal complement of chromosomal material
- Inversions
- Reciprocal translocations
- Robertsonian translocations
Unbalanced:
abnormal chromosomal content 1. Deletions
- Duplications
- Isochromosomes
- Marker (ring) chromosomes!
Structural Rearrangements Require
Double Strand Breaks of the DNA
95% of patients with CML have _______
the Philadelphia chromosome and an abnormal chromosome 9
Reciprocal Chromosome Translocation Leads to
to Chronic Myelogenous Leukemia
Robertsonian translocations can give rise to _________
trimsomy 21
Isochromosomes
refers to a chromosome in which one arm is missing and the other arm is duplicated in a mirror-like fashion
two models for isochromosomes
1) mis-division through the CEN in meiosis II
2) exchange between one arm of a chromosome and its homolog at the proximal edge of the arm, adjacent to the centromere
most common isochromosome is one involving the
long arm of the chrom
_____& of the viable offspring of a carrier of isochromosome 21 are abnormal
100
Summary of Mechanisms that Lead to Down Syndrome
•meiosis I nondisjunction (maternal) (95% of Down patients) e.g. 47,XY,+21
•Robertsonian translocation (4% of patients) e.g. 46,XX,der(14;21)+21
•Isochromosome (21q21q translocation) e.g. 46,XY,i(21)+21
•Mosaic Down syndrome
phenotype can be milder than typical trisomy 21, but patients exhibit wider variability in phenotypes due to variable portion of trisomy 21 cells in the embryo during development
•Partial trisomy 21
very rare, has only a portion of chromosome 21 duplicated!
Aberrant Recombination Events Lead to
Unbalanced
Chromosomal Rearrangements
Charcot-Marie-Tooth CMT 1A1
Charcot-Marie-Tooth CMT 1A1
– duplication of the gene for peripheral myelin protein-22, 17p11.2
Hereditary neuropathy with liability to pressure palsies
– deletion of the gene encoding peripheral myelin protein-22, 17p11.2
Hereditary sensory motor neuropathy - a genomic disorde
- Charcot-Marie-Tooth CMT 1A1
2. Hereditary neuropathy with liability to pressure palsies
Contiguous gene syndromes
1. Velocardiofacial syndrome
cleft palate and septal defects
2. diGeorge syndrome
neural crest, branchial pouches, great vessels
outflow tract defects in the heart
Prior to the initiation of meiosis,
cells complete one round of DNA replication
Meiosis is a
type of cell division in which diploid germ line cells give rise to haploid gametes.
Two key differences between mitosis and meiosis are that
- paternally- and maternally- derived homologous chromosomes pair at the onset of meiosis (prophase I), whereas the two homologs segregate independently in mitosis;
- reciprocal recombination events between maternal and paternal sister chromatids generate chiasmata (physical linkages) between homologs.
recombination between homologs is rare during ______
mitosis
Meiotic prophase I is a critical period during meiosis.
Maternal and paternal homologs of each chromosome become paired or synapsed along their entire lengths, forming structures known as “bivalents”.
This process requires the formation of a proteinaceous structure called the synaptonemal complex. Reciprocal recombination events occurring at this stage generate physical links between homologs. These attachments, or crossovers, are also known as chiasmata.
synaptonemal complex, promotes
inter-homolog interactions
On average,________, resulting in geneticreassortment between chromosomes.
2-3 crossovers occur on each chromosome,
Importantly, the synaptonemal complex disassembles at the end of ______ and bivalents are therefore held together only by ______
prophase 1
chiasmata
______ is the most error-prone step of the process, and _______ at this stage is the most frequent mutational mechanism in humans.
Meiosis I
chromosome nondisjunction
In the first meiotic division,
homologs are segregated to opposite poles of the cell.
Unlike mitosis, chromosomes undergo a second round of segregation in ______. Meiosis II is very much like a_______
in meiosis II without an intervening round of DNA replication.
mitotic division.
Genetic consequences of meiosis:
A. reduction in chromosome number from diploid to haploid
B. random segregation of homologous chromosomes, giving ~8x106 (or 223 ; 2
homologs for each of 23 chromosomes) different possibilities
C. random shuffling of genetic material due to crossover events, resulting in a vast
increase in genetic variability from the above estimate
Mitosis
A. one round of chromosome segregation, resulting in daughter cells identical in
chromosomal content to the parental cell
B. DNA replication precedes each round of chromosome segregation
C. no pairing of homologous chromosomes
D. infrequent recombination
E. centromeres on paired sister chromatids segregate at each anaphase
Meiosis
A. two rounds of chromosome segregation without an intervening round of DNA
replication
B. parental cells must be diploid and the chromosome number is halved in the
resultant cells
C. requires the pairing of homologous chromosomes and recombination for its
successful completion
D. centromeres on paired sister chromatids divide only at anaphase II in a normal
meiosis
mitosis occurs in
occurs in somatic cells and in germ line precursor cells prior to entry into meiosis
meiosis occurs in
germ line only
Metacentric
the centromere is located in the middle of the chromosome such that the two chromosomes arms are approximately equal in length
submetacentric
the centromere is slightly removed from the center
acrocentric
the centromere is near one end of the chromosome
Chromosomes are also classified cytogenetically based on
banding patterns observed microscopically after treatment with stains such as Giemsa, quinocrine, DAPI (4’,6- diamino-2-phenylindole), Hoechts, etc.
chromosome patterns result from
These patterns result from the differential staining of various chromosomal regions (e.g. regions with high G+C, or A+T base compositions, or the presence of heterochromatin) with the dyes listed above. The banding pattern is unique to each human chromosome and allows the unequivocal identification of each chromosome.
Somatic chromosomal errors that occur during development lead to
chromosomal mosaicism. Examples: 47,XX +21/46,XX (mosaic Down syndrome); 46, XX/46,XY (true hermaphroditism)
Somatic chromosomal mutation is a common mechanism through which
cell lines come to overexpress oncogenes or lose tumor suppressor genes.
Mosaic parents with mild phenotypes can have
fully affected offspring.
X turner syndrome
Short stature, webbed neck, edema of hands and feet, broad shield-like chest, narrow hips, renal and cardiovascular anomalies, gonadal dysgenesis (failure of ovarian maintenance).
XXY – Klinefelter syndrome
Tall stature,
hypogonadism,
elevated frequency of gynecomastia,
high frequency of sterility, language impairment
Trisomy 13 – Patau syndrome
Characteristic facies, severe intellectual disabilities Congenital malformations – holoprosencephaly, facial clefts, polydactyly, renal anomalies
Trisomy 18 – Edwards syndrome
Intrauterine growth retardation, characteristic facies,
severe intellectual
disabilities,
characteristic hand positioning.
Congenital malformations – valvular heart disease,
posterior fossa
CNS maldevelopment, diaphragmatic hernias,
renal anomalies
Trisomy 21 – Down syndrome
Characteristic facies,
short stature,
hypotonia,
moderate intellectual disabilities Congenital malformations – endocardial cushion defects, duodenal atresia and
other gastrointestinal anomalies, Hirschprung disease.
maternal age two hit theory
The first “hit” is diminished recombination, caused either by a lack of chiasma or their mislocalization, resulting in a chromosome more susceptible to possible nondisjunction. The ability of oocytes to successfully complete chromosome segregation in the presence of unfavorable recombination events is thought to diminish over time, representing the second “hit” in this model.
Aneuploidy is the
condition in which cells contain an abnormal chromosome number.
nondisjunction,
the missegregation of chromosomes at metaphase in either mitosis or meiosis, such that daughter cells receive extra or fewer than the normal number of chromosomes.
Monosomy
Monosomy describes the condition in which a cell lacks one copy of a chromosome,
trisomy is the
situation in which an extra copy of an entire chromosome is present in the cell
Mechanism of nondisjunction:
Meiotic recombination events (crossovers) are essential for tethering homologous chromosomes during the first meiotic division. Not surprisingly, disturbances in the recombination pathway are associated with abnormalities in chromosome segregation in the first meiotic division.
Nondisjunction events are related to the positioning
chiasmata; crossover events that occur too near or too far from the centromere increase chromosome nondisjunction. Centromere-distal exchanges are less effective in ensuring appropriate spindle attachment and separation of paired homologs in meiosis centromere-proximal or excessive numbers of exchanges lead to entanglement of paired homologs in MI that then undergo reductional division leading to what appears to be MII errors.
Nondisjunction events are also related to the frequency of
the frequency of crossover events. The reduction or absence of recombination events increases the likelihood of nondisjunction.
metracentric
centromere in middle of chrome
submetacentric
centromere slight removed from center
acrocentric
centromere near 1 end
mosacism is
presence of 2 genetically different cells in tissue from 1 zygote
