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human genetics

Terms

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copy deck
Metacentric
centromere is at the middle of the chromosome
p arm
Short arm
q arm
Long arm
Submetacentric
centromere is slightly at the end of the chromosome
Acrocentric
centromere is at the end of the chromosome
Satellites
protect DNA from degradation.
Chemical Stains
used in determining which chromosomes are partners depending on their banding patterns; not easy to do if bent, curved (GIEMSA banding)
FISH
fluorescence in situ hybridization; uses probes for determining locations of certain genes in chromosomes.
Chromosome painting
use of multiple fluorescent probes for determining multiple gene loci
Mitosis
normal form of cell division; daughter cells are genetically identical
Meiosis
a specialized reductive cell division giving rise to sperm and egg cells; daughter cells are genetically different as a result of independent assortment of homologs and recombination.
Meiosis I
Duplicated maternal and paternal homologs undergo synapsis by pairing together to form bivalents.
Chiasmata
Recombination occurs at these cross-over points.
Meiosis II
chromosomes separate again, but in the absence of DNA duplication (46-23 chromosomes)
Non-disjunction
abnormal chromosome segregation
Muscle cells
have naturally occurring polyploidy cells in the body
Polyploidy
lethal in fertilization
Triploidy
dispermy; diploid ovum; diploid sperm (nn, n; 2n,n; n,2n)
Tetraploidy
normal fertilization, DNA duplication but no cell division aneuploidy (one extra chromosome)
Mixoploidy
2 distinct genetic lineages within one individual
Mosaicism
- fertilization-> genetic change (non-disjunction) -> trisomy, etc. -> cell lineages arise from same zygote.
Chimerism
fertilization (2 separate fertilization events)-> fusion or exchange of cells (happens early in development- fusing of twins) -> cell lineages rise from different zygotes
Aneuploidy
arises due to non-disjunction during cell division; common in meiosis but can also happen to mitosis (single chromosome in individual)
47+21
(2n+1) Down Syndrome; autosomal aneuploidy (one extra chromosome)
47+13
(2n+1) Patau Syndrome
47+18
(2n+1) Edward Syndrome
45, X
(2n 1) Turner Syndrome (monosomy); sex chromosome aneuploidy (45, XO; missing 1 x- chromosome, no Barr body).
47, XXY
(2n+1) Klinefelter Syndrome
48, XXYY
(2n+2)
47, XXX
(2n<>1) Triplox Syndrome
Cri du chat syndrome
deletion of part of chromosome 5p; terminal deletion
Continuous gene syndrome
multiple genes are involved in the formation of phenotype.
Williams Syndrome
microdeletion of the 7q11.23 region
Duplication
overexpression of genes
Deletion
underexpression of genes
Paracentric
2 breaks in the same arm which excludes centromere. Outcomes of meiosis include normal, inverted, dicentric and acentric.
Dicentric
two centromeres; spindle fibres can still separate them
Acentric
no centromeres; fertilization with normal gamete will not be viable due to loss of material.
Pericentric
2 breaks in different arm therefore includes centromere. Outcomes of meiosis include normal, inverted, terminal deleted, and terminal duplicated.
Inversion carriers
balanced but at a risk of producing gametes with unbalanced chromosome.
Translocations
segment from one chromosome detaches and attaches itself to another. If balanced, no net gain or loss of chromosomal material, therefore no effect on the phenotype unless gene is disrupted.
Robertsonian translocation
occurs in acrocentric chromosome (13, 14, 15, 21, and 22). It is formed by the fusion of 2 acrocentric chromosomes at the centromere. End result is that the person will have 45 chromosomes. Fertilization by a normal gamete results to a normal, balanced carrier, partial trisomy for chromosome 1, partial monosomy for chromosome 1, partial trisomy for chromosome 2, partial monosomy for chromosome 2.
Reciprocal translocation
acentric fragments exchanged -> stable in mitosis; centric and acentric fragments exchanged unstable in mitosis. Balanced translocation will result to normal, balanced translocation, partial monosomy and partial trisomy.
Burkitt's lymphoma
caused by a reciprocal translocation; upregulated expression of structurally normal MYC protein
Law of segregation
- two copies of the gene separate so that each gamete receives only one copy
Law of independent segregation
alleles of different genes are assorted independently of one another during gamete formation. It does not take linkage into account.
Autosomal dominant inheritance
both males and females affected; both can transmit to offspring. Affected person usually has one affected allele.
Vertical transmission
affected individuals in each generation.
Achrondoplasia-
autosomal dominant condition; full penetrance; dwarfism; AA (lethal form), Aa (viable form), aa (normal). Incomplete dominance.
Marfan syndrome
autosomal dominant condition that shows allelic heterogeneity
Allelic heterogeneity
different mutant alleles same phenotype therefore difficult to determine the mutation in gene based on the phenotype. (MD and CF)
CFTR
(cystic fibrosis transmembrane regulator) regulates the flow of Cl- towards the epithelial cells.
Autosomal recessive inheritance
can be both male and female as carries therefore need to generate many generations and intermarriages to be found in pedigrees. Parents are likely unaffected therefore the trait may appear sporadically and without prediction. If both parents are affected, all offspring will be affected.
Heterozygous cross
one gene AaxAa
X-linked disorders
not absolutely dominant/recessive
X-inactivation
allows for dosage compensation. It occurs randomly and independently by each cell during embryogenesis. Each daughter cell then expresses the same X. Heterozygous female is a mosaic of both alleles.
X-linked recessive inheritance
- affects mainly males. Usually born to unaffected parents (mother may have affected male relatives) and females may be affected if the father is affected and mother is a carrier, or by non-random x-inactivation. No male to male transmission.
X-linked dominant inheritance
affects females more than males; females are mildly/ variably affected. Females have a 50% chance to transmit to offspring. Affected males will have 100% affected daughter.
Hemizygosity
1 X chromosome
Congenital Generalized Hypertrichosis (CGH)
x-linked dominant; passes y to son; daughter will have 100% chance of getting it.
Incontinentia pigmenti
affected females show patchy, mosaic involvement of tissues such as skin; cells become susceptible to apoptosis; lethal in male offspring.
Y-linked inheritance
affected males always have affected father (unless new mutation)
Red/green colour blindness
sex-linked trait
Hemophilia A
- recessive; if female hemophiliac is biochemically abnormal, but phenotypically normal.
Duchenne Muscular Dystrophy
is an x-linked condition. Manifesting heterozygote - female is carrier; highly mutable.
Incomplete dominance
1 allele produces a phenotype in the heterozygote that is intermediate between that of either homozygote.
Gene dosage effect
can be seen in the severity of the phenotype
Comparative genomic hybridization (CGH)
or Chromosomal Microarray Analysis (CMA) is a molecular-cytogenetic method for the analysis of copy number changes (gains/losses) in the DNA content of a given subject's DNA and often in tumor cells. CGH will detect only unbalanced chromosomal changes. Structural chromosome aberrations such as balanced reciprocal translocations or inversions cannot be detected, as they do not change the copy number.
Cytogenetic analysis
allows researchers to profile chromosomal aberrations such as amplifications, deletions, rearrangements, point mutations, copy number changes, and copy-neutral loss of heterozygosity (LOH) events.
bivalent
sometimes referred to as a tetrad, is a pair of associated homologous chromosomes held together by a complex after chromosome replication. During meiosis (the Prophase I stage of Meiosis I), the process of synapsis occurs in which these are formed. Each replicated chromosome is composed of two chromatids.
familial hypercholestorolemia
hereditary; mutations in the LDL receptor (blood cholesterol uptake); number of receptors is directly related to the genotype (CLEAR DOSAGE EFFECT).
codominance and multiple alleles
a gene can have >2 alleles but a diploid individual only has 2 of them. Different allele combinations can produce different phenotypes/ symptoms.
codominance
heterozygote expresses phenotypes of both homozygotes. Neither allele is dominant.
Reduced/incomplete penetrance
dominant condition is not observed; environmental condition; individuals do not express a trait even though they have the genotype.
Age-related penetrance
Huntington's disease (autosomal dominant). Phenotype does not manifest itself until adult life; progessive neurodegenerative disorder. Probability that an individual carrying the disease gene will have developed symptoms by age 30.
variable expressivity
degree of severity (mild to severe) varies between different members of the family ; combinations of phenotype.
anticipation
type of variable expressitivity. It is the tendency for some variable dominant conditions to become more severe, or have an earlier onset, in successive generations. Mutation is not stable from generation to generation. It is caused by the expansion of the TNR more likely due to slipped strand mispairing. Severity of onset correlates with repeat length which tends to grow as the gene is transmitted down the generations.
Slipped strand mispairing
polymerase jumps back expanding the region adding length to the repeats
fragile- x syndrome
normal allele for FMR1 but 5' end of gene has CpG islands which tend to get hypermethylated (hotspots for mutations) causing no production of the protein which is needed for normal neurological development. affects more boys than girls. First methylated C acts as a recruiter for 2nd methylated C.
methylation
central to genomic imprinting which leads to unusual inheritance patterns. Certain genes are marked or tagged with their parental origin and this determines their expression (only 1 allele is expressed). It is a reversible form of gene inactivation (not a mutation).
epigenetic effect
a change in the gene expression that does not depend on a change in DNA sequence.
Prader-Willi syndrome
mother's 15q cannot compensate for dad's loss of 15q
Angelman syndrome
dad's 15q cannot compensate for mom's loss of 15q
Uniparental disomy
child inherits both copies of single chromosome from one parent due to a non-disjunction in meiosis II.
trisomy rescue
one chromosome is lost to form a normal, diploid chromosome complement.
mitochondrial dna
maternally transmitted; homoplasmic and heteroplasmic
matrilineal inheritance
sperm do not contribute mitochondria to zygote
heteroplasmy
mixed population of normal and mutant genomes. Different variations depend which replicates more resulting to differnt phenotypes. May lead to some offspring being clinically affected although all inherit mutant DNA.
dilution
phenotypic manifestation of genotype (normal vs mutant) depends on the number of mtDNA present and severity depends on how far away it is from the threshold.
Homoplasmic
all children inherit mutant DNA; no affected male transmits disease.
Monogenic/Mendelian
presence or absence of character depends on genotype at a single locus
multifactorial/complex
character may be influenced by two or more loci as well as environmental factors
oligogenic
small number of loci
polygenic
large number of loci
PKU
autosomal recessive, screening for this involves growing cultures on RBC on agar lawn and halo develops on plate
locus heterogeneity
the same clinical phenotype can result from mutations at any one of the several different loci
clinical heterogeneity
mutations in the same gene produce 2 or more disease in different people
Pleiotropy
one mutation has many different effects on the same person ie Waardenburg
Discontinuous traits
individuals can be placed in discrete classes. Trait is either present or absent. ie height and weight
continuous traits
continuum of expression, no discrete classes, measurable. eg BMI
polydactyly
reduced penetrance, multifactorial ****the greater the number of possible influences, the farther it is from Mendelian inheritance patterns
threshold trait
appears as discontinuous but is a function of underlying continuous genetic and environmental variation.
proband
the person of interest to the genetic councillor
concordant
2 related individuals in a family with the same disease
discordant
when only one member of the pair of relatives is affected
concordance
used to determine the total phenotypic variance that is due to genetic variation.
heritability
indicates the relative contributions of genes and environment to variation in a specific trait.
monozygotic
identical, single fertilized egg
dizygotic
fraternal, separate fertilized egg
multigene families
originate through gene duplication (copy # variation between individuals of the same family) during the course of evolution. it may also occur via unequal crossover or unequal sister chromatid exchange
pseudogenes
also arise from duplication events. defective gene copy that contains multiple exons of a functional gene.
Xist
remains active on an inactive chromosome. It produces RNA which remains in nucleus and binds to the inactive x-chromosome. Role in epigenetic gene regulation: helps condense chromosome to form Barr body.
microRNA
novel small RNA molecules.
heterochromatin
long arrays of high copy # tandem DNA repeats ie satellite (centromeres), minisatellites (telomeres) and microsatellite.
retrotransposons
LINES, SINES, retrovirus like elements that are transposon-derived repeats.
microsatellites
can be used to detect tandem repeat polymorphisms since patterns of repeats are inherited. PCR size depends on the # of repeats you have
transposable elements
can influence gene expression: my provide new upstream regulatory sequences, insertion within an intron may promote antisense transcription, and it may be incorporated as an alternative exon (via cryptic splice donor and splice acceptor sites).
SNPs
most abundant type of genetic variant. Most SNPs have 2 alternative forms (ie alleles)
mutations
any change in nucleotide sequence or arrangement of DNA
missense mutations
the new nucleotide alters the codon so as to produce an altered amino acid in the protein product.
silent mutations
a change in any one of the nucleotides in a codon which encode the same protein therefore causing no change in their product and cannot be detected without sequencing the gene (or its mRNA).
nonsense mutations
the new nucleotide changes a codon that specified an amino acid to one of the STOP codons. Therefore, translation of the messenger RNA transcribed from this mutant gene will stop prematurely.
CpG nucleotides
CG islands that are hotspots for mutations.
point mutations
changes in a DNA sequence caused by substitution of one nucleotide for another
frame-shift mutation
mutation that shifts the "reading" frame of the genetic message by inserting or deleting a nucleotide
dynamic mutations
trinucleotide repeats become unstable and expand during gametogenesis, through a DNA replication error known as SSM. MUTATIONS ARE NOT THE SAME FROM ONE GENERATION TO THE NEXT
myotonic dystrophy
Autosomal dominant, trinucleotide repeat of CTG.
heterozygote advantage
also known as balancing selection, arises when there is a survival (selective) advantage for hybrids (heterozygotes) as compared to that of either homozygous recessive genotype or homozygous dominant genotype. Some diseases are lethal only in the homozygous state. In the example of cystic fibrosis, heterozygotes may be more resistant to life-threatening dehydration caused by diseases such as cholera, which is accompanied by massive diarrhea. Another example is the high frequency of heterozygotes for sickle cell anemia in Africa (and increased resistance to malaria).
Splice-site mutations
The removal of intron sequences, as pre-mRNA is being processed to form mRNA, must be done with great precision. Nucleotide signals at the splice sites guide the enzymatic machinery. If a mutation alters one of these signals, then the intron is not removed and remains as part of the final RNA molecule. The translation of its sequence alters the sequence of the protein product.
high penetrance
low allele frequency (single gene)
low penetrance
high allele frequency (multiple + environment)
linkage analysis
based on recombination events found in pedigrees (single mendelian inheritance pattern).
recombination
tells us how closely two loci are associated (distance to each other). The closer they are, the lesser the chances of this.
haplotype
the set of alleles whose phase is in coupling at closely linked loci (a combination of genes or DNA sequences that are inherited as a single unit)
recombination fraction
the statistical measure of the distance between loci. loci are on different chromosomes will assort independently and θ=0.5. loci that are on the same chromosome (syntenic) may have a decreased cross-over θ=0.1 -probability that a two locus haplotype is not transmitted intact.
linkage phase
the positioning of linked alleles
coupling
linked alleles on the same homologue
repulsion
linked alleles on different homologues
marker
polymorphic character used to follow chromosome segment
cytological maps
banding patterns on chromosome; Map that locates genes with respect to chromosomal features
genetic maps
places genes on cytological/chromosome map using measurements that reflect the amount of recombination between loci. It is constructed using molecular markers and is measured in centimorgans.
physical map
places genes on cytological/chromosome map using measurements that reflect actual distance between loci. It is constructed using nucleotide sequences and is measured in bp and megabases.
association analysis
population based, does not rely on recombination and instead on those that have NOT undergone recombination. Increased or decreased frequency of particular allele (s) in a sample of affected individuals compared to unaffected people in a population.
RRR
relative risk ratio; ratio of frequency of disease in those that have susceptibility allele to frequency of disease in those that do not have susceptibility allele.
direct causation
allele A makes you susceptible to disease D
fitness epistasis
people with disease D more likely to survive with A
population stratification
D and A are more frequent in one subset
linkage disequilibrium
A is present on an ancestral chromosomal fragment that carries a sequence variant causing susceptibility to D; 2 alleles appear more often/less by chance, change in haplotype frequency , INDIVIDUAL FREQUENCIES REMAIN THE SAME
GWAS
genome wide association studies , Genome-wide association studies - used to ID susceptibility genes for common diseases - involves thousands of samples, case-control or family trios, using scads of SNPs, this approach to discovering that a DNA variant is associated with disease begins with a comprehensive screen of genetic markers, requires large scale screening of case-controls, requires validation studies, and is not associated with a preconceived hypothesis.
Sanger sequencing
Dideoxynucleotides halt DNA polymerization at each base, generating sequences of various lengths that encompass the entire original sequence. Terminated fragments are electrophoresed and the original sequence can be deduced.
capillary sequencing
elecrophoresis through capillary containing polyacrylamide detection of fluorescently labeled products at a real time manner
pyrosequencing
This sequencing method does not require making a sequencing ladder and relies on the generation of light utilizing Luciferase as the reporter. This greatly increased the speed of processing in DNA sequencing No gels, dyes, or ddNTPs needed
single molecule sequencing
approach to determining the sequence of a polymer using only a single molecule
copy number variation (CNV)
Identified differences in copies of small to medium regions of DNA (1kbase - 5Mbase). Many of these have been identified using Array CGH. It is another source of genetic variation that is implicated in disease, and copy number changes which can be detected.
genome capture
targeted sequences, add linkers, hybridize to micro-array, remove not hybridize, amplify what is left.
Array-CGH
hybridization target is a microarray of normal genomic DNA, which may provide complete coverage of entire genome or high resolution cover of a specific region.
population screen
:Identifies heterozygotes—people with one copy of a mutant gene, Ex: College students are offered testing for sickle cell disease carrier status
diagnostic testing
used to determine a specific disease condition or possible illness
newborn screening
tests performed to help early detection of disease, especially genetic disorders, at birth. It helps identify babies with rare but treatable diseases. eg PKU, CF
prenatal screening
Non-invasive - maternal serum (16weeks), Ultrasound (18weeks). Invasive - amniocentesis (16weeks), Chorionic villus sampling (10-12 weeks), Detects neural tube defects which are congenital conditions involving malformations in the spinal cord or skull., look for recognizable chromosomal or genetic defects in the growing fetus by a Maternal Blood test (eg. Alpha-fetoprotein levels- elevated incases of neural tube defects, decreased in cases of certain trisomies; used mostly for down-syndrome.
ultrasonography
using the reflections of high-frequency sound waves to construct an image of a body organ (a sonogram). Increased fetal nuchal translucency is consistent with trisomies 21,13 and 18.
amniocentesis
A technique of prenatal diagnosis in which amniotic fluid, obtained by aspiration from a needle inserted into the uterus, is analyzed to detect certain genetic and congenital defects in the fetus.
CVS
Chorionic Villi Sampling: 8-10 weeks, Invasive, Risk to embryo
preimplantation diagnosis
is a technique used to identify genetic defects in embryos created through in vitro fertilization (IVF) before transferring them into the uterus
carrier screening
Indiscriminate examination of members of a population to detect heterozygotes for serious disorders.
personalized medicine
An individual's genetic make-up can impact the response to a medicine , as well as what side effects are likely to occur Determine drugs based on a patient's genetic profile instead of trial and error to decrease the likelihood of adverse reactions
manifesting heterozygote
a female heterozygous for an X-linked disorder in whom, because of unfavorable X inactivation, the trait is expressed clinically with about the same severity as in hemizygous affected males.

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