Genetic Mechanisms I&II Flashcards
trisomy 21, 18, 13
only autosomal trisomies that can occur in nonmosaic form & have viable births
-very gene poor
trisomy 21
- most gene poor –> least severe
- more live births
- palmar crease, extra skin on hand, epicanthal folds, heart problems (AV canal & VSD)
- 55 year life expectancy
trisomy 13
- less gene poor –> most severe
- less live births
- rocker bottom feet, microcephaly,
- die w/I 1st month or year
trisomy 18
- prenatal growth deficiency, low birth rate, rocker bottom feet, heart problems (VSD)
- die w/I 1st month or year
Down syndrome
- trisomy 21 causes 90% of cases
- also caused by: Robertsonian translocation, 21q21q translocation, or partial trisomy 21
balanced vs unbalanced translocations
- balanced –> no loss of genetic material
- unbalanced –> loss of genetic material
risk of Down syndrome or other trisomy
risks increase after 35 y/o, but most are born in women under 35 y/o
trisomy 21 in Down syndrome
extra copy of 21st chromosome
-random chance parents will have Down syndrome kid
Robertsonian translocation in Down syndrome
translocation b/w 21q and 14 or 22
- does not alter phenotype
- translocation came from one of the parents (one of them has 45 chromosomes) –> high chance of having another child w/ Down syndrome
21q21q in Down syndrome
fusion of chromosome 21 in parents to make single chromosome
-offspring will have mono or trisomies
partial trisomy 21
extra copy of part of chromosome 21
-help identify genes responsible and therapeutics
DiGeorge Syndrome
micro deletion due to haploinsufficiency
- craniofacial problems, intellectual disability, heart problems, immune deficient
- TBX1 in CHD
what causes duplication syndromes?
abnormal crossing over –> one chromosome will have more genetic material than other
2 kinds of duplication syndromes
-22q11.2 (swapped evenly)
-cat eye syndrome (duplication and inversion)
idiopathic chromosome abnormalities
don’t know exactly where problem is occurring
ex. Cri du chat
- 13 chromosome deletion (deletion varies) –> variable phenotype
- increased eye distance, skin fold of eye lid, jaw behind other
- degree of disability correlates w/ size of deletion
sex chromosomes
- different from autosomes
- sex determination in distinct steps
- sexual development disorders if chromosomal sex does not line up with gonadal sex
Y chromosome
can also undergo recombination with X chromosome –> pseudoautosomal genes
- SRY determines male –> defects lead to abnormal devel. & knock out TFs
- gene poor –> 2 dozen for gonadal/genital devel.
micro deletions of Yq
low sperm count to no sperm production
-nonobstructive azoospermia to oligospermia
AZF region (azoospermia factors)
important for spermatogenesis
- mutations leads to low sperm count or no sperm
- ADZ genes (deleted in azoospermia)
X chromosome
Aneuploidy of X chromosome - most common abnormality
- females - Barr body –> X chromosome inactivates one X keeping other one active
- males - no Barr body bc only X is active
- structurally abnormal X almost always inactive (secondary selection)
- not all genes from inactive X are inactive
klinefelter syndrome (male)
XXY
-low sperm count, lack of maturity, small genitalia
47 XXY (male)
taller, intellectual delays, ADHD
Turner syndrome (female)
one X
-webbed neck, short, edema
trisomy X
developmental delays
-increasing severity with increasing Xs
loss of function mutation in SRY or SOX9 in males
go down female pathway –> XY gonadal dysgenesis
extra SRY or SOX9 in XX individual
go down male developmental pathway –> XX testicular or XX ovotesticular disorder
- SRY –> testicular disorder
- SOX9 –> ovotesticular
mutations in CAIS or PAIS
occur during puberty
- incomplete masculinization
- have testes but switch to female characteristics
mutations in CAH
occur during puberty
- XX virilization
- have ovaries but switch to male characteristics
congenital adrenal hyperplasia
virilization of 46, XX infants
androgen insensitivity syndrome
incomplete masculinization of 46, XY infants
neurodevelopmental disorders and intellectual disability
hard to determine genetic cause
-genetic unbalanced translocations –> genomic imbalances with intellectual disability and autism
X-linked intellectual disability
caused by mutations, micro deletions, and duplications
-fragile X syndrome –> FMR1 mutation (CGG repeat)
DNA methyltransferase
adds methyl group to 5’C of cytosine
- DNA into heterochromatin (packed more tightly) which silences expression
- can be passed on during cell division
role of methylation
- silence gene expression
- recruitment of HDAC to turn off genes
HATs (histone acetylases)
transfer acetyl group to remove positive charge on lysine –> DNA loosely packed –> accessible to TFs
HDACs (histone deacetylases)
restore positive charge on lysine –> DNA tightly packed –> less accessible to TFs
-drugs for HDAC inhibitors
role of epigenetics
modification to expression pattern of DNA w/o altering bases
-how environment and genotype change phenotype leading to disease
genomic imprinting
regulatory system where a single allele is expressed and is always parent specific
-beneficial even though you are more susceptible to disorders
paternal imprinting
growth promoting for offspring - produce more powerful individuals
-silenced growth limiting genes
maternal imprinting
growth limiting for offspring
-silenced growth promoting genes
Prader-Willi syndrome
paternal transmission when having mutation
-maternal copy is silenced & does not affect offspring
angelman syndrome
maternal transmission when having mutation
-paternal copy is silenced
epigenetic regulatory system
1st generation imprints passed on from gonads of mother and father –> go through cell division of somatic cells –> imprints erased w/I germ cells of embryonic gonad –> imprints reestablished based on sex of embryo
- if male, pass paternal imprints through testes (prenatally)
- if female, pass maternal imprints through egg (postnatally)
why is methylation used in imprinting?
can be passed on (maintainable) and erased
how is methylation passed on?
Dnmt3 methylates unmethylated DNA –> replication –> hemimethylation –> Dnmt1 completes methylation of hemimethylated strands
how is methylation removed?
- erased by passive dilution on maternal chromosomes
- erased by active demethylation via Tet protein on paternal chromosomes
mutations in Dmnt3 and Dmnt1
alterations in imprinted gene regions
imprinted genes and imprint control elements
imprint genes usually packed together –> lead to a RNA, not protein
- methylation/imprinting occurs at DMR or ICE
- imprinted protein coding genes expressed on same parental chromosome & lncRNA expressed from opposite parental chromosome
imprint control elements
- imprinting/methylation of DMR or ICE –> inhibit IG-NC –> expression of protein coding
- no expression of protein coding w/o imprinting bc the IG-NC will not be inhibited
- non-imprinted gene always expressed
deletion of DMR control region in imprinted chromosome
no change in gene expression
-still get protein coding gene and silence non-coding
deletion of DMR control region in non imprinted chromosome
change to imprinted gene
-get protein coding gene and silence non-coding
insulator model of imprinting
- CTCF is the insulator for maternal copy –> binds to ICE –> blocks promoter enhancer interaction –> inhibit protein coding expression
- in paternal copy –> methylation/imprinting occurs –> inhibit CTCF binding –> silence long noncoding –> promoter enhancer interaction –> expression of protein coding
- activate paternal copy, inhibit maternal
- depends on protein to block promoter enhancer interaction
long coding RNA model of imprinting
- maternal copy methylated/imprinted –> silence long noncoding –> express protein coding gene
- paternal copy –> no methylation/imprinting –> Airn NC silences protein coding genes
- activate maternal, silence paternal
- depends on RNA to silence protein coding
beckwith-wiedemann syndrome
- somatic overgrowth
- embryologic malignancies
- increase organ size
silver Russell syndrome
growth retardation
short stature
what is IGF2?
a growth factor
-overexpression leads to excess growth
what is CDKNC1?
cell cycle regulator
- inhibitor of G1 cyclin/cdk complexes
- deficiency leads to overgrowth
beckwith-wiedemann syndrome genomic imprinting
- maternal chromosome –> CTCF binding to to iGF2 cluster on ICR1 –> no inhibition on H19 (noncoding) –> no expression of Igf2 gene (no protein coding)
- paternal chromosome –> methylation/imprinting of ICR1 –> inhibition of H19 noncoding –> expression of Igf2 (protein coding)
- Igf2 comes from paternal, silenced on maternal
silver Russell syndrome
loss of paternal ICR1 methylation
- maternal chromosome –> methylation of ICR2 –> silence noncoding (KCNQ1) –> express protein coding (CDKN1C)
- paternal chromosome –> no methylation of ICR2 –> expression of noncoding (KCNQ1) –> silence protein coding (CDKN1C)
- CDKN1C comes from maternal, silenced on paternal
