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100 Cards in this Set

  • Front
  • Back
What is chromosome abberation?
Any deviation either in number or structure of chromosomes is referred as chromosomal aberration or abnormality
What are the characteristics of chromosome abberation?
May involve one or more chromosomes

May affect autosomes or sex chromosomes
How many infants are affected by chromosome disorders and how do they usually occur?
affecting about 7/1000 live infants and accounting for about half of all spontaneous first trimester abortions
What is Euploidy? What are some examples?
Euploidy:
Change in whole set of chromosomes
Examples:
Haploidy: single set , seen in human gametes – 23 in number

Diploidy: Two sets , seen in human somatic cells – 46 in number
What is triploidy? How is it caused?
Triploidy: Rare, may be seen in infants but they do not survive long

Triploidy mostly results from fertilization of an ovum by two sperms ( dispermy)

Failure of one of the meiotic division – formation of diploid sperm or ovum can also account for triploidy on fertilization
What is tetraploidy? How is it caused?
: A temporary pattern of tetraploidy may be seen during normal cell cycle
Otherwise it may be due failure of completion of an early mitotic division of Zygote
What is aneuploidy? What are the types? What chromosomes are they usually found?
Aneuploidy:
The term refers to an addition or deletion of one or more chromosomes from the normal set (mostly diploid) of chromosomes

Aneuploidy is of three kinds:
Monosomic
Nullisomic
Polysomic

Again Aneuploidy may be Autosomal or Sex chomosomal
What is monosomic aneuploidy?
One chromosome of a pair is missing in a diploid set – 2n-1
More dangerous/serious than polysomic
What is nullisomic aneuploidy?
One pair of chromosome in a diploid set is missing – 2n-2
What is polysomic aneuploidy?
Addition of one or more chromosome to a diploid set. Addition of one chromosome is called as Trisomy (2n+1)
What causes aneuploidy? What phase? What else occurs during this phase?
Aneuploidy results from nondisjunction during meiosis

It may occur during first or second meiotic division

Only occurs in ANAPHASE..The meiotic anaphase is mort important b/c occurs during gene mapping (homologous) chromosome.
the distribution pattern of extra chromosome is________when nondisjunction occurs at 1st or 2nd meiotic divisions.
the distribution pattern of extra chromosome is different when nondisjunction occurs at 1st or 2nd meiotic divisions.
What are th possibilities of nondisjuntion?
Rarely a gamete may contain more than one extra chromosome

Rarely nondisjunction can also take place at two successive meiotic divisions

There is also possibility of simultaneous nondisjunction in both male and female gametes resulting in zygote with unusual chromosome number. However this case is very rare
What are the results of nondisjunction at Meiosis II?
Nondisjunction at Meiosis II: gametes with extra chromosome: either paternal or maternal (but not both)
When are the cases of aneuploidy found?
Most cases of aneuploidy is by Meosis I Anaphase I, by nondisjunction
What are the types of aneuploidy? Which are likely not to survive?
Monosomy & Trisomy

Monosomies usually incompatible to survive
What does this phrase apply to? The body can tolerate excess of genetic materials than deficit’
Trisomies being less severe than monosomies
What is trisomy 21? What is the chromosomal Karyotype?
Down Syndrome

Chromosomal Karyotype:
47, XY +21 or 47, XX +21
What is common amongst males with down syndrome? Females?
Males with Down Syndrome are more or less always sterile

However, many females can reproduce

But most of the conceptions are spontaneously aborted, thus females risk of producing affected live child is considerably lower
What is the most common cause of down syndrome? What is an alternate cause?
Nondisjunction(95%) in the mother(90%)
mostly in Meiosis I (75%), remaining in Meiosis II

Chromosomal Translocation
What chromosomal disorder is also involved in Trisomy 21?
Mosaicism, due to having normal somatic cells with some trisomy 21 during embryonic development
What is Trisomy 18? What is the chromosomal karyotype?
Edwards Syndrome

Chromosomal pattern: 47, XYs +18 &
47,XX +18

Second most common autosomal trisomy
How is Trisomy 18 usually seen?
cases of conception leading to stillbirth with congenital malfotmations
How is Trisomy 18 usually developed?
Mosaicism, Maternal extra chromosome, maternal age
What is Trisomy 13? What is the chromosomal karyotype?
Patau Syndrome

Pattern: 47, XY +13 and 47, XX +13
How is Trisomy 13 usually caused? What is the survival rate?
Conventional Trisomy(80%), Chromosomal translocation

Extra maternal chromosome

Maternal age dependent
What is sex chromosomal aneuploidy?
Addition or deletion of the sex chromosome more viable than autosomal
What is Turners syndrome chromosomal karyotype? What is the sex of affected individuals?
Pattern: 45, X

The individuals are females
What % of indiv. with Turners have 45,X? What are the other kary affected?
About 50% of Turner Syndrome patients have the pattern of only 45, X karyotype, whereas 30 to 40% are mosaics, most commonly 45, X / 46 XX or occasionally 45, X / 46 XY
What problem arises when mosaics have Y chromosome?
Mosaics having Y chromosomes in some cells are predisposed to malignancy in their gonads (Gonadoblastoma)
What are the majority of cases of Turners syndrome caused by? How?
caused by the absence of paternally derived X chromosome

This may occur either during the early mitosis in embryo or during meiosis in father
What mutation produces short stature? Where is the gene located? How many of these genes are in Turners?
Mutation in SHOX gene=short

Gene located at tip of X & Y(pseudoautosomal region)

Normally 2 copies but onely 1 in Turners
What results in having one copy of SHOX gene?
Haploinsufficiency
What is Klinefelter syndrome? What is the chromosome kary?
Example for Sex Chromosomal Trisomy

Pattern: 47, XXY
How is the extra chromosome derived in Klinefelters?
Maternally (50%) the incidence increases with the advancing age of the mother

50% conception cases undergo spontaneous abortion
What type of disorders caused due to structural chromosomal abnormalities?
A. Autosomal deletion syndrome
What are PWS and Angelman syndrome examples of? Where is the deletion?
Microdeletion

15q
What is Camptomelic dysplasia?
Autosomal disorder, lethal skeletal abnormalities
Sex reversal (male become pheno females)
What happens if duplication of SOX 9?
Duplication of SOX 9 is reported to cause sex reversal of females
What is Pseudohermaphroditism?
have gonadal tissue of only one sex (as per chromosomal constitution)
What are the types of Pseudohermaphroditism?
Female pseudoheraphroditism
-- Male pseudohermaphroditism
What is Female Pseudohermaphroditism? What is the chrom kary?
46 XX karyotypes

Normal ovarian tissues

Ambigous or male external genitalia
How is Female Pseudohermaphroditism caused?
caused by Congenital adrenal hyperplasia (CAH), an inherited disorder affecting cortisol biosynthesis in adrenal cortex
What features do female pseudoherm have?
excessive androgen production causes masculinization of external gentilia, clitorial enlargement and labial fusion to form a scrotum –like structure
What enzymeis deficient in Female Pseudoherm?
21-hydroxylase is the most common defect in CAH, which results in –
-- blockage of normal biosynthesis of glucocorticoids & mineralocorticoids
-- overproduction of androgens
What is male pseudoherm? What is the chrom kary?
46,XY karyotype
Gonad is exclusively testis
What are the feaures of male pseudoherm?
Incompletely masculinized or having female genitalia

Pseudohermaphroditism may be caused by abnormalities of gonadotropins, inherited disorders of testosterone metabolism and abnormalities of androgen target cells
What is genome mutation?
entire chrom. extra or missing

Trisomy, Down Syn. Patua, Turners
What is chromosome mutation?
small but big enough to span more than one gene

PWS, AS
What is gene mutation?
Entire gene piece of the gene missing problem is that you do not know what has been deleted like stop codon
What are the types of nucleotide substitution/point mutations?
Missense Mutation (AA substitution)

Nonsense mutation(premature stop codon)

RNA processing mutation(destroy consensus splice site, cap site & polyadeylation sites or create cryptic sites)

Splice site mutation(leading to frameshift mut. & premat stop codon)

Regulatory mutations(affecting Tc control or other aspects of gene expression)
What is chain termination? What is the result?
Loss of stop codon
mRNA will be extended to the nxt stop codon

Protein will have abnormal extra AA
What is RNA processing mutation? What occurs?
Splicing mutations

5" donor & 3" acceptor sites
Abolition of site
Intro. of new competetive site-confuses splicesome
What are types of Mutation hotspots?
Transitions & Transversions
What is the process of transition?
C is methylated when 5’ to G

Me-C then deaminates to give T

C > T or G > A on complementary strand
If a deletion is not a multiple of 3 what will occur?
There will be a frameshift if a coding region is affected
The expressed protein will have a few aberrant AA’s and then be truncated
If a deletion/insertion is a multiple of 3 what will occurs?
No frameshift

A few extra AA’s inserted / deleted in protein
What are LINE sequence? What disease is it found?
Long interspersed nuclear elements[8] are a group of genetic elements that are found in large numbers in eukaryotic genomes. They are transcribed (or are the evolutionary remains of what was once transcribed) to an RNA using an RNA polymerase II promoter that resides inside the LINE.
What are the facts of Huntingtons regarding mutation?
In a coding exon
Abnormal protein
What are the facts of Fragile X regarding mutation?
Transcribed but untranslated region
mRNA processing affected
What are the notation for mutations?
Genomic g
In cDNA sequence c
Mitochondrial m
Protein p
What is nucleotide change and example?
Nucleotide number original base > new base

E.g. g.12245G>C Transversion if a transtion it would be purine to purine or pyr to pyr
What is the notation of insertion and deletion?
Numbers of nucleotides deleted separated by _ and followed by the word del

E.g. c.1227_1229delCCT

Numbers of nucleotides between which insertion has happened followed by ins

E.g. c.1227_1228insCAATAG
What are the missense or nonsnse notations at a protein level?
Original AA, number and new AA (X for stop codon)

E.g. Gln39X or Gly6Val
What is the avg human mutation rate?
Average rate approximately 1 X 10-6 ± 10-3 mutations per locus per generation
What affects the rate of human mutation?
Gene size
Fraction of mutations that give a detectable phenotype
Age and gender of parent
Mechanism of mutation- single base pr is more freq than single genes mutations
Hot spots (e.g. CG regions) – repeats are prone to mutations
How many mitoses do males undergo up to puberty? And after?
Spermatogonia undergo about 30 mitoses up to puberty then 20-25 divisions per year thereafter
What are the amount of mutations and age that males encounter?
180 mutations by age 25
600 mutations by age 55
Most are not pathological (about 1/2000 are)
1/10 to 1/3 sperm carry a deleterious mutation
How many mitotic divisions to females undergo? When is oogonium arrested?
22 mitotic divisions to birth
Oogonium arrested in meiosis I
The longer the arrest the greater the likeliood of failure of the microtubule system resulting in nondisjunction
What are the most common maternal origin mutations?
Trisomies 13, 18 and 21 (Patau, Edwards and Down) and XXX almost always of maternal origin
What type of mutation are males more prone to than females and why?
Sperm undergo more mitoses than ova so are more prone to point mutations old sperm =pt mutation
What are the most common cause of highly penetrant AD disorders?
For highly penetrant AD disorders, missense point mutations of paternal origin are most common cause.
Achondroplasia
Apert, Pfeiffer, Crouzon
MEN2
What are the causes DMD?
DMD caused by point mutations is 90% paternal

DMD caused by deletions (non disjunction or partial ND) is 80% maternal
How is Juvenile Huntingtons found?
Juvenile Huntington’s is caused by a massive repeat expansion that is paternal in origin
How is Fragile X usually caused?
CGG expansion in fragile X is usually maternal
What are Indels? How many in the genome? What are the types?
Insertions & Deletions (Indels)
Insertions or deletions of 2-100 b.p.
About 105 in the genome

Simple & Multiallelic
What are simple indels?
2 possible alleles (indel present / indel absent)
What is multiallelic indels?
Variable repeats of the indel
Microsatellites, Minisatellites and Copy Number Polymorphisms examples of indels
What is Rhesus Factor(Rh) produced by?
Rh+ has Rh D antigen produced by the RHD gene

Rh- are homozygous for a non-expressed form of the gene
Why is the mothers Rh important when carrying a fetus?
Rh- mothers develop anti-Rh antibodies to Rh+ blood from fetus.
Mothers Rh antibodies can cross the placenta and destroy the fetus’ RBCs
What is the blood group, sugar, Ag, & Ab it produces?
ABO on chromosome 9, Rh, MHC

Type A person  has A antigens, and will produce anti-B antibodies
N-acetylgalactosamine

Type B person  has B antigens, and will produce anti-A antibodies
Galactose

Type AB person  has both A and B antigens, won’t produce any antibodies
Has both galactose and N-acetylgalactosamine
Codominant

Type O Person  doesn’t have any antigens, will produce antibodies to both A and B sugars.
No sugar present
Recessive
What are MHC I genes? What are they made of?
Class I (HLA-A, HLA-B, HLA-C) genes
All nucleated cells
Integral part of cell membranes

2 peptide chains

Heavy chain (MHC coded)

β2 microglobulin (not polymorphic)

Intracellular proteins degraded to peptides by large multifunctional protease bind to HLA

Visible to T lymphocytes
What are MHCII genes? Made of?
Class II (HLA-DP, HLA-DQ, HLA-DR)

Heterodimer of α, β units

Presents peptides from exogenous proteins to T helper cells
What is HLA?
Haplotype gene given to off offspring is identical. Purpose is for transplantation using HLA to see the best match.

Diff in ethnic groups--linkage disequilibrium
What is HEMOCHROMATOSIS?
Mutation Cys282Tyr in HFE gene

HLA-A*301 on this same HFE gene.

you will see HLA-A in most people with Hemochromatosis
What is ANKYLOSING SPONDYLITIS?
Inflammatory condition of the spine and sacroiliac joints.

B27 serotype has 150x’s greater risk for this disorder
PKU in Ireland
PKU is autosomal recessive
Incidence of PKU is 1/4500

Calculate the expected carrier (heterozygote) frequency in the population
Homozygous ppl affected w/ disease=q2 = 1/4500 so q = √1/4500 = 0.015
p = 1- q = 0.985
Carriers occur at a frequency of 2pq
2 X 0.015 X 0.985 = 0.029
2.9% chance of a random individual being a carrier of PKU in Ireland
Note p2 + 2pq + q2 = 0.00022 + 0.029 + 0.970 = 1.0
What are the possible genotypes of X linked genes for males and females?
Males have only two possible genotypes A1 or A2
Females have three A1A1, A1A2 or A2A2
Example: X-linked recessive dysgenesis of corpus callosum
Incidence of affected males is 0.02 (2%) in one region of China
What is the frequency of affected males and females?
What proportion of females are carriers?
GENO & ALLELIC freq are the same in X-Link Recessive

The male allelic and genotypic frequencies are the same so q = 0.02 and p = 0.98 (i.e. 1 – 0.02) so frequency of non-affected males is 0.98
In females
q2 or (0.02)2 = 0.0004 are affected (0.04%)
p2 + 2pq or (0.98)2 + 2(0.98)(0.02) = 0.9996 females unaffected (99.96%)
2pq or 2(0.98)(0.02) = 0.0392 females are carriers (3.92%)
What is stratification?
A population has subdivisions that do not interbreed
Groups are reproductively separated
Causes may be racial, religious or cultural
What is assortive mating?
Individuals chose mates that have particular traits that are the same (positive assortive mating) or different (negative assortive mating) from themselves
What is Negative Assortive mating?
increase the frequency of autosomal recessive disease because they increase the likelihood that carriers of recessive alleles mate.
What are the types of fitness?
Absolute fitness is the number of progeny surviving to reproduce

Relative fitness f compares the individual’s fitness with the best fitness observed in the population
What is selection coefficient?
Selection coefficient s: proportion of indiv. That don’t get to reproduce. The bigger S the worse off you are. Measure of how badily compromised you are.
s = 1 - f
What are the X-linked recessive conditions of fitness?
Mutant alleles lost through selection must be balanced by new mutations
The mutant alleles are partitioned 1/3 in males, 2/3 in females.
Usually selection is only against hemizygous males
μ = sq/3
For a genetically lethal X-linked disease s = 1 so 1/3 of all persons with this allele are new mutations, and their genetically normal mothers are at low risk of producing a second affected child.
What is genetic drift?
Through random events, some individuals fail to reporcuse and pass genes, effect is reates in sm pop.
In a screening program to detect carriers of β-thalassemia in an Italian population, the carrier frequency is about 4%.
Calculate
The frequency of the β-thalassemia allele, assuming that there is only one common β-thalassemia mutation in the population
The proportion of matings in this population that could produce an affected child
The incidence of affected fetuses or newborns in the population
Incidence of β-thalassemia among offspring of couples both found to be heterozygous
Allele frequency
The heterozygote frequency is 4% = 0.04

2pq = 0.04
q = 1-p
2p(1-p) = 0.04
2p2 - 2p - 0.004 = 0
Using the quadratic formula
X = -b±√(b2 – 4ac)/(2a) gives roots 0.02 and 0.9775
p allele frequency is 0.02
What is alleles are on the same chromosome in NR?
DM paternal
dm maternal
DM paternal
dm maternal
Genes on the same chromosome are syntenic
If no recombination occurs between the loci we get only non-recombinant (NR)
If one or more crossovers take place between the loci NR:R = 1:1
If loci are far enough apart NR:R = 1:1
What amount designates R or NR?
R = 0
NR = 1
How do we detect recombination?
The parent must be heterozygous at both loci
We must know which allele of each locus is on which chromosome
phase