Topic 2: developmental genetics Flashcards
What is developmental genetics?
The study of how genes and their encoded proteins regulate and participate in the growth and development of an organism.
What is mitosis?
The process of duplicating genomic material and dividing it into equal portions to faithfully replicate the original genomic information. Occurs nearly everywhere in the body, especially during development, and is required for growth.
What is meiosis?
The process where four haploid (unique) cells are created from parent cells. Occurs in germ cells only and creates new versions of genetic material through meiotic recombination.
What is the purpose of making the polar body in oocytes?
To save energy for the next steps, ensuring enough energy for proper formation, which is crucial for early embryo development.
What role do the position of the polar body and the orientation of the sperm play?
They play a role in early embryo development.
How many polar bodies are made in sperm?
Four polar bodies are made.
What are the stages of normal development from a fertilized egg up to when the embryo hatches?
Fertilized egg, day 0, with 2 pronuclei and polar bodies.
Two-cell embryo, day 1.
Four-cell embryo, day 2.
Eight-cell embryo, day 3.
16-cell embryo, day 3 - totipotent cells.
Morula (compaction), day 4.
Blastocyst formation, day 5.
What are totipotent cells?
What are some medical applications?
Cells that can give rise to all tissues necessary for embryo survival. Medical applications include IVF, PGD, and scientific research.
What is the significance of blastocyst formation?
Differentiation begins, and cells become pluripotent, meaning they can differentiate into many different cell types depending on their development path. Medical applications include transplantations and iPSC for scientific research.
What is the medical importance of totipotent hematopoietic stem cells?
They can be transplanted into a deficient individual to restore specific types of hematopoietic cells. Genetic mutations in myeloid progenitor cells affect a wide range of cells.
What happens on Day 6 of embryonic development?
Clear polarizations form, with cells forming an outer layer called trophoblasts.
What happens on Day 7 of embryonic development?
Growth extends further into the endometrium to gather resources for further growth, supported by trophoblasts.
What happens on Day 8 of embryonic development?
Expansion into the endometrium with trophoblast expansion and the beginning of the formation of the amniotic cavity.
What is gastrulation?
A morphogenetic process leading to the development of 3 primary germ layers – ectoderm, mesoderm, and endoderm. It is an extremely critical phase of development.
What does the ectoderm give rise to?
The nervous system and skin.
What does the endoderm give rise to?
Many visceral organs and the lining of the gut.
What does the mesoderm give rise to?
All connective tissues, bone, vasculature, lymphatic, and hematopoietic systems.
What do the neural tube and crest give rise to?
Cells in the peripheral and enteric nervous system, muscle craniofacial bones and cartilage, melanocytes. They arise at the ectoderm-neural ectoderm boundary.
Front: What is the embryonic period?
Back: The first 8 weeks of development where the organism does not resemble the adult, all major organ systems are established, and sensitivity to teratogens varies.
Front: When are organisms less sensitive to teratogens during development?
Back: Up to week 2, with an all-or-nothing effect (will live or die).
when are organisms more sensitive to teratogens?
early to later-embryonic period (2-8 weeks)
Front: What is the fetal stage?
Back: Weeks 9-40, where the organism resembles a human, focusing on the maturation and further differentiation of organ components, and is susceptible to functional defects or minor physical abnormalities.
Front: What is the importance of brain development in the context of early-onset diseases?
Back: Genes affecting brain development are considered for early-onset diseases, while genes controlling brain maintenance are considered for late-onset diseases.
What percentage of infant deaths are due to birth defects?
More than 20% of infant deaths.
Can genetic defects manifest later even if a baby is born ‘normal’?
Yes, congenital diseases may manifest themselves later (minutes, hours, weeks, months, years).
What is chromosome imbalance and which trisomies are most common?
Chromosome imbalance involves autosomal trisomies of chromosomes 21, 18, and 13.
What are some examples of single gene mutations causing birth defects?
Achondroplasia and Waardenburg syndrome.
What are multifactorial birth defects and examples?
Birth defects with no identifiable cause, considered multifactorial. Examples: cleft palate and congenital heart defects.
What are the three major categories of birth defects?
Malformations, deformations, and disruptions.
What are malformations and what causes them?
Result from intrinsic abnormal developmental processes, often due to a genetic cause. Example: Proteus syndrome.
What is pleiotropy?
A birth defect resulting from a single causative gene affecting more than one organ system at different times during intrauterine life.
What is a syndrome in the context of birth defects?
Multiple abnormalities occurring in parallel, such as Proteus syndrome (develop asymmetrical and disproportionate overgrowth of body parts (malformations in vascular system, skeleton, and connective tissue). Caused by somatic mosaicism for de novo activating mutations in AKT1)
What is a sequence in the context of birth defects?
When a single organ system is affected, leading to other pleiotropic effects as secondary effects. Example: Greig cephalopolysyndactyly (loss of function in transcription factor GLI3)
What are deformations in birth defects?
Caused by mechanical forces. Example: congenital arthrogryposis, thalidomide effects.
What are disruptions in birth defects?
Destruction of irreplaceable normal fetal tissue, harder to treat, not inherited.
What are neural tube defects and when do they form?
Defects due to improper closure of the neural tube by day 28 of development, most common and devastating among birth defects.
What factors can influence the frequency of neural tube defects?
Social factors, season of birth, and time, with a marked decrease in recent years, with a small proportion with known specific causes (e.g. single gen defects)
What is anencephaly?
Absence of the forebrain, overlying meninges, vault of the skull, and skin. Most infants with anencephaly are stillborn or die shortly after birth.
What is spina bifida?
Failure of fusion of the arches of the vertebrae, typically in the lumbar region. Severity ranges from spina bifida occulta (defects in bony arch only) to spina bifida aperta (protrusion of meninges)
What is the greatest factor causing neural tube defects?
Maternal folic acid deficiency, exacerbated by a genetic variant of the enzyme 5,10-methylenetetrahydrofolate reductase (MTHFR).
How can neural tube defects be prevented?
Dietary supplementation with folic acid (400 to 800 µg per day) one month before conception and continuing for two months after conception, and prenatal screening.
What is prenatal screening for neural tube defects?
Detecting excessive levels of alpha-fetoprotein (AFP) and other fetal substances in the amniotic fluid, and ultrasonographic scanning.
What is pattern formation and why is polarization important?
Proper polarization is needed to determine positions and axes for budding out. Important genes include SHH (sonic hedgehog) and GLI3R. Malformations occur when this process is perturbed.
What are the different axes in development?
Dorsal-ventral, cranial-caudal, and left-right.
How is the dorsal-ventral axis determined in development?
Sperm entry point determines the boundary between trophoblast and inner cell mass.
How is the cranial-caudal axis determined in development?
Determined by the position of the second polar body.
How is the anterior-posterior axis determined?
Determined by SHH and GLI3. SHH inhibits the conversion of transcription factor GLI3 to GLI3R in the posterior region of the limb bud.
What happens when there are mutations in GLI3?
GLI3 mutations cause two pleiotropic developmental syndromes: polydactyly and polydactyly with severe cutaneous syndactyly.
What are morphogen gradients?
Secreted chemicals that signal to allow cells in a tissue to determine their position.
Example: Zone of polarizing activity (ZPA).
What are some effects of SHH mutations?
SHH missense mutation in a mother and her daughter causes different manifestations. The daughter has severe abnormalities, while the mother has a single central upper incisor.
What is situs inversus and which gene is associated with it?
An abnormality in the X-linked gene ZIC3, involved in left-right axis determination, associated with cardiac anomalies.
What are HOX genes and their significance?
HOX genes encode transcription factors with a conserved DNA-binding motif called the homeodomain. The segment encoding the homeodomain is called a homeobox.
What are the effects of a gain-of-function mutation in HOXD13?
Creates an abnormal protein with a dominant negative effect, causing synpolydactyly.
What is Congenital Vertical Talus and which HOX gene is associated with it?
A condition called ‘rocker bottom foot’ associated with HOXD10.
What is Hand-foot-genital syndrome and which HOX gene is associated with it?
A syndrome causing shortening of thumbs and toes, genital and urinary tract anomalies, associated with HOXA13.
Why is programmed cell movement critical in development?
Critical for development, especially in the central nervous system.
What is Miller-Dieker syndrome and its cause?
Caused by a deletion involving one copy of the LIS1 gene on chromosome 17, leading to disorganized cortical neuron migration and severe brain abnormalities (progressive waves of migration of cortical neurons do not occur in an organized fashion because of reduced speeds of migration. Result is a thickened, hypercellular cerebral cortex with undefined cellular layers and poorly developed gyri).
What is Lissencephaly and its characteristics?
A severe abnormality of brain development causing a ‘smooth brain’ with profound intellectual disability, associated with Miller-Dieker syndrome.
What are the categories of chromosomal and genomic abnormalities?
Nondisjunction, recurrent chromosomal syndromes, idiopathic chromosomal abnormalities, unbalanced familial chromosomal abnormalities, chromosomal and genomic events revealing regions of genomic imprinting.
What are the mechanisms of chromosomal abnormalities?
Aneuploidy, Uniparental Disomy, Microdeletion and duplication syndromes, Idiopathic chromosome abnormalities, Disorders associated with genomic imprinting, Neurodevelopmental disorders.
What is aneuploidy?
Errors in chromosome segregation leading to trisomy or monosomy. Only three well-defined nonmosaic autosomal chromosome disorders compatible with postnatal survival: trisomy 21 (Down syndrome), trisomy 18, and trisomy 13.
What determines the developmental abnormalities in trisomies?
The extra gene dosage. Current research is beginning to localize specific genes responsible for the abnormal phenotypes.
What is Down Syndrome (trisomy 21)?
The most common genetic defect of moderate intellectual disability. Diagnosed by dysmorphic features and intellectual disability. Caused by an extra copy of chromosome 21 due to meiotic nondisjunction.
What are the features of Down Syndrome?
Hypotonia, short stature, brachycephaly, short neck with loose skin, single transverse palmar crease, and clinodactyly. Intellectual disability varies among patients.
How does meiotic nondisjunction lead to Down Syndrome?
This occurs in 95% of down’s syndrom. Usually occurs during maternal meiosis (90% of cases) in meiosis I. Results in an extra copy of chromosome 21.
What is mosaic Down Syndrome?
Approximately 2% of patients. The phenotype may be milder with wide variability due to variable proportion of trisomy 21 cells during early development.
What is Robertsonian translocation in Down Syndrome?
Approximately 4% of patients have 46 chromosomes with a Robertsonian translocation between chromosome 21q and another chromosome’s long arm. Involves fusion of whole long arms of acrocentric chromosomes.
What is uniparental disomy?
A disomic cell line containing two chromosomes or portions thereof, inherited from only one parent. Can lead to recessive traits and imprinting related traits.
What are microdeletion and duplication syndromes?
Syndromes characterized by developmental delay, intellectual disability, and dysmorphic features due to recurrent subchromosomal or regional abnormalities.
where the phenotype is due deletion or duplication of only a single gene within the region.
Example: 22q11.2 deletion associated with DiGeorge syndrome, velocardiofacial syndrome, and conotruncal anomaly face syndrome.
What is the significance of the TBX1 gene in 22q11.2 deletion syndrome?
Thought to play a role in up to 5% of all congenital heart defects and is a frequent cause of left-sided outflow tract abnormalities.
What is Cri du chat syndrome?
Terminal or interstitial deletion of part of the short arm of chromosome 5. Characterized by a distinctive cry resembling a mewing cat, microcephaly, hypertelorism, epicanthal folds, low-set ears, and micrognathia.
What is genomic imprinting?
For some disorders, the expression of the disease phenotype depends on whether the mutant allele or abnormal chromosome has been inherited from the father or the mother. Results from parent-of-origin effects.
what are the different ways Trismy 21 (down’s syndrome can occur)?
- meiotic nondysjunction (often mother’s side during meiosis 1)
- mosicism (a nondysjucntion event occuring in mitosis, so not related to the parents)
- robertsonian translocation
- 21q21q translocation
- partial trisomy (very rare) where only part of the long arm in chromosome 21 is presetn in triplicate
what is an isodisomy and a heterodisomy?
they are different situations in uniparental disomy:
iso: the two chromosomes are derived from identical sister chromatids
hetero: if both homologues from one parent are present
where in the genome are microdeletion and duplication syndromes often found?
breakpoints localize to low-copy repeated sequences in the genome termed segmental duplications
what is CATCH22 and what type of genetic defect is it?
Cardiac abnormality (commonly interrupted aortic arch, truncus arteriosus and tetralogy of Fallot),
Abnormal facies,
Thymic aplasia,
Cleft palate, Hypocalcemia/Hypoparathyroidism
associated with a 22q11.2 microdeletion
