Unit 2 Day 1 Flashcards
What does a family history consist of information wise?
- Biological relationships between family members
- any medical conditions they may have
What can a family history reveal?
- Patterns of inheritance
- what type of inheritance may be part of a condition
- distinguishing btw. conditions with similar presentations
How many generations should be included in a family history?
3 (if in doubt)
genotype
- an individual’s collection of genes. The term also can refer to the two alleles inherited for a particular gene. The genotype is expressed when the information encoded in the genes’ DNA is used to make protein and RNA molecules.
- the DNA sequence*
phenotype
- an individual’s observable traits, such as height, eye color, and blood type. The genetic contribution to the phenotype is called the genotype. Some traits are largely determined by the genotype, while other traits are largely determined by environmental factors.
- refers to observed traits*
dominance
- the phenomenon whereby, in an individual containing two allelic forms of a gene, one is expressed to the exclusion of the other.
- phenotype that is expressed in the heterozygous state*
recessive
- relating to or denoting heritable characteristics controlled by genes that are expressed in offspring only when inherited from both parents, i.e., when not masked by a dominant characteristic inherited from one parent.
- a phenotype that is expressed only in homozygotes or hemizygotes*
semidominant
One of a series of terms applied to the phenotypic effect of a particular allele in reference to another allele (usually the standard wild-type allele) with respect to a given trait. An allele “A” is said to be semidominant with respect to the allele “a” if the A/A homozygote has a mutant phenotype, the A/a heterozygote has a less severe phenotype, while the a/a homozygote is wild-type. An example is Pmp22(Tr-J) in mouse. Pmp22(Tr-J)/Pmp22(Tr-J) animals display a myelination defect associated with a “trembler” phenotype, while Pmp22(Tr-J)/Pmp22(+) animals are less severely affected, and Pmp22(+)/Pmp22(+) animals are wild-type.
when the heterozygous phenotype is intermediate btw the 2 homozygous phenotypes
single-gene disorders
When a certain gene is known to cause a disease, we refer to it as a single gene disorder or a Mendelian disorder. For example, you may have heard of cystic fibrosis, sickle cell disease, Fragile X syndrome, muscular dystrophy, or Huntington disease.
Mendel’s First Law
The principle of segregation (First Law): The two members of a gene pair (alleles) segregate (separate) from each other in the formation of gametes. Half the gametes carry one allele, and the other half carry the other allele.
Mendel’s Second Law
The principle of independent assortment (Second Law): Genes for different traits assort independently of one another in the formation of gametes.
penetrance***
the percentage of individuals with a given genotype who exhibit the phenotype associated with that genotype. For example, an organism may have a particular genotype but may not express the corresponding phenotype, because of modifiers, epistatic genes, or suppressors in the rest of the genome or because of a modifying effect of the environment.
the fraction of individuals with a trait genotype who show manifestations of the disease
expressivity***
measures the extent to which a given genotype is expressed at the phenotypic level. Different degrees of expression in different individuals may be due to variation in the allelic constitution of the rest of the genome or to environmental factors.
the degree to which a trait is expressed in an individual (severity)
pleiotropy***
occurs when one gene influences two or more seemingly unrelated phenotypic traits, an example being phenylketonuria, which is a human disease that affects multiple systems but is caused by one gene defect. Consequently, a mutation in a pleiotropic gene may have an effect on some or all traits simultaneously.
some mutations–>multiple and different phenotypes. different than variable expressivity
homozygous
2 identical alleles at a given locus (wt or mutant)
heterozygous
2 different alleles at a given locus
hemizygous
mostly refers to males (XY) who have just a single copy of each X-chromosomal gene
autosomal dominant
pattern of inheritance characteristic of some genetic diseases. “Autosomal” means that the gene in question is located on one of the numbered, or non-sex, chromosomes. “Dominant” means that a single copy of the disease-associated mutation is enough to cause the disease.
autosomal recessive
one of several ways that a trait, disorder, or disease can be passed down through families. An autosomal recessive disorder means two copies of an abnormal gene must be present in order for the disease or trait to develop.
mitochondrial inheritance
They are maternally inherited because they are supplied by the egg at fertilization. Mitochondria contain their own their own DNA, including 39 genes that are susceptible to mutations at a rate 10-20 times higher than nuclear DNA.
x-linked dominant
a mode of genetic inheritance by which a dominant gene is carried on the X chromosome.
x-linked recessive
a mode of inheritance in which a mutation in a gene on the X chromosome causes the phenotype to be expressed in males (who are necessarily heterozygous for the gene mutation because they have one X and one Y chromosome) and in females who are homozygous for the gene mutation, see zygosity.
not male-to-male transmission
What are the major patterns of Mendelian inheritance?
autosomal dominant
autosomal recessive
sex linked/x-linked recessive
age dependent penetrance
the likelihood of manifesting the disease in mutation carriers is dependent on age
sex influence and sex limitations
the manifestation of a trait is dependent on the individual’s sex
environmental factors
some environmental factors can affect the expression of Medellian diseases
modifier genes
genetic factors that influence a phenotype
stochastic effects
random effects can influence the expression of phenotypes
phenocopies
same phenotypes (as genetic condition) due to non-genetic factors
human genome structure
3x10^9 base pairs distributed on 46 nuclear chromosomes
how many pairs of chromosomes are there?
23
how many autosomes?
22
how many sex chromosomes?
1 pair
What can mutations in the beta globin gene cause?
variety of disorders in hemoglobin
How many exons are in the beta globin gene?
3
What are mutations in BRCA1 responsible for?
cases of inherited breast cancer, or breast and ovarian cancer
What are mutations in beta-myosin responsible for?
inherited hypertrophic cardiomyopathy
Globing-How are they expressed?
as a function of development. they are turned on or off in the gene. In Chromosome 11 they are turned on in the order they appear in the genome (unusual)
What types of genes are retained?
genes that are adaptive
genotype+environment=phenotype
What is the significance of random variation?
fuel of evolution
almost always a deleterious consequence
but allows for variation/evolution
How many mutations occur in each individual?
~30
When are genes shuffled/recombined?
Meiosis
produces somatic and germ line DNA changes
What composes the majority of the human genome?
stable regions
AT rich regions (54%)
What is clustering?
non-random distribution of GC rich and AT rich regions as a basis for chromosomal binding patterns
allows for G banding
How much of the genome is translated?
1.5% for protein coding
how much of the genome is made of genes?
20-25% (exons, introns, flanking sequences)
What is a more relaxed region called?
Euchromatic
where gene sequencing is focused
What is a more condensed region called?
Heterochromatic (repeat rich areas)
essentially unsequenced
Tandem repeats
“satellite DNA”
used as basis for cytogenetic banding
found as part of human-specific heterochromatic regions on the long arms of Chr 1, 9, 16, Y (hotspots for evolution)
alpha satellite repeats
171 bp repeat unit
near centromeres
may be important in chromosomal segregation in mitosis and meiosis
dispersed repetitive elements
insert and become pseudo genes
retrotransposition may cause insertional inactivation of genes
facilitate abberant recombination events btw diff copies of dispersed repeats leading to disease
segmental dynamic mutation
non-allelic homologous recombination btw blocks of segmental duplication during meiosis that leads to micro deletion/duplication of unique region bracketed by the duplication
insertion-deletion polymorphisms
minisatellites (tandem repeat 10-100bp blocks, VNTR)
microsatellites (di, tri, tetra nucleotide repeats)
single nucleotide polymorphisms
also known as simple nucleotide polymorphism, (SNP, pronounced snip; plural snips) is a DNA sequence variation occurring commonly within a population (e.g. 1%) in which a single nucleotide — A, T, C or G — in the genome (or other shared sequence) differs between members of a biological species or paired chromosomes.
copy number variations
variation segments of genome
can range from one extra copy to many
array comparative genomic hybridization
gene family
composed of genes with high sequence similarity that may carry out similar but distinct functions
how do gene families arise?
through duplication. allows one copy to vary while the other carries out critical functions
copy number variations
primary type structural variation
may cover 12% of genome
implicated in many diseases
what are they types of constitutional abnormalities
de novo, sporadic
familial
m phase
where we visualize metaphase of chromosomes
many macromolecules doubled
kinectochore
protenatious complex that allows pulling apart of chromosomes into daughter cells
How is ISCN written?
label arm (p, q)
then region
then band
human chromosome pairs are numbered 1022 autosomes, arranged by size and centromere position, sex chromosomes (x, y)
metacentric
these are X-shaped chromosomes, with the centromere in the middle so that the two arms of the chromosomes are almost equal. A chromosome is metacentric if its two arms are roughly equal in length.
submetacentric
having the centromere situated so that one chromosome arm is somewhat shorter than the other.
acrocentric
having the centromere situated so that one chromosomal arm is much shorter than the other
all short arm often is is repetitive, satellite sections
from where do you get the best chromosomes for banding study?
from peripheral blood-highest resolution
other types: bone marrow (smallest), amniotic (middle length)
ploidy
number of homologous chromosome sets present in cell or organism
dipoid
has 2 sets of chromosomes (46)
haploid
has 1 set of chromosomes (23)
euploidy
good ploidy-has full set of chromosomes
polyploidy
many ploidy, having chromosome number that is more than double the basic or haploid number (69, etc)
aneuploidy
not good aploidy-incomplete set
trisomy (47), monosomy (45)
When can aneuploidy occur?
during meiosis 1 (maternal/paternal)
during meiosis 2 (maternal/paternal)
post zygotic (after fertilization, anytime)
what are the basic steps of meiosis?
- Before meiosis begins, the chromosomes are in a threadlike form.
Each chromosome make identical copy of itself, forming two exact halves called chromatids. The chromosomes then thicken and shorten into a form that is visible under a microscope. The nuclear membrane disappears. - Each chromosome is now made up of two chromatids, the original and an exact copy. Similar chromosomes pair with one another, forming homologous chromosomes
pairs. The pair homologous chromosomes line up at the equator of the cell. - The chromosomes separate from their homologous partners and move to the opposite ends of the cell.
- The nuclear membrane re-forms, and the cell divides. The paired chromatids are still joined.
- Each cell contains one member of each homologous chromosome pair. The chromosomes are not copied again between the two cell divisions.
- The chromosomes line up at the equator of each cell.
- The chromatids pull apart and move to the opposite ends of the cell. The nuclear membrane forms around the separated chromosomes, and the cells divide.
- The results: four new cells have formed from the original single cell. Each new cell has half the number of chromosomes present in the original cell.
meiotic recombination
2-3 cross over events (chiasma)
pair of homologous chromosomes
each event generates a physical link btw. homologues that is critical for normal disjunction
where does genetic variability arise from?
recombination meiotic prophase 1
independent assortment of maternal/paternal chromosomes
what are tolerated aneuploidies?
conceptions: 45X; trisomy 16, 21, 22
Births: trisomy 13, 18, 21
sex chromosome aneuploidy (gain/loss)
trisomy 21
associated advanced maternal age
most common (1 in approx 800-900)
majority result of maternal meiosis 1 nondisjunction errors
trisomy 18
small, abnormalities, die in first year, 1/8000 births
turner syndrome
most common spontaneous abortions
1/2500 female births
only 1 x
can have mosaicism (tissues and whole person)
kleinfelter syndrome
47 xxy 1/1000 men paternal or maternal mosaicism in tissues, variants more x's can mean more severe phenotypes
triploidy
in karyotypes of 1-3% conceptions
mostly from 2 sperm in 1 egg
some could be 2n sperm or egg
69 chromosomes
mosaicism
2 or more diff karyotypes individual/tissue
caused mostly by nondisjunction
if it occurs later it’s better
germ line mosaicism
mitotic nondisjunction in germ cell precursor
pseudomosaicism
occurs in laboratory, not in patient somatic cells
