Exam 1 Genetics Thread Flashcards
“n”
Designation
The number of chromosomes in a cell.
Diploid = 2n
Haploid = n
“N”
Designation
The amount of DNA in a haploid genome.
3x109 base pairs
Bivalent
Sister chromatids attached at the centromere.
Cell Cycle
Stages
- Interphase
- Prophase
- Prometaphase
- Metaphase
- Anaphase
- Telophase and cytokinesis
Interphase
- G1: makes proteins needed for replication
- S: DNA replication
- G2: grows, makes microtubules
Prophase
- Chromosomes condense and coil
- Becomes visible by LM
- Centrioles migrate to opposite poles
- Centrosomes start to form mitotic spindle
Prometaphase
Nuclear membrane disappears
Metaphase
- Mitotic spindles attach to centromere @ kinetocore
- Chromosomes align on metaphase plate
- Continues to condense
- Most karyotyping taken here
Anaphase
Sister chromatids split at centromere and separate.
Guided by spindle fibers and centrioles.
Telophase
Chromosomes have migrated to opposite ends of the cell.
Nuclear envelops begins to reform.
Cytokinesis forms two daughter cells.
Cell Cycle
Checkpoints
- Exists throughout interphase and M-phase.
- Ensures steps occured correctly.
- Apoptosis can be a normal process here.
Mitotic Spindle
Drugs
Halts cell cycle in metaphase.
- Vincristine (Oncovin)
- Binds tubulin dimer preventing microtubule assembly
- Paclitaxel (Taxol)
- Prevents depolymerization of microtubules
Meiosis
Characteristics
Reductive division
- Produces haploid gametes
- 1 n chromosomes
- 1 N base pairs
- Meiosis I ⇒ seperates homologous chromosomes
- Promotes genetic variation
- Independent assortment
- Recombination
Tetrads
2 homologous chromosomes = 4 sister chromatids
Meiosis I seperates homologous chromosomes
4N ⇒ 2N
Meiosis II seperates sister chromatids
2N ⇒ N
Synapsis
“Crossing-over”
- Occurs during prophase I
- Chiasmata: site where crossing over occurs
- # formed depends on chromosome size
Equatorial Divisions
Cell division where the number of chromosomes remains the same.
i.e. Mitosis and Meiosis II
Anaphase Lag
Delayed chromosome movment during anaphse of mitosis or meiosis.
- Lagging chromosome not incoorporated into new nucleus
- Can occur with chromosomes or chromatid
- Failure to connect to spindle apparatus
- Moves too slow
- Normal cell forms 1 normal karyotype and 1 monosomy
- Trisomy cell forms 1 trisomy karyotype and 1 “normal” karyotype ⇒ trisomy rescue
Uniparental Disomy
When both copies of a chromosome are inherited from one parent.
Usually results from anaphase lag then aneuploidy correction.
Non-disjunction
Failure of one or more chromosomes/chromatids to separate appropriately during mitosis or meiosis.
- Meiosis ⇒ aneuploidy of all cells
- Meiosis I ⇒ 2 cells w/ extra chromosomes, 2 cells w/ no chromosomes
- Meiosis II ⇒ 1 cell w/ extra, 1 cell with none, and 2 normal cells
- Mitosis ⇒ mosaicism
Mosaicism
Definition
Single individual with two or more genetically different cell types.
Euploidy
Normal chromosome number.
46 chromosomes
Trisomy
47 chromosomes
Usually incompatible with life ⇒ spontaneous abortion
Except trisomy 21, 13, 18, XXX, XXY, XYY
Monosomy
45 chromosomes
Usually incompatible with life except for Turner’s syndrome (45,X)
Spermatogenesis
Steps
Type A spermatogonia ⇒ mitosis ⇒ some type A spermatogonia & some type B spermatogonia
Type B spermatogonium ⇒ mitosis ⇒ primary spermatocytes (diploid, 2N)
Primary spermatocyte ⇒ meiosis I ⇒ secondary spermatocytes (diploid, 2N)
Secondary spermatocyte ⇒ meiosis II ⇒ spermatids
Spermatids ⇒ spermiogenesis ⇒ spermatozoa
Spermiogenesis
Radical morphological change of spermatids into mature spermatozoa.
- Acrosome creation
- Shedding of cytoplasm
- Middle piece formation ⇒ lost of mitochondria
- Flagellum development
Primordial Follicles
1º oocyte (arrested in prophase I) housed in layer of flat epithelial cells.
Begin to mature into primary follicles at puberty.
Oogenesis
Overview
Primordial follicle ⇒ 1º follicle ⇒ 2º follicle ⇒ 3º follicle ⇒ graafian follicle.
Primary oocyte completes meiosis I three hours prior to ovulation producing a secondary oocyte (haploid, 2N DNA) + first polar body.
FSH surge triggers ovulation.
Secondary oocyte only completes meiosis II if fertilized by sperm.
Formation of
Primary Follicles
- Epithelial cells of primordial follicle become cuboidal ⇒ now considered a primary follicle
-
FSH stimulates 1º follicle to form more cuboidal cells
- Cells now called granulosa cells
- Provides nutritional and hormone support
- Cells now called granulosa cells
Formation of
Secondary Follicles
1º follicle ⇒ 2º follicle when:
- Zona pellucida forms around 1º oocyte
- Mucopolysaccharide layer
- Liquor folliculi accumulates
Primary oocyte and surrounding granulosa cells remain on one side of the follicle.
Secondary Follicle
Characteristics
- Sits on cushion of granulosa cells called cumulus oophorous.
- Provides nourishment and support
- Liquor folliculi continues to accumulates
- Becomes a 3º follicle when the follicular antrum becomes large and filled with fluid
Tertiary Follicle
Characteristics
- Outer thecal cells divide into two layers:
-
Theca interna
- procudes androgens that granulosa cells convert into estrogens
-
Theca externa
- Vascularized
- Provides nutritional support
-
Theca interna
- Continues to enlarge
- Usually only one 3º follicle will become a graafian follicle
Ovulation
3 hours prior to ovulation the 1º oocyte within the graafian follicle will complete meiosis I to form a 2º oocyte.
FSH surge triggers follicle rupture and ovulation.
Releases 2º oocyte, zona pellucida, and corona radiata.
Remaining granulosa cells become the corpus luteum.
Sertoli Cells
Provides protection and nutrition to the developing spermatozoa.
DNA Content
for
Spermatogenesis and Oogenesis
Single-gene
(Mendelian)
Disorders
Disease caused by pathogenic mutations in an individual allele or pair of alleles at a single genetic locus (1 gene).
Chromosomal disorders
Disease due to aberrations of one or more chromosomes.
Two main groups:
Those caused by abnormalities in the number of chromosomes.
Those caused by abnormalities in chromosome structure.
Multifactorial Diseases
Due to the interaction of multiple genes as well as environmental factors.
Do not follow a Mendelian pattern of inheritance.
Acquired Somatic Cell
Genetic Diseases
Results from mutations not present at the time of conception.
Pedigree Symbols
Genetic Relatedness
SNPs
Single nucleotide polymorphism
A single base pair change anywhere in the genome.
SSRs
Simple sequence repeat polymorphisms.
Stretches of DNA with di-, tri-, or tetranucleotide repeat sequences.
The actual number of repeats varies in individuals.
Tandem Repeats
Repeats of ten to hundreds of bases where the number of repeats varies between individuals.
Copy Number Variation
Different numbers of copies of specific DNA sequences.
Hemizygosity
A state where only a single allele exists at a given locus in an otherwise diploid cell.
Ex. normal males are hemizygous for all X chromosome alleles.
Law of Segregation
Parental genes are randomly seperated during meiosis so that each gamete contains only one gene of the pair.
Law of Independent Assortment
Genes for different traits independently seperate from one another during meiosis, giving traits an equal opportunity of occuring together.
Law of Dominance
An organism with alternate forms of a gene wil express the form that is dominant.
Autosomal Dominant
Characteristics
- Assume that affected individuals are heterozygous unless there is other information
- Both a verticle and horizontal pattern of inheritance.
- ♂ and ♀ equal in frequency and severity
- Males can transmit disease
- Offspring of affected individual with 50% chance of inheriting disease
Autosomal Recessive
Characteristics
- ♂ and ♀ equal in frequency and severity
- Pedigree
- Rare trait ⇒ single sibship (horizontal pattern in 1 family)
- Common trait ⇒ scattered families with the trait
- Risk of disease increases with consanguinity
Compound Heterozygote
An individual with 2 different mutated alleles at a given locus.
Obligate Carrier
An individual who by pedigree analysis must carry a gene but otherwise has a normal phenotype.
X-chromosome Inactivation
Dosage compensation for two X-chromosomes in females through transcriptional silencing via non-coding RNA.
- XIST (X-inactive specific transcript) gene expressed by the X chromosome that is undergoing silencing.
- ncRNA produced coats the chromosome that made it.
- Recruits silencing protein complexes.
- Results in DNA methylation and histone hypoacetylation.
- Condensation into a Barr body
XIST only expressed in cells containing 2 or more X chromosomes.
X inactivation is random except for placental cells which undergo imprinted inactivation of the paternal X chromosome.
Results in mosaicism of cells in females.
X-Linked Recessive
Characteristics
-
No male to male transmission
- Affected males with normal sons and carrier daughters
- Mother of sporadic affected male can:
- Be heterozygous
- Have mosaic gametes
- Affected male + heterozygous female could look like autosomal dominant on pedigree
- 1/2 ♂ affected ⇒ likes like ♂ to ♂ transmissions
- 1/2 ♀ affected as severely as hemizygous ♂
X-linked Dominant
Characteristics
- Females affected twice as often as males
- Males often more severely affected than females
- Affected females ⇒ 1/2 of ♂ and 1/2 of ♀
- If the disorder is lethal in utero in hemizygous males
- only see affected females
- affected females have fewer sons than daughters
- affected females have more spontanous abortions
Y-linked Inheritance
Characteristics
- Only males affected
- Only male to male transmission
Male Sex
Determination
- SRY gene codes for sex-determining region Y protein
- Transcription factor causes fetus to develop as a male
- SRY mutations gives rise to XY females with gonadal dysgenesis
- Translocation of SRY gene from Y to X chromosome results in 46,XX testicular disorder of sex development
- Present in phenotypic females who lack functional androgen receptors
Sex-Limited
Trait
A trait that is only expressed in one sex.
Ex. BRCA-1 and BRCA-2 mutations cause ovarian cancer in females only.
Sex-Influenced
Trait
A trait that is expressed differently in the two sexes.
Ex. BRCA-1 and BRCA-2 mutations cause different instances of breast cancer in females and males.
Mitochondrial Inheritance
Characteristics
- Maternally inherited
- No male to male transmission
- Carrier will have both normal and defective mtDNA ⇒ heteroplasmy
- Ratio of defective/normal mtDNA in ova will affect inheritance, severity, and onset ⇒ threshold effect
- Mitochondrial donation ⇒ “three-parent” inheritance
- Female pronuclei of a person with known mitochondrial disease inserted into cell with normal mitochondria
Heteroplasmy
A mixture of two or more mitochondrial genotypes within a cell or individual.
Ratio of normal vs altered mtDNA can influence the severity and timing of disease onset ⇒ threshold effect
Threshold Effect
% of mutant mtDNA must be above a threshold to produce clinical manifestations.
- Threshold varies according to tissue oxidative need
- Brain, heart, and muscle most
- % of mutant mtDNA in daughter cells can shift during cell division ⇒ mitotic segregation
- mtDNA can surpass pathogenic threshold in just one tissue ⇒ skewed heteroplasmy
New Mutations
Sudden appearance of an autosomal dominant or X-linked recessive trait assumed to be a sporadic case caused by a new mutation.
Ex. 1/3 of new cases of Duchene muscular dystrophy (DMD) represent a new mutation.
- De novo mutation in offspring ⇒ nearly zero chance of recurrence
- De novo mutation in parent ⇒ recurrence risk varies and can approach 50%
Mixed Mosaicism
Mutation occurs very early in pre-embryo or embryo before seperation of germline cells from somatic cells.
Can be present in the germ and/or somatic cells.
Can result in phenotypic expression and/or transmission to offspring.
Somatic Mosaicism
Mutation effects somatic cells only.
Will affect the tissue(s) that arise from those cells.
Will have little effect onse the embryo has reached a certain size.
Will not be transmitted to offspring.
Germline Mosaicism
Mutation in germ line cell precursor persists in all the clonal descendant of that cell.
Individuals will have normal phenotype and normal DNA tests but likely to have multiple affected offspring.
Strongly suspected when phenotypically normal parents have two or more offspring with autosomal dominant disease.
Pleiotropy
When a single gene influences multiple phenotypic traits including those that seem unrelated.
Penetrance
The observable expression of a phenotype given presence of a genotype.
All-or-none in an individual.
Reduced penetrance or incomplete penetrance used to describe a population.
Variable Expressivity
The quantitative and qualitative phenotypic differences among individuals who carry the same mutation.
Variation of age of onset
A static mutation could lead to a phenotype that could develop over a broad age range.
Anticipation
Phenotype becomes more severe from one generation to the next.
- Indications of anticipation:
- earlier age of onset with each generation
- increasing severity with each generation
- Usually due to dynamic mutations ⇒ expansion of trinucleotide repeats
- Threshold number of repeats must be reached for disease manifestation
Allelic Heterogeneity
Different alleles of the same gene underlie disease.
May lead to the same disease or a different disease.
Locus Heterogeneity
Mutations in different loci leading to a clinically similar disease.
Epistasis
The expression of one gene depends on the presence or absence of one or more nonallelic “modified” genes.
Means that most phenotypes are affected by more than one gene.
- Whenever two or more loci interact to creat new phenotypes
- Whenever an allele at one locus makes the effects of alleles at one or more other loci
- Whenever an allele at one locus modifies the effects of alleles at one or more other loci
Epigenetics
The study of heritable changes in gene expression that are not due to changes in DNA sequence.
- Changes may be reversible or permanent
- Usually due to DNA methylation
- Can be influenced by environmental events
- During embryogenesis widespread, almost complete demethylation occurs which must be re-established.
Genomic Imprinting
The differential expression of alleles depending on the parental source.
Chromosome structure
Types of
Chromosome Shapes
Acrocentric Chromosomes
Chromosomes 13, 14, 15, 21, 22, and Y
- Have masses called satellites attached to short arm by stalks (secondary constrictions)
- Short arm contains hundreds of copies of genes encoding ribosomal RNA
- Includes nucleolus organizer regions (NORs) critical for nucleolus formation
Idiogram
The numbered banding pattern of a chromosome.
To identify a site on a chromosome, four items are required:
- Chromosome number
- Arm designation
- Region number
- Band number
G-Banding
Use cells in metaphase typically
Use cells in prometaphase for high resolution
Called a karyotype when chromomes put into an ordered arrangement.
- Use phytohemagglutinin (PHA) to include
- Use colchicine to stop cells in metaphase
FISH
(fluorescent in situ hybridization)
- Used to ID structurally abnormal chromosomes
- Can quantify a specific number of copies of a specific DNA segment
- Often used after chorionic villus sampling (CVS) or amniocentesis
- To determine the # of chromosomes 21, 13, 18, X, and Y
- Effective to ID microdeletions
- Need to know what you are looking for
Comparative Genomic Hybridization (CGH)
or
Chromosomal Microarray Analysis (CMA)
- Used as first-tier testing in patients who do not fit a specifically known syndrome
- Can identify copy number changes
- Detects unbalanced chromosomal changes (gains/losses)
- Does not detect balanced structural changes (translocations and inversions)
- Clinical interpretation can be complicated
Chromosomal Abnormality
Types
Numerical anomalies ⇒ abnormal number of chromosomes per cell
Structural aberrations ⇒ a change in the molecular organization of the chromosome. Can be balanced or unbalanced
Aneuploidy
The gain or loss of one or more chromosomes.
Results from nondisjunction or anaphage lag during mitosis or meiosis.
Cell does not contain an integral multiple of 23 chromosomes.
Balanced abberations
A structural chromosomal abnormality with no net change in essential genetic material.
Usually a normal phenotype.
Unbalanced aberrations
A structural chromosomal abnormality with a gain or loss of essential genetic material.
Tranlocation
Definition
A piece of one chromosome becomes inappropriately attached to another.
The resulting chromosomes are called derivatives (der).
Reciprocal translocations
Involves breaks in two different chromosomes with mutual interchange and no apparent loss of chromosomal material.
If no critical material is lost, it is a balanced translocation.
Ex. Philadelphia chromosome and chronic myeloid leukemia (CML)
Robertsonian Translocations
The union of the long arms of two acrocentric chromosomes at the centromeres.
Loss of the repetitive copies of ribosomal RNA in short arms does not constitute a loss of critical DNA.
Are initially balanced.
May result in monosomy or trisomy following gametogenesis ⇒ form unbalanced gametes
Deletions
A piece of chromosome breaks off, does not reattach to any chromosome, and becomes lost in the cell.
A partial monosomy for the deleted region can result.
Clinical impact varied based on affected genes.
Two types:
Deletion ⇒ visible loss of chromosomal material that can be detected by traditional metaphase banding.
Microdeletion ⇒ loss of a smaller amount of chromosomal material only visible with high resolution banding or FISH. Associated syndromes referred to as continuous/contiguous gene syndromes.
Insertions
When a single chromosome breaks and a piece of that chromosome is reinserted elsewhere
Duplications
When a segment of a chromosome is copied and then inserted back into the chromosome resulting in multiple copies.
Inversions
When a chromosome has two breaks liberating a piece that flips upside down and reinserts into the same chromosome.
Most are balanced rearrangements.
Isochromosomes
Chromosome that is missing 1 arm (either p or q) and have a second copy of the remaining arm.
Karyotype Notation
- p ⇒ short arm
- q⇒ long arm
- ⇒ missing
- ⇒ additional
- t ⇒ translocation
- inv ⇒ inversion
- dup ⇒ duplication
- del ⇒ deletion
- / ⇒ seperates two distinct cell lines (e.g. mosaicism)
Triploidy
Chromosomal change with 69 chromosomes (3n).
Usually results in spontaneous abortion.
Caused by dispermy, digyny, diandry, mosaicism.
Dispermy
Fertilization of a haploid egg by two haploid sperms.
Digyny
Fertilization of a diploid egg due to maternal nondisjunction by a haploid sperm.
Diandry
Fertilization of a haploid egg by a diploid sperm due to paternal nondisjunction.
Contiguous gene syndromes
Complex phenotypes apparently resulting from the disturbance of two or more unrelated genes in a chromosomal region to produce a consistent and recognizable phenotype.
Usually detected by FISH or CMA.f
Diagnostic Genetic
Testing
Used to confirm or rule out a know or suspected genetic disorder in a symptomatic individual.
Predictive Testing
Testing of an asymptomatic individual with a family history of a genetic disorder.
Two types:
- Presymptomatic ⇒ eventual development of symptoms is certain when the gene mutation is present
- Predispositional ⇒ eventual development of symptoms is likely but not certain when the gene mutation is present
Carrier Testing
Peformed to identify individuals who carry one copy of a gene mutation.
Can be offered as part of:
- As part of universal screening protochols for diseases such as CF or spinal muscular atrophy
- As indicated by population screening
- Ex. Tay Sachs in Ashkenazi Jews or Irish decent
Preimplantation Genetic Testing (PGD)
Performed very early following in vitro fertilization.
New techniques biopsy and anlyze the polar bodies.
Offered to couples with high change of having a child with a serious disorder.
Prenatal Testing
Performed during pregnancy to asses health status of embryo or fetus.
Available to all pregnant women in US.
Includes US, maternal serum screening, cell-free DNA (cfDNA) analysis of maternal blood, amniocentesis, chorionic villus sampling.
Newborn Screening
Done shortly after birth to identify serious genetic conditions so treatment can be started asap.
Mandatory in the US.
Major Anomaly
Birth defect with a major functional or cosmetic significance.
Minor Anomaly
Birth defect that poses no significant functional, health, or cosmetic burden.
Dysmorphic Features
Trait present at birth that includes mild variations seen in the population.
Isolated Birth Defects
An anomaly affecting a single body site.
Can be inherited in a defined manner but most have multifactorial cause.
Multiple Congenital Anomalies
Two or more unrelated major structural defects occuring in a single child.
A pattern might exist ⇒ a combination of anomalies or dysmorphologies found together in an individual.
Syndrome
A group of well-characterized major and minor anomalites (freatures) that are commonly found together due to a single etiology.
Association
A group of malformations occuring together more often than one would expect based on their individual frequencies but does not have a predictable pattern of recognition and/or a suspected underlying ethiology.
Can be a manifestation of several recognized disorders rather than a distinct anatomic or etiologic entity.
Sequence
A pattern of anomalies derived from a single known defect or mechanical factor, which may have multiple etiologies.
May produce multiple secondary and tertiary anomalies in a cascading fashion.
Developmental Field Defect
Disturbances in the developmental field organization or communication of specifc cells in the embryo results in a pattern of anomalies.
DiGeorge Syndrome
(22q11 deletion syndrome)
Type of developmental field defect caused by inadequate neural crest contributions to the embryonic pharyngeal pouches.
Caused by a microdeletion at 22q11.
CATCH-22:
Cardiac abnormalitiy
Abnormal facies
Thymic aplasia
Cleft palate
Hypocalcemia/Hypoparathyroidism
Chromosome 22
Malformation
Any defect resulting from an error in morphogenesis or an intrinsically abnormal developmental process.
“Abnormal from the beginning.”
Disruption
An anomaly caused by in utero desctruction of a previously normally formed structure.
Can be caused by physical forces, vascular disruptions or clots, and teratogens.
“Started out normal but was destroyed.”
Deformation
An anomaly involving the change in size or shape of an anatomic structure due to mechanical forces that distort an otherwise normal structure.
Generally not caused by a chromosome or single gene abnormality.
“Started out normal then altered but still there.”
Dysplasia
A dysmorphic deffect caused by the abnormal organization or functional of a specific tissue type throughout the body.
Often due to a single gene disorder that impacts embryogenesis.
MTHFR Mutation
SNPs in the Methylene Tetrahydrofolate Reductase (MTHFR) gene can significantly decrease the effectiveness of normal folic acid supplementation.
Expecting mothers need to take bioactive form of folic acid instead.
Teratogenic Agent
A toxin, drug, infectious agent, physical condition, or deficiency where in utero exposure can alter fetal morphology or function.
Factors Affecting
Teratogenicity
- Need for maternal exposure
- Nature of the agent
- Determines the mechanism of transport and action
- Existence of a critical window of exposure
- Dose-related response
- Maternal and embryo genotypes
- Consistent deviation of normal development
Phenocopy
A similar phenotype due to different etiology.
Critical Period
A time in prenatal development during which a particular organ or body part is most susceptible to teratogenic damage.
3-8 weeks gestation is most sensitive to teratogens.
Threshold Effect
Teratogenic effects only occurs once a critical dose or a threshold is exceeded.
Interaction Effect
The effective dose of a teratogen can be altered by the presence of other substances.
Thalidomide
If taken during the critical period 21-35 days after implantation, organogenesis during that time affected in a dose dependent fashion.
Phenotypes:
Symmetrical limb reduction defects
Heart defects
Cleft lip or palate
Ear malformations w/ hearing impairment
Duodenal or biliary atresia
Ionizing Radiation
- Able to penetrate tissues
- Appears to exhibit the “all or none” rule
- Between 2-15 weeks, there is a dose response:
- microcephaly, intellectual disability, cancer
- Later exposure associated with leukemia and severe intellectual disability
Hyperthermia
Effects
- Can result in neural tube defects and growth issues
- In rare cases cause heart, abdominal wall, or oral cleft defects
Congenital Infections
Accounts for 2-3% of congenital anomalies.
Pathogen must be able to cross the placenta.
TORCH infections:
TOxoplasmosis ⇒ parasitic infection from cat feces
Rubella ⇒ worse during 1st trimester
Cytomegalovirus (CMV) ⇒ most will not have signs or symptoms, some w/ severe microcephaly if during 1st, and hearing impairment if during last trimester
Herpes ⇒ most from lesions in birth canal
Environmental/Chemical
Teratogens
-
Anticonvulsants (ex. Dilantin)
- Can lead to fetal hydration syndrome ⇒ intrauterine growth deficiencies
-
Accutane (isotretinoin)
- Causes brain defects, hydrocephalus, heart/limb/face defects, inc spontaneous abortion
-
Antibiotics
- Usually safe except aminoglycosides, tetracycline, and doxycycline
-
Alcohol
- Fetal Alcohol Syndrome (FAS)
- Fetal Alcohol Effect (FAE)
-
Cigarette smoke
- Impacts blood flow to fetus
Maternal Diabetes
-
Type I and II DM have difficulties with BGL control throughout pregnancy.
- Diabetic embryopathy can affect any developing organ system
- Hyperglycemia during 1st trimester increases risk of major malformations by 3-4 fold
-
Gestational DM develops ~ 24 weeks.
- Generally do not have increased risk of malformations
Try to control BGL before pregnancy and throughout gestation.
Take more folic acid.
Polygenic Traits
Traits caused by the combined effects of multiple genes/alleles at different loci.
Ideally, excludes environmental influenes.
Multifactorial Traits
Includes the combined effects of multiple genes at different loci, the environment, and stochastic events.
Multifactorial Inheritance
Factors
- Genes/alleles
- Environmental exposures
- Stochastic events
Categories of Multifactorial Traits
- Discontinuous variation traits:
- Qualitative
- Ex. cleft lip, DM, schizophrenia
- Continuous variation traits:
- Quantitative
- Ex. height, IQ, blood pressure
Liability
The genetic, environmental, and stochastic events that underlie all multifactorial disease.
Threshold of Liability
Model
The phenotype does not develop unless the individual crosses a threshold through the cumulative effects of genetic, environmental, and stochastic components.
Multifactorial Disease
Recurrence Risks
Empirical risks determined by direct observation of prevalence in the population.
Differ substantially from one population to another.
- Decreases rapidly in more remotely related relatives.
- If more than one close family member, recurrence risk higher in that family.
- If phenotype severe, recurrence risk higher.
- If trait more common in one sex, offspring of less freq. sex has a higher recurrence risk
- Recurrence risk for relatives of affected person increases as population risk decreases
Heritability
(H2)
How much genetic factors play in the varibility of a specific trait in a specific population and a specific environment.
Genes play no role ⇒ H2 = 0
Genes completely control the trait ⇒ H2 = 1
Use familial aggregation studies, twin/sibling/adoption studies for condordance and correlation, animal models.
Thrifty Genotype Hypothesis
Links the current high prevalence of obesity and type 2 DM to selective events in human evolution.
Thought that certain advantagous genetic variants that allowed survival during periods of erratic food supply now increase risk of disease.
