Biochemistry 2 Flashcards
Autosomal trait is one wherein the gene is localized to
chromosome 1-22 (autosomes) rather than sex-linked (X or Y) or mitochondrial
3 classes of genetic disorders
- monogenic, unifactorial or Mendelian trait
- multifactorial trait
- chromosomal disorder
Monogenic, unifactorial, or Mendelian trait
defined as one produced by a single gene. It might be autosomal or sex linked or mitochondrial, depending on the location of the gene
Multifactorial
one produced by multiple genes and environmental factors
Chromosomal disorder
where an entire chromosome (or large portion of it) is missing, duplicated or altered.
OMIM
“online mendelian inheritance in man” is recognized as the authoritative source of information abut human genes and genetic traits
gene
DNA sequence that codes for the amino acid sequence of one or more polypeptide chains. It specifies an inherited trait.
Locus (loci)
the location in the chromosome of a particular gene
Allele
one or more alternative forms/DNA sequences that a gene may have in a population
Allele is a _________ on a theme
variation
For one gene, there can be many ________ that are slightly different at the ___ level.
alleles, DNA
Principle of Segregation (First Law)
sexually reproducing organisms possess genes in pairs and only one of each pair is transmitted to a particular offspring
In the first law, genes remain
Intact and distinct in the next generation. Previously, hereditary factors were thought to become blended in new offspring.
New offspring can, in turn, __________ the intact genes inherited from tis parents to subsequent generations
transmit
Principle of Independent Assortment (second law)
genes that reside at different loci are transmitted independently. an allele transmitted at one locus has no influence on which allele is transmitted at another locus
exception: genes that are very close on the same chromosome can be transmitted together
Gregor Mendel proved that the effect of one allele may?
mask those of another
dominant
allele that determines how the trait will appear in an organism
recessive
allele that is present in the genome but is phenotypically masked by the dominant allele when present together
Homozygous
having two identical alleles for a given gene
HH or hh
Heterozygous
having two different alleles for a given gene
Hh
dominant allele is written?
uppercase and the recessive allele is lowercase
Punnett square
diagram that allows to predict the outcome of a particular breeding experiment
Probabilities are very important in?
Genetic counseling. they are routinely used to provide couples with an understanding of the risks of producing a child with a genetic disorder.
Probability defined as the
proportion of times a specific outcome occurs in a given number of events
ex: the probability of rolling a 2 on a die is 1/6
In meiosis, each allele has a _______ change probability of being transmitted to the offspring
50%
Principle of independence
each probability is independent of every other
What are the chances of having a boy? If two parents have produced 6 girls, what are the chances of having a boy with number 7?
1/2 for both
Multiplication Rule (AND)
In two independent trials, the probability of obtaining a given outcome in both trials is the product of their independent probabilities.
What is the probability of having two girls
1/2 x 1/2 = 1/4
Addition rule (OR)
if we want to know the probability of one outcome OR the other, we add the probabilities together
What is the probability of having two girls or two boys?
Probability of first event (two girls) + probability of second event (two boys) = 1/4 + 1/4 = 1/2
Allele frequency
how often a particular allele occurs in a population
ex: T and t
genotype frequency
how often a given genotype occurs in a population
ex: TT and Tt and tt
Population information example
in a large population, most individuals will have the non-mutated allele for a CF mutation and will have virtually 0% chance of passing on a mutant allele
Individual information example
If John Doe is known to carry a CF mutation, the frequency of this mutation in his offspring will be 50% since he has a 50% chance of passing on the gene with each child.
When family history is available, we use it to calculate gene and? If not available?
genotype frequency. If not available, we use the Weinberg principle
HW principle
states that the frequency of the alleles in a population is mathematically related to the frequency of genotypes in a population according to the equation
HW equation
HW principle requires several conditions with respect to the population:
large population
random mating
no mutations, migration, or natural selection
Pedigrees
one of the most common tools that geneticists use to understand the transmission of a genetic disease
Pedigrees diagrams that show the relationship among the members of a family, and show which?
family members are affected with the disease and which appear unaffected
Pedigrees are typically based on
observed phenotype and are not fool proof.
Proband
first person in the pedigree to be identified clinically as having the disease in question
1st degree relatives
related to the proband through a sibling relationship (brother/sister) or by being the parent of the proband
2nd degree relatives
persons separated from each other by one additional generational steps. example: grandparents, grandchildren, aunts/uncles, and nephews/nieces
3rd degree relatives
persons separated from each other by two additional generational steps. example: great grandchildren, great grandparents, first cousins
Autosomal dominant diseases are relatively?
rare in human population, with maximum allele frequencies of 0.001 (0.1%)
Autosomal dominant requires only one
diseased allele for manifestation of the diseased phenotype
non-enzymatic structural proteins is an example
autosomal dominant. collagen is an example, or protein comments of membranes or receptors.
ex: Ehler’s Danlos syndrome
Dominant
a genetic variant that causes a recognizable phenotype in the homozygous and heterozygous state
complete dominance
one allele completely masks the other. Example: Huntington disease (HH = Hh)
Huntington’s disease is considered an example of complete dominance because a person only needs to inherit one copy of the mutated gene (from one parent) to develop the disease, meaning even if they have a “normal” copy of the gene from the other parent, the mutated gene will still manifest the disease, demonstrating complete dominance in its inheritance pattern
Incomplete dominance
most cases: one allele does not completely mask the other and the result in somewhere in between (blended)
ex: familial hypercholesterolemia or achondroplasia (HH does not equal Hh)
codominance
neither allele masks the other, and the result in a little of each (not blended)
ex: presence of antigens A, B, both or none for ABO blood type
recessive
a genetic variant that causes a recognizable phenotype only in the homozygous state
Characteristics of Autosomal Dominant Diseases
- Males and females are equally affected and equally likely to transmit the trait to their offspring
- Affected individuals transmit the trait to approximately half of his or her offspring. Unaffected couples do not transmit the trait to their offspring.
- No skipping generations (vertical transmission).
- Male to male transmission. This excludes X linked inheritance.
Autosomal Dominant Pedigree
Huntington disease (HD) gene
HD or huntingtin. HD is a trinucleotide repeat expansion disease. The function of he protein encoded is unknown.
HD symptoms
progressive dementia, intellectual disabilities, choreic movements and late age of onset
Incidence of HD
variable but highest in western European ancestries
Occurence risk
the risk of producing an affected child when no children have yet been produced
Recurrence risk
the risk of producing an affected child when one or more children with the disease have already been produced
When one parents is affected by an autosomal dominant disease and the other is not, the occurrence risk is?
1/2. The likelihood of producing an affected child from this type of mating is not influenced by previous events.
Achondroplasia is autosomal ______
autosomal dominant
Autosomal dominant gene for achondroplasia
FGFR-3 gene (fibroblast growth factor receptor gene 3), thought to be a gain of function mutation
Achondroplasia symptoms
short limbed dwarfism, characteristic faces and radiological features of the spine
Achondroplasia: as much as
90% of patients studied are the result of new mutation in the gene
homozygotes are much more
severely affected than heterozygotes. This is true for all dominant diseases except for Huntington’s Disease.
We will assume that in dominant diseases, affected individuals are
Aa, and NOT AA
Neurofibromas type 1 and type 2 are
autosomal dominant
what are the Neurofibromas type 1 and type 2 genes?
NF1 and NF2, respectively
NF1 and NF2 symptoms
cafe au lait spots, fibromatous skin tumors and increased risk of malignant tumors
-as much as 50% of patients studied are the result of a new mutation
Marfan syndrome
autosomal dominant
Marfan syndrome gene
FBN1 (fibrillin)
Marfan symptoms
disproportionate tall stature, araechnodyactly (flexible fingers), skeletal abnormalities, and serious CV system problems
approximately 25% of patients studied are the result of a new mutation in the gene
Familial hypercholesterolemia is
autosomal dominant
Familial hypercholesterolemia gene
LDL receptor gene, loss of function mutation
Familial hypercholesterolemia symptoms
heterozygous: elevated levels of LDL cholesterol in plasma –> deposition of cholesterol in the tendons and skin and, later in life, in the arteries leading to an increased risk of coronary artery disease
homozygous: similar clinical features only much earlier and more extreme.
Death due to MI is common during childhood.
autosomal recessive inheritance
requires both diseased alleles to manifest a disease phenotyope
parents of affected children of autosomal recessive inheritance will usually be both?
heterozygous carriers
In an autosomal recessive fashion, a recessive gene and a non-mutated gene will be?
Carrier, but healthy
Most autosomal recessive diseases characterized to date have been mutations in genes that encode?
enzymes
(AR) There appears to be a margin of safety wide enough to allow?
normal function in heterozygotes even though only pair of alleles is fully functional
Loss of function mutations (3 things)
- Haplosufficient
- Haploinsufficient
- Dominant negative
Haplosufficient.
______ inheritance
50% activity (Aa) is enough to avoid disease. Recessive inheritance.
Haploinsufficient
________ inheritance
50% activity (Aa) is not enough to avoid disease. Dominant inheritanace
Dominant negative
homo-oligomerization results in 0-49% activity (Aa), not enough to avoid disease
Dominant inheritance.
Gain of function mutations are _________ inheritance
dominant
Dominant negative mutation
not only is the mutant gene product is inactive, but it also interferes with the activity of the normal gene product, resulting in 0-49% activity. It often occurs in genes whose products must function as multimers.
Characteristics of Autosomal recessive inheritance
- Disease is usually seen in one more more siblings, but not in earlier generations (no vertical transmission). There is usually no prior family history.
- Males are females are equally affected.
- On average, 1/4 of the offspring between two heterozygotes carriers will be affected
- Consanguinity may be present, especially in rare autosomal recessive disease
A 1/4 risk means that, after birth of an affected child, the next three children will be unaffected. True or false?
false, 1/4 risk for each individual
Autosomal recessive pedigree
