Genetic Inheritance Flashcards
Genes
Segments of DNA in a chromosome, Each gene occupies a specific place, or locus (plural, loci)
Chromatid
One of two identical copies of a chromosome.
Centromere
Connects identical sister chromatids.
Telomere
Is a region at the end of a chromosome for stability.
Human somatic cells
Diploid cells that are differentiated. There are over 200 types of differentiated human somatic cells.
Gametes
Are haploid
Stem cells
Undifferentiated cells that can divide into two diploid cells..
Homologous chromosomes
Refer to pairs of chromosomes.
karyotype
- Entire set of a patient’s chromosomes.
- 46 chromosomes shown in the karyotype are in each of the patient’s diploid cells, unless mosaicism occurs.
- Normal human karyotype is written 46XY.
- Each chromosome in the karyotype is presented as a single condensed or as a duplicated chromosome.
Mosaicism
Is a condition in which cells from a patient have different genotypes (& karyotypes): - Downs Syndrome: some 46XX; some 47XX,+21 - Klinefelter Syndrome: some 46XY; some 47XXY - Turner Syndrome: some 46XX; some 45XO
Lyonization
Is called X- inactivation. The choice of which X chromosome to be inactivated is random.
Interphase
Chromosome duplication (E.C.C)
Cell division
One copy of each chromosome and 1⁄2 of the cytoplasm/organelles are distributed between the two daughter cells. (E.C.C)
Meiosis
Reduces the total number of chromosomes by half, producing four gametes.
Consists of: one round of DNA replication and two rounds of nuclear divisions.
Homologous recombination (meiosis)
Can produce new combinations of genes.
Non-disjunction
Is the failure of one or more pairs of homologous chromosomes, or sister chromatids, to separate normally during division.
Autosomes
Chromosomes common
in both genders, one from each parent.
Sex chromosomes
- X, female
- Y, male
Meiosis creates genetic diversity in 2 ways:
- Random segregation of
homologs. - Cross-over exchange.
Nondisjunction
Meiotic Errors
Homologs fail to separate properly. - Common and increase with advancing maternal age. - Cause of spontaneous abortions and mental retardation.
Aneuploid (Meiotic Errors)
Cells with abnormal chromosome number. - Trisomy 21 (Down syndrome): most common cause of mental retardation. - In 90% of trisomy 21 patients, the additional chromosome is maternal. - 70% occur during MI - 30% in MII
Euploid (Meiotic Errors)
Cells with normal number of chromosomes.
Genomic Imprinting
- Imprinted genes = methylation = down regulated. - Two chromosomes from same parent that have parent-specific imprinting = no gene product (Deletion of non-imprinted genes).
Two different outcomes of deletion on chromosome 15.
- If paternal chromosome is deleted = Prader Willi syndrome. - If Maternal chromosome deleted = Angelman syndrome.
Pedigree analysis
Mechanisms of inheritance from family history.
Gene defect
Etiology of a disease.
Molecular diagnosis
Disease from a patient’s tissue/fluid samples.
Personalized medicine
Optimal course of treatment.
Population genetics
Allele and disease frequency.
Genotype
- An individual’s genetic
makeup.
EX: Individuals with distinct
genotypes can have a
single phenotype
(Cystic Fibrosis).
Phenotype
- What is actually observed.
EX: Individuals with the
same genotype can
have multiple
phenotypes (PKU).Pedigrees
- Proband (propositus): First diagnosed person in the pedigree. - Arrow denotes the proband. - (Slide 22 & 23)
Autosomal Dominant Inheritance
- Only 1 allele of a gene is needed for expression. - Affected offspring has one affected parent. - Unaffected individuals do not transmit trait. - Males and females can transmit trait to both males and females – autosomal. - Trait is expected in every generation - Recurrent risk is 50% EX: Postaxial Polydactyly
Punnet Square
for Autosomal Dominant Inheritance
- Affected female mates with unaffected male. - Combinations of alleles from the fertilization of egg by sperm. (Slide 25)
Autosomal Dominant: Pedigree
- Affected offspring have one affected parent. - Unaffected individuals do not transmit trait. - Both males and females can transmit trait to both males and females. - Trait is expected in every generation at 50%. (Slide 26)
Autosomal Recessive Inheritance
- 2 copies of a gene is
needed to influence
phenotype.
EXAMPLE: TYROSINASE-NEGATIVE ALBINISM
Punnet Square
for Autosomal Recessive Inheritance
- Carrier female mates with carrier male. - Resulting combinations of alleles from the fertilization of egg by sperm. (Slide 28)
Autosomal Recessive: Pedigree
- Affected individuals have normal parents - Recurrent risk for heterozygote parents is 25%. - Both males and females may be affected. - Affected individuals who mate with normal individuals tend to have normal children. - Occurrence is more likely among individuals who share genes, as with consanguinity (first cousin mating). (Slide 29)
X-linked Recessive
males, one X females, two X
- Disease allele on X in males is termed “hemizygous.” - Females can be heterozygous or homozygous. - Unaffected males don’t transmit the trait (no carriers) - Female carriers transmit the disease allele to 50% of sons and 50% of daughters - All daughters of affected males are heterozygous carriers. EXAMPLE: DUCHENNE MUSCULAR DYSTROPHY
X-linked Dominant
- Very rare; no carriers.
- Males with the disease allele
transmit the trait:- only to females
- 100% transmission
- Females with the disease
allele transmit the trait:- To both males and females
- 50% transmission to
offspring
EXAMPLE: HYPOPHOSPHATEMIA
- Low phosphorus in blood due
to defective reabsorption of
phosphate in kidney Deficient
absorption of calcium in
intestines causes softening of
bone (Rickets) - Vitamin D metabolism
abnormal Short stature - Incidence: 1/60,000
Treatment: oral phosphate &
vitamin D
Reduced Penetrance
- The frequency a gene manifests itself is called penetrance - In some cases, 100% of individuals inheriting a genetic defect show the clinical presentation (phenotype) of the disease (100% penetrance) - In other cases penetrance is less than 100% EXAMPLE: RETINOBLASTOMA: autosomal dominant inheritance Phenotype occurs in 90% of individuals inheriting gene defect; so 90% penetrance.
Variable Expressivity
- Term used to describe the range of phenotypes that vary between individuals with a specific genotype. EXAMPLE: NEUROFIBROMATOSIS - Develop tumor-like growths called neurofibromas - Patients have café-au-lait spots – pigmented areas the color of coffee with cream (spots differ in number, shape, size and position).
Locus Heterogeneity
- Single disorder, trait, or
pattern of traits caused by
mutations in genes at
different chromosomal loci
EXAMPLE:
OSTEOGENESIS IMPERFECTA
- Brittle-bone disease.
- Mutations in
collagen genes (two loci:
chromosome 7 and 17),
either mutation exhibits
the same phenotype.Basic Concepts of Probability
Probability helps us: - Understand transmission of genes thru generations. - Analyze genetic variation in populations. - Conduct risk assessment (for genetic counseling)
Probability
- Is defined as the proportion of times that a specific outcome occurs in a series of events. - As proportions, probabilities are between 0 and 1. EXAMPLE: - coin tossing: the probability of ‘Heads’ is 1⁄2, of ‘Tails’ is 1⁄2 - meiosis: the probability that a given member of a pair of chromosomes will be transmitted is 1⁄2, the other is 1⁄2. - Gender: the probability of producing a girl is 1⁄2, a boy is 1⁄2.
INDEPENDENCE PRINCIPLE
Multiplication Rule & Addition Rule
MULTIPLICATION RULE
Probability of a given outcome in multiple trials is the product of the probabilities of each trial outcome.
EX: What’s the probability of producing three girls? 1⁄2 x 1⁄2 x 1⁄2 = 1/8 What’s the probability of producing three boys? 1⁄2 x 1⁄2 x 1⁄2 = 1/8
THE ADDITION RULE
Probability of either one outcome or another is the sum of the two probabilities.
EX: Probability of producing either three girls or three boys? 1/8 + 1/8 = 1⁄4
Gene & Genotype Frequencies
- Measure and understand population variation in the incidence of genetic disease. - Under simple conditions these frequencies can be estimated by direct counting.
Gene Frequencies
Specify the proportions of each allele in a population.
Genotype Frequencies
Specify the proportions of each genotype in a population.
Slide 39
Hardy- Weinberg Principle
- Specifies the relationship between Gene Frequencies and Genotype Frequencies - Useful in estimating Gene Frequencies from Disease Prevalence Data and in estimating the incidence of heterozygous carriers of recessive disease genes - In the previous example (MN blood group), due to co-dominance, the three genotypes can be easily distinguished, blood-typed and counted. (Slide 40 & 41)
Cystic Fibrosis
- In recessive disease, only the affected homzygotes, with genotype aa, are distinguishable - H-W tells us that the frequency of aa should be q2. - The incidence of CYSTIC FIBROSIS (in European population) is 1/2500 = q2. - Therefore, q = 1/2500 = 1/50 = 0.02 - Because p + q = 1, then p = 0.98 - 2pq equals about 1/25, suggesting a lot of recessive disease alleles are effectively “hidden."
Autosomal Dominant Inheritance
Is characterized by vertical transmission of the disease phenotype, a lack of skipped generations, and roughly equal numbers of affected males and females. Father-to- son transmission may be observed.
Autosomal Recessive Inheritance
Is characterized by clustering of the disease phenotype among siblings, but the disease is not usually seen among parents or other ancestors. Equal numbers of affected males and females are usually seen, and consanguinity may be present.
Consanguineous
- Mating’s that are more likely to produce offspring affected by rare Autosomal Recessive Disorders. - Studies show that mortality rates among the offspring of first-cousin mating's are up to 9% higher than those of the general population.
Multifactorial Inheritance: Basic Model
- Traits in which variation is t thought to be caused by the combined effects of multiple genes are called POLYGENIC (“many genes”) - When environmental factors cause variation in the trait, the term MULTIFACTORIAL is used. - Because these traits are caused by the additive effects of many genetic and environmental factors, they tend to follow a normal, or bell-shaped, distribution in populations. (Slide 45)
Multifactorial Inheritance: Threshold Model
- For diseases that do not follow the bell- curve distribution there is an underlying liability distribution. - For multifactorial diseases that are either present or absent, it is thought that a threshold of liability must be crossed before the disease is expressed. - Below the threshold, the person appears normal - Above the threshold, the person is affected by the disease. (Slide 46)
Pyloric Stenosis
- Muscular hypertrophy
between stomach and
duodenum – leading to
vomiting and obstruction
- Five times more common in
males than females.
- Males need less risk genes
to show disease; females
need more risk
genes.
- The least affected sex has a
higher risk threshold and
transmits the
condition more often to the
most frequently affected
sex.
- Children of women with
pyloric stenosis are more
likely to be born with
condition (especially
males)
- Children of affected males
with pyloric stenosis are
less likely to be born with
condition.Recurrence Risks
And Transmission Patterns
- In contrast to most single-
gene diseases, recurrence
risks for multifactorial
diseases can change
substantially from one
population to another - This
is because gene
frequencies as well as
environmental factors can
differ among populations
› The recurrence risk is
higher if more than one
family member is affected
› If the expression of the
disease in the proband is
more severe, the
recurrence risk is higher
› The recurrence risk is
higher if the proband is of
the less commonly
affected sex
› The recurrence risk for the
disease usually decreases
rapidly in more remotely
related relativesMultifactorial vs Single- Gene Inheritance
- Multifactorial Disease is caused by the simultaneous influence of multiple genetic and environmental factors. - In some cases, a trait may be influenced by the combination of both a single gene with large effects and a multifactorial background in which additional genes and environmental factors have small individual effects. (Slide 48)
