General study guide Flashcards
Triploidy-
is a multiple of haploid number- 1 too many of each chromosome
- Severe intrauterine growth retardation
- Macrocephaly
- Total syndactyly of 3rd and 4th fingers
- CNS, heart and renal defects
- Dysplastic cranial bones
- Eye defects
- Cleft L/P
- Malformed ears
- Micrognathia
- Genital anomalies
- Rarely spinobifida, hypotonicity and atrophy of cerebral cortes and corpus callosum
nullisomy-
absence of a homolog pair (2N-2)
monosomy-
1 too few chromosomes (2N-1)
- Turner’s syndrome- monosomy X-
- Only monosomy compatible with life
trisomy-
1 too many chromosomes (2N+1)- result of nondisjunction- can happen mainly in the female cell line during early stage of mitotic division, mosaic division can happen but has minor effect - Klinefelter’s syndrome male with XXY o 1/1500 o Variance- XXXY, XXXXY etc o Low fertility o Poor beard growth Trisomy 13, 18, 21
Klinefelter’s syndrome
male with XXY o 1/1500 o Variance- XXXY, XXXXY etc o Low fertility o Poor beard growth
Meiotic divisions in oogenesis/spermatogenesis
- Importance
o Recombination of genes through crossing overvatiation
o Constancy of chrom #–>haploid gametes
o Random assortment of maternal and paternal chrom
Oocyte
- begins Meiosis I prior to birth
- During dictyotene stage of Prophase I, division is arrested
- Follicular cells secrete “oocyte maturation factor” that keeps oocyte suspended in this phase for up to 45 years
- At ovulation, the 1st meiotic division is competed of primary Oocyte forming secondary oocyte and 1st polar body
- The first polar body will be expelled and the nucleus starts 2nd meiotic division, but stops in metaphase until fertilization
- First polar body undergoes meiosis II as well, forming 2 more polar bodies
- After fertilization 2nd polar body is expelled, and 2nd meiotic division completes to form ovum/zygote
Sperm
- Mitotic division of primordial germ cell forming primary spermocyte (diploid)
- Meiosis I creates 2 haploid secondary spermatocytes
- Meiosis II then forms 4 haploid spermatids
- 4 spermatids undergo spermiogenesis and form sperm
o 4 changes in spermiogenesis
o 1- most of cytoplasm is shed
o Formation of neck, middle piece and tail
o Condensation of nucleus
o Formation of acrosome
- Results of fertilization
o 2nd meiotic division completed
o Restores diploid number
o Variation of species
o Sex determination
o Initiates cleavage
The 1st division
Continues with the cell number doubling every division
Compaction: Zygote doesn’t increase in size to the cell become progressively smaller
Outside of zygote has bulges from rapid growth of cells=mulberry appearance=morula stage at 7 days
Enters uterus
Epigenetics, Major mechanisms
- Definition: changes in gene expression without changes at DNA sequence
o DNA methylation (imprinting) and Chromatin modifications are the only with associations with epigenetics
o Heritable trait
o Dosage dependent
o Inheritance pattern mostly random
- Epigenetics and cellular functions
o Organization of chromatin o Gene activation o Gene silencing o Silencing retrotransposal elements o X-chromosome inactivation o Maternal/paternal signature o Reprogramming (iPS-induced pluripotent stem cells) Epigenetics determines whether the neural crest cells will be skin…..etc…
- Genes involved in epigenetics:
o DNMT1/2/3: methyl transferase
Methylation of cytosine-essential for life
o MeCP2- methylated cytosine binding proteins-recognize the methylated cytosine and silence chromatin
Also recruit HDAC’s that will also silence chromatin
o SWI/SNF- huge protein complexes able to twist, evict, change the order of chromatin- can completely remove or add histones- like powerful bodyguards
o HDAC- histone deacetylase- proteins that remove the acetyl group from histones- essential for life
Cause deactivation of the chromatin
They are recruited by MeCP2
o HAT- histone acetyltransferase- opposite of HDAC- it adds acetyl group and activates chromatin
o PcG/TrxG- polychrome G and Trithorax G- PcG recognize the methylated cytosines and silence the chromatin or trithorax G does the opposite and recognizes the active chromatin and keeps it that way
Role of apoptosis in development of lip/palate
- P63 important factor
- 3 possibilities- migration, apoptosis, or EMT
P63- and apoptosis- they think this is important to allow fusion of the LNP and maxillary prominences
-Pbx1 and 2 are involved in apoptosis, so believe this is important for palate development
-Disruption in any of these factors can lead to CLP
IRF6, AP2a, Lef1, K1, p63, Wnt, & k14
BMP, FGF, SHH and WNT- all important in epithelial development- they are signaling factors that need to be secreted from ectoderm to indue the transcription factors
Then the TF’s have to feedback to ectoderm to verify they got the signal to form the dental placode
Acrocentric-
chromosomes with very short p Arm-
- 13, 14, 15, 21, 22
- Genes that are in acro portion that can be lost—-a lot of ribosomal DNA
- Can produce dicentric and acentric chromosomes through robertsonian translocation
Robertsonian translocation
- Leads to aneuploidy
o Monosomy and trisomy (13, 21 and 18) - Acrocentric chromosomes exchange material on their p arms
- No pathological consequence, but their offspring may be affected by producing unbalanced gametes
Dynamic mutations
- Trinucleotide repeats
o Fragile X syndrome
o HD
o Common features of trinucleotide repeat diseases
Anticipation
• Increase in repeat length correlates with increased severity and earlier onset
Pre-mutation carriers are usually asymptomatic
• -premutations are unstable and can expand in one generation to a full mutation
• Germline specific expansion
o Fragile X expansion occurs in femaile
o HD expansion occurs in female - Simple tandem repeats (STRs)
o Fragile X syndrome
X-linked mental retardation
Discovered in 1969
Silencing of Fragile X mental retardation 2 (FMR1) 5’UTR methylation CpGG
Fragment of BAC clone
Fragment contained variable CGG repeat
Pre-mutation 50 to 200 repeats
• Female carriers at risk for premature ovarian failure
• Male carriers at risk for fragile X assoc. with tremor/ataxia syndrome
Full mutation>200 repeats
• Severity is dependent on somatic mosaicism and methylation
- Undergo dynamic mutation due to replication slippage
o change (expansion or contraction) can occur in one generation
o imperfect repeats appear to be more stable
o trinucleotide repeats appear to be the most dynamic
o HD
All have CAG repeats in open reading frame
• Polyglutamine disease
• Are dominantly inherited
• Neurons are aggregate sensitive
• All involve degeneration of different neuron populations
• Aggregates of PolyQ protiens found in cells
• PolyQ expansion causes gain of function
- non-syndromic
o no other phenotype o non-mendelian complex (spontaneous mutation) o common (1/700) o subjects have altered brain tissue distribution anterior- excess gray matter=thick cortex posterior-deficit in white matter cerebellum- decreased volume associated with social dysfunction – from volume of ventral frontal cortex
o genes involved in non-syndromic CLP
IRF6, TGFA, MSX1, PVRL1, TGFB3, RARA, BCL3, CRISPLD2, SUMO1, MMP3, 8q24 locus, 17q22 locus, GREM1 and others, WNT signaling pathway (WNT3)
TGFA- transforming growth factor alpha
• Taq I polymorphism
• Modifier gene- smoking and gene interaction
• Gene interaction with other SNPs and IRF6
TGFB3
• Genetic heterogeneity and this gene may contribute in Asian population
o Environmental factors of CLP
Nutrition • Folate- MTHFR C667T involved in folatemet Hyperthermia Stress Obesity Occupational exposures Ionizing radiation infection
- Syndromes assoc. with clefting
o Holoprosencephaly- GLI2, SHH, SIX3 o Van der Woude/popliteal pterygium – IRF6 o Crouzon- FGFR2 o Apert- FGFR2 o Gorlin- PTCH1 o CLP- ectodermal dysplasia- PVRL1 o Tetra-amelia with CLP- WNT3 o Pierre Robin- SOX9 o X-linked CP and ankyloglossia- TBX22 o Treacher Collins- TCOF1 o Loeys-Dietz- TDFBR2 o Saethre Chotzen- TWIST1 o Wolf-Hirschorn syndrome- MSX1 at 4p16.3 (deletion at 16.3
Gene classes in CLP
- IRF6
- MSX1
CLP associated syndromes/epidemiology of
May result from disturbances at any stage:
- inadequate composition of palatal matrix
- delayed or failed shelf elevation
- inadequate disappearance of medial epithelial seam
- failure of mesenchymal consolidation and differentiation
- defective shelf fusion
Van der Woudes syndrome!!!
- Lip pits
- Autosomal dominant
- Rare (1/30,000)
- 70% have VWS exonic mutation
- Have problem with wound healing
- Mutation in IRF6 gene
o Missense mutation in functional domain
Clusters at DNA binding domain and protein binding domain
o Truncation (nonsense) mutations evenly distributed
Normally loss of function and cause RNA to decay
Causes of non-syndromic CLP
- Gene-gene interactions
- Gene-environment interactions
- Environmental factors
Link between tooth agenesis and colon cancer
- WNT’s and FGF;s
- AXIN2 mutations cause familial tooth agenesis and colorectal cancer predisposition
- CDH1- cleft L/P and cadherin mutations in families with hereditary diffuse gastric cancer
o Show cleft on one side and tooth agenesis on the other
• Penetrance:
Percentage (%) of affected individuals that carry the same mutation
• Expressivity:
Variation in the severity of a phenotype
• Sensitivity
– proportion of affected individuals correctly identified
• High sensitivity – low false negative rate
• Specificity –
proportion of normal individuals correctly identified
• High specificity – low false positive rate
• Genes associated with isolated tooth agenesis
• MSX1 (homeobox-role in limbs, CF dev.,
• PAX9 (oligodontia)
• AXIN2 (negative reg. of WNT signaling, assoc with colorectal cancer)
• FGFR1
• TGFA
• EDA
• EDAR
• EDARADD
• WNT10A
-MSX1 and IRF6 appear to contribute to preferential agenesis of premolars and molars
-AXIN2 appears to contribute to preferential agenesis of incisors
Many gene-gene interactions are likely to contribute to tooth agenesis
MSX1-PAX9
MSX1-IRF6
TGFA-IRF6
• SYNDROMES WITH TA
- Ectodermal dysplacia- gene EDA
- Oral-facial-digital syndromes (wiktop)- gene MSX1
- Oral cleft syndromes
- VWS- IRF6 in 70% of cases
- Pierre Robin- SOX9 in 50% of cases
- CLPED1- PVRL1
MSX1 and PAX9
Msx1-/- mice present cleft palate, deficient mandibular and alveolar bones and failure of tooth development.
5 mutations in humans cause dominantly inherited posterior tooth agenesis
Pax9-/- mice lack derivatives of 3rd and 4th pharyngeal arches, have craniofacial and limb anomalies, and fail to form teeth beyond the bud stage.
11 mutations in humans with tooth agenesis
Single Gene Forms: MSX1
Autosomal dominant
Cleft Lip and Palate/Oligodontia syndrome
Witkop syndrome
Oligodontia
Preferential premolar and 3rd molar agenesis
-Mutations in this gene have been associated with nonsyndromic cleft lip with or without cleft palate, Witkop syndrome, Wolf-Hirschorn syndrome, and autosomal dominant hypodontia.
Single Gene Forms: PAX9
Autosomal dominant
Oligodontia
Preferential molar agenesis
-play critical roles during fetal development and cancer growth
-Specific function yet unknown but may involve development of stratified squamous epithelia as well as various organs and skeletal elements
AXIN2
Axis inhibitory 2
Negative regulator of WNT signaling
Mutations associated with colorectal cancer
Mixed pattern of tooth agenesis
Chromosomal Modifications
methylation of the cytosine, or the modifications that will happen on the N-terminus of the histones
- Acetylation of N terminus of histone makes that area active-
- Methylation of histones involved more in activation of genes rather than silencing, but not necessarily for everything, that is why it is diverse, can turn off or on
Acetylation- always think about activating the gene
histone modifications: methylation, acetylations, and phosphorylations
DNA Imprinting
Methylation of Cytosine in CpG
DNMT1 = DNA methyltransferase 1
Mutations of these cause embryonic lethality
Dnmt1/2/3 & HDAC1
DNA Methylation & Folic Acid
S-adenosyl-methionine is a methyl group donor for the DNMT1 during DNA methylation.****why folate has an effect of human health
Vitamin B9 – important in pyrimidine synthesis – DNA bases – C,U,T
And in biosynthesis of methionine- very important because every gene starts with methionine
**Also, methionine will get converted to S adenosyl methionine which is the donor group that is needed to make the DNMT1*why folate has effect on human health
Histone Proteins & Octamer Core
H1- linker H2A, H2A.Z, H2A1 H2B H3, H3.3 H4
H3 & H4 Histone Modifications
-2 marks happen at histone H3 (but they can happen on any histone monomer)
- H3 K4- monomethylation, dimethylation, or trimethylation- one of the most important modifications that can happen in the cell- will determine the structure of the chromatin- whether talking about intergenic enhancers, promotors and the body of the gene
- Another important is on histone H3 K9- and the switch between acetylation and Methylation
Chromatin Silencing by HP1
Bind the methylated cytosine and compacts the chromatin
Epigenetic Abnormalityies that Results in Phenotypic Variation
Quantitative changes - UPD - Imprinting Defects Hypo / hypermethylation Disruption of methylation by disrupted DNA methylase - Defects in Chromatin structure - Chromatin remodeling (compact, condensed) - Chromatin modification
Angelman’s syndrome
- gene: deregulation of the imprinted UBE3A locus on 15q11-13
epigenetic anomalies: disruption of the parental DNA methylation markers
Beckwith-Wiedeman syndrome
- gene: disruption of the imprinted IGF2/CDKN1C loci on 11p15.5 epigenetic anomalies: loss of genomic imprinting
Fragile X syndrome
- gene Loss of FMR1/FMR2 function
epigenetic anomalies: promotor methylation due to an expansion of the CGG repeat
Klinefelter syndrom
e- gene: Extra X chrom. In males
Epigenetic anomalies: abnormal X-inactivation/imprinting
Epithelial-Mesenchymal Interaction during Mandibular Development
One of the important genes to determine the fate of the pharyngeal arches are the homeotic genes
The genes that determine the fate of the pharyngeal arches to become maxilla and mandible are called Dlx codes
-if they stay only as 1 and 2, they will form the maxilla
If you add 5 and 6 then they will make the mandible,
Then if add to that 3 and 4, you will make the hyoid bone of the 2nd pharyngeal arch
Endothelin 1- signaling molecule secreted from the epithelial cells from first or 2nd pharyngeal arch that regulates the homeotic genes- it binds to its receptor (Ednr A) and it will upregulate the Dlx5/6 only in the mandible
