MOI = X-linked recessive

Used to describe a disease state and the mode of inheritance.

Duchenne Muscular Dystrophy

(DMD)

X-linked recessive

Genetic lethal - boys have no offspring

Can assume via Haldane's rule that mutation rates in males and females are equal:

- 1 in 3 affected boys due to new mutation

- 2 in 3 mothers are carriers

• A trait is dominant if it is phenotypically expressed in heterozygotes i.e. carriers express disease.
• A disease will have a dominant MOI if product from a heterozygote is NOT enough to cross the threshold (have disease if below threshold).

A trait that is expressed only in homozygotes and compound heterozygotes, NOT in carriers.

A disease will have a recessive MOI if product from a heterozygote IS enough to cross the threshold.

• Genes, traits determined by genes located on the X chromosome
• Incidence is much higher in males
• Transmitted by affected male to all his daughters to carry (carrier females)
• Verticle pattern, often jumps generations
• Ex: Rett syndrom - lethal in males, only seen in females (as carriers)

Appearance of increasing disease incidence, severity or earlier onset in successive generations with a heritable disorder.

Caused by expansion of the number of unstable repeates within the gene responsible for the disease i.e. Triple repeat expansion.

Ex: Fragile X Syndrome, DM, Spinocerebellar Ataxias, HD

Individual composed of cells derived from two genetically different zygotes.

Ex: Recipient of a bone marrow transplant from a donor

Karen from boston's kids are her deceased in utero DZ sister's. She absorbed her DZ sister's germline cells. 

The presence in males of a single allele at X-linked loci.

Genotype of an individual with only one representative of a chromosome or chromosome segment, rather than the usual two.

Trait appears to be inherited exclusively through females.

All offspring will probably be affected.

Variable expression & can show a lack of penetrance.

Not passed on from affected males.

Mitochon is densely packed with important genes and has high mutation rate. Accounts for disproportionally high # of diseases.

Can result in heteroplasmy.

Germline and somatic mosaicism.

Tissue has two or more cell lines of different genotype derived from a single zygote.

Patchy diseases - ex: Biaschko's lines - unusual pigmented patterns

Mutation in germline so doesn't show up in blood.

 Impacts Haldane's Rule.

Is shown by traits that are determined by a combination of multiple factors, genetic and usually also environmental.

Recurrance risk is higher the more family memberss that are affected.

Ex: 1. At least 71 loci assoc. with Crohn's disease.

2. Cancer (5% are familial)

3. Venous thrombosis

Tends to run in families with recurrence rates less than in single genes diseases.

All or none expression of a genetic disease genotype.

Fraction of individuals with a genotype known to cause a disease who have any signs or symptoms of the disease.

Multiple phenotypic effects of an allele or gene on tissues/systems not ordinarily thought to be related.

Reflects diversity of cell types that use a common molecular pathway for transcriptional regulation.

Gene with effects on multiple organ systems.

Ex: unrelated co-occurance of nearsightedness and malformation of the sternum in Marfan Syndrome

The occurance together in a population of two or more alleles, each at a frequency greater than 1%.

Useful in linkage studies.

Examples include 2 major classes:

1. Single Nucleotide Polymorphisms (SNP's)

2. Microsatellites (variable # of tandem repeats, VNTRs)

1. X-linked recessive disease

2. No affected maternal relatives with disease

3. Disease has reduced fitness

Classic example: DMD (x-linked genetic lethal)

and Hemophilia A (x-linked, f<1)

(1-f)u/2u+v where f=effective fertility

u = female mutation rate

v = male mutation rate

A particular genotype at one locus is both necessary and sufficient for the character to be expressed, given an otherwise normal genetic and environmental background (no other factors contribute).

Occurs in 1.25% births.

For about 200 genes, gender of origin is important.

In these genes one allele is imprinted (methylated) in one gender and so is not expressed.

Ex: Paternally imprinted gene means that only the maternally inherited allele is expressed.

Occurs though misdivision in meiosis and subsequent chromosomal loss.

Fetus would have 2 non-functional allele inherited from same parent.

Increase in number of nucleotide repeats.

Recurrence depends on size of repeat, which changes btwn generations.

Ex: Huntington Disease and Fragile X syndrome

Associated w/ dynamic mutations.

Earlier onset or increasing severity with each successive generation.

Explains tendency for repeats to increase in number through meiosis.

Are from these two phenomena:

1. Mosaicism

2. Chimerism

Turns off (methylates) one of the X chromosomes in each cell of a female to equilibrate the X-linked gene production by the two genders. Irreversible.

Thus both M and F have ONE ACTIVE X chromosome.

Occasionally by chance a critical # of normal X are inactivated in a female X-linked recessive mutation carrier and results in mild disease.

Predisposing allele to Alzheimer disease along with other genetic and environmental factors.

Not all e4 homozygotes have Alzheimers and not all patients with Alzheimers have the APOE e4 allele.

Example of Multifactorial inheritance pattern.

Interaction between Prothrombin (F2) alleles interact with environmental factors.

Ex: women with certain gene mutation should avoid taking contraceptives which in combination increase risk for venous thrombosis.

Example of an inheritance pattern btwn single and quantitative genes.

Genotype at 2 genes contributes to manifestation of the disease; all affected patients are mutated at both genes

The proportion of phenotypic variance caused by additive genetic variance.

Estimate of the degree to which relatives resemble one another

A correlation coefficient which can be calculated using Normal distribution statistics.

More accurate measurement can be taken from Identical (MZ) twins raised apart. Although genetically same, diff environ factors and epigenetics will result in their diverging characteristics.

Bayes Theorem

Definition

Bayes Theorum

Calculation

X is a carrier            X is not a carrier

prior                A                            1-A=B

conditional      C = modifies risk       D=usually 1

joint               AC                            BD

posterior        (AC)/(AC+BD)            (BD)/(AC+BD)

Quantitative Traits

(Multifactorial inheritance)

Are traits and diseases that are not inherited in a simple Mendelian fashion nor associated with chromosomal abnormalities, but in which this is considerable evidence that genetic factors play an important role in their causation.

Ex: Height (heritability of 0.8) and weight

Two mutually exclusive events.

Add together.

Probability of having a boy or a girl = p+q

Independent events, probability of the second does not depend on the first.

Probability of having two boys = p x q

Linkage analysis

-used when there are too many mutation, gene is too large or if disease gene is mapped to a locus but no yet identified.

-assumes pedigree is accurate.

1. Mutation

2. Polymorphism

3. Rare genetic variation

Allele/mutation at a frequency of 1% or greater.

2% or more of individuals will carry at least one autosomal copy.

A way of flaggin chromosomes.

Ex: 1. SNP's

2. Microsatellites

Distance between genes, measured in cM.

1cM represents 1% chance of a crossover.

1cM = 1 million bp

Value of 50cM indicates loci are on different chromosomes or sufficiently far apart and thus not linked.

A recombination event - reciprocal exchange of segments btwn chromatids of homologous chromosomes

If marker within gene (intragenic) are close together then more likely for crossing over to occur btwn them.

On avg. 3 crossovers per chromosome per generation.

IN MEIOSIS!

recombination hotspots.

Knowing whether two allels at different loci were inherited by the same parent (are on same strand of DNA)

Cis (coupling) = on same strand

Trans (repulsion) = on opposite strands

Genes/loci close together on the same segment of chromosome are said to form haplotypes.

Tend to travel together through meiosis.

Crossovers seldom occur.

Disease assoc. haplotype ordinarily spans a region of DNA of a few kb to a few 100 kb.

Tendency of specific combination of alleles at 2 or more linked loci to occur together on same chrom more frequently than would be expected by chance.

If found btwn marker and a disease then disease gene must be physically close to the marker.

Recombination btwn loci is very rare.

Decays with recombination distance and time (generations).

Gives statistical measure of how likely the disease gene and marker are a certain distance apart (θ).

Max lod score (>3) gives best estimate of dist. btwn them.

The smaller the θ the closer the marker is to the disease gene.

The best markers have high lod score (>3) and θ of zero - ie. not expected to recombine.

When parents are homozygous (1/1 or 2/2) you cannot "flag" the bad allele because all progeny are 1/2.

Cannot predict fetal phenotype from fetal genotype.

Parents are heterozygous.

assuming no recombination, the disease phenotype can be predicted by knowing the marker genotype of the fetus, as can the carrier status.

2/2 affected, 1/2 carrier, 1/1 "normal"

1/1 and 2/2 are carriers 50% of time.

1/2 will have 50% risk of being affected:

1/2 or 1^m/2^m

1. Linked extragenic markers - tag on string tied to suitcase. Use direct analysis.

2. Intragenic Markers - tag on suitcase. Assume no recomb.

3. Disease causing mutation - bomb.

Exception = DMD - such big gene, intragenic markers may still have signif recomb rate with disease causing mutation