(oct 22) Genomic Imprinting & Parental Effects: Mechanisms and Examples

How can two copies of a gene inherited from different parents have identical DNA sequences yet differ in activity?

They can carry different regulatory or epigenetic states established during parental gametogenesis.

What do the terms "maternal copy" and "paternal copy" indicate about a gene?

The parent of origin through which the gene was inherited (egg or sperm), not the sex of the offspring in which it functions.

What is the fundamental difference between genotype and phenotype?

Genotype is the genetic constitution at a locus, whereas phenotype is an observable or measurable physical, physiological, or molecular characteristic.

Does an uppercase symbol for an allele automatically indicate dominant inheritance?

No; allele symbol capitalization does not inherently establish ordinary dominant inheritance.

What defines epigenetic regulation?

Heritable or persistent changes in gene activity associated with DNA and chromatin modifications that occur without altering the underlying DNA sequence.

Why is a stable epigenetic mark in a somatic cell not automatically transmitted to future generations?

Somatic epigenetic marks persist through mitosis, but transgenerational transmission requires surviving germline reprogramming during gametogenesis.

What is a CpG site in mammalian genomes?

A DNA locus where a cytosine base is immediately followed by a guanine base along the same single strand ($5'\text{-CpG-}3'$).

Why is "methylated means inactive" an inaccurate general rule in gene regulation?

DNA methylation at a regulatory boundary can block repressor binding, which frees enhancers to activate neighboring gene expression.

What structural units are formed when nuclear DNA wraps around histone proteins?

Nucleosomes, which alter local chromatin accessibility and regulatory protein binding.

How do small interfering RNAs (siRNAs) and microRNAs (miRNAs) regulate gene expression?

They guide regulatory protein complexes to specific target RNA or DNA sequences to induce cleavage, translational suppression, or chromatin modification.

What are two primary functions of long noncoding RNAs (lncRNAs) in cellular regulation?

Recruiting chromatin-modifying protein complexes and directly influencing gene transcription or RNA stability.

What protein binds unmethylated DNA at imprinting boundaries to establish chromatin insulators?

CTCF protein.

What defines genomic imprinting?

An epigenetic mechanism in which allele expression depends on whether the allele was inherited from the mother or the father.

Why might an imprinted gene be silenced in brain neurons but active in liver cells?

Imprinting patterns can vary depending on tissue type and developmental stage.

What is the key functional difference between a differentially methylated region (DMR) and an imprinting control region (ICR)?

A DMR is any locus displaying parent-of-origin methylation differences, whereas an ICR specifically exerts a functional regulatory role over an imprinted domain.

What happens to inherited genomic imprints during mammalian germline development?

They are erased and then re-established according to whether the germ cells develop into eggs or sperm.

If a male inherits an imprinted allele from his mother, what imprinting state will that allele possess when he passes it to his offspring?

A paternal imprinting state, because it is reset during spermatogenesis.

In standard genomic imprinting analysis, which parent determines the expression state of a transmitted allele in the offspring?

The immediate parent who transmitted the allele in that specific cross.

Which chromosomal region is altered in both Prader-Willi syndrome and Angelman syndrome?

Chromosome region 15q11-q13.

What primary molecular loss causes Prader-Willi syndrome?

Loss of expression of active paternal genes in the 15q11-q13 region.

What primary molecular loss causes Angelman syndrome in brain neurons?

Loss of functional maternal UBE3A expression.

What is uniparental disomy (UPD)?

A genetic condition where both copies of a chromosome pair (or chromosomal segment) are inherited from a single parent.

Why does maternal uniparental disomy of chromosome 15 cause Prader-Willi syndrome despite a normal diploid copy number?

Because both copies originate from the mother, leaving the paternally expressed genes in 15q11-q13 completely silent.

In the standard fetal development model, what are the reciprocal imprinting expression states of IGF2 and H19?

IGF2 is expressed from the paternal allele, while H19 is expressed from the maternal allele.

What type of functional product is encoded by the H19 gene?

A long noncoding RNA (lncRNA).

Where is the imprinting control region located relative to the IGF2 and H19 genes?

Between the IGF2 gene promoter and the downstream shared enhancers.

Why is maternal IGF2 silenced while maternal H19 is expressed?

The unmethylated control region allows CTCF to bind and form a boundary that blocks downstream enhancers from reaching IGF2, directing them to H19.

Why is paternal IGF2 active while paternal H19 is silenced?

Methylation of the control region prevents CTCF binding, allowing shared downstream enhancers to access IGF2, while paternal H19 is repressed.

How is the long noncoding RNA H19 processed to regulate placental growth?

It contains the sequence for microRNA miR-675, which is released by targeted cleavage to repress target genes like Igf1r.

If a mutation prevents CTCF from binding the maternal H19/IGF2 control region, what effect is predicted for maternal IGF2?

The maternal IGF2 promoter gains access to the downstream enhancers and becomes expressed.

What defines a maternal effect in genetics?

A phenomenon where the mother's genotype determines the phenotype of her offspring through products or conditions provided in the egg or uterine environment.

How does maternal inheritance differ from a maternal effect?

Maternal inheritance is the direct genetic transmission of organelles (like mitochondria) solely through the mother, whereas a maternal effect involves the mother's nuclear genotype shaping offspring development.

Why can an embryo with a functional paternal gene copy still fail early development due to a maternal effect mutant allele?

Because early embryogenesis relies on maternal gene products deposited into the egg before the embryo's own nuclear gene is transcribed.

What gene mutation is linked to congenital eye abnormalities in Irish soft-coated wheaten terriers?

A lysine deletion in the RBP4 gene (p.K30del precursor / K12del mature protein).

What is the physiological role of the RBP4 protein?

Transporting retinol (a form of vitamin A) in the bloodstream.

What combined maternal and offspring genotype requirement causes the reported RBP4 eye abnormality in dogs?

Both the dam (mother) and the puppy must be homozygous for the deletion allele ($d/d$).

If a homozygous deletion ($d/d$) female dog is crossed with a homozygous normal ($N/N$) male dog, what percentage of puppies will display small eye abnormalities?

0%, because all puppies inherit $N$ from the father and are heterozygous ($N/d$).

If a heterozygous ($N/d$) female dog is crossed with a homozygous deletion ($d/d$) male dog, why do zero offspring develop RBP4 eye defects?

Because the mother is not homozygous deletion ($d/d$), failing the maternal genotype requirement.

What are the genomic copy ratios of maternal to paternal genomes in angiosperm embryo and endosperm tissues?

The embryo is $1\text{m}:1\text{p}$ (diploid), whereas the endosperm is $2\text{m}:1\text{p}$ (triploid).

What is the aleurone layer in a maize seed?

The outermost cell layer of the endosperm that accumulates anthocyanin pigments.

How does allele transmission direction affect aleurone pigmentation for sensitive maize R alleles?

Maternal inheritance of the R allele produces solid aleurone color, whereas paternal inheritance produces mottled, weaker color.

Why is observing a 2:1 ratio of maternal to paternal RNA reads in endosperm tissue insufficient to prove genomic imprinting?

Because endosperm naturally contains two maternal genome copies for every paternal copy ($2\text{m}:1\text{p}$), expecting a 2:1 RNA ratio under equal expression per allele copy.

What phenotypic effect does paternal expression of dosage effect defective1 cause in developing maize seeds?

An immediate paternal influence (xenia) on seed weight.

What is the core premise of the parental conflict hypothesis for the evolution of genomic imprinting?

Maternally and paternally inherited alleles experience conflicting evolutionary selection pressures over maternal resource allocation to offspring.

Why do paternally inherited alleles generally favor higher maternal resource investment in offspring compared to maternally inherited alleles?

Because the father has lower genetic relatedness to the mother's future offspring by other males, favoring maximum extraction for current offspring carrying his allele.

Is a difference in underlying DNA sequence required for evolutionary parental conflict between alleles?

No; alleles with identical DNA sequence experience conflicting evolutionary interests based solely on their parental origin and relatedness to half-siblings.

Why does a decrease in seed protein concentration percentage not automatically mean total protein yield per hectare decreased?

If total seed biomass yield increases significantly, overall protein mass produced per hectare can rise even if protein percentage drops.

What physical phenotype characterizes Callipyge sheep?

Marked muscle hypertrophy and enlargement of muscle fibers, particularly in the hindquarters.

What specific parental allele combination causes the Callipyge phenotype under polar overdominance?

Heterozygosity with maternal normal allele ($N$) and paternal Callipyge variant ($CLPG$), written $N^{\text{mat}}/CLPG^{\text{pat}}$.

Why do homozygous Callipyge sheep ($CLPG/CLPG$) lack the double-muscling phenotype?

Maternally expressed noncoding transcripts and microRNAs counter paternal gene expression in homozygotes.

If a $CLPG/N$ ram mates with an $N/N$ ewe, what percentage of lambs are predicted to exhibit the Callipyge phenotype?

50% of lambs (those receiving paternal $CLPG$ and maternal $N$).

If a $CLPG/N$ ram mates with a $CLPG/N$ ewe, what percentage of offspring are predicted to show the Callipyge phenotype?

25% of offspring (the $N^{\text{mat}}/CLPG^{\text{pat}}$ genotype).

If a homozygous Callipyge ram ($CLPG/CLPG$) mates with a normal ewe ($N/N$), what percentage of lambs will express the Callipyge trait?

100% of lambs (all inherit paternal $CLPG$ and maternal $N$).

Can a ram that inherited the $CLPG$ variant from his mother pass the Callipyge phenotype to his offspring?

Yes; upon transmission through his sperm, the allele acquires paternal imprinting status and activates the phenotype in $N^{\text{mat}}/CLPG^{\text{pat}}$ offspring.

What specific molecular mutation causes the Callipyge phenotype on sheep chromosome 18?

A single nucleotide substitution from A to G in an intergenic noncoding region within an imprinted domain.

Which two paternally expressed protein-coding genes are upregulated in Callipyge sheep muscle?

DLK1 and PEG11 (also known as RTL1).

What does "identity by descent" (IBD) mean in genetic mapping?

DNA segments in different individuals are identical because they were inherited from a shared recent common ancestor without recombination.

What is synteny in genomics?

The conservation of gene order and chromosomal positioning across different species.

What gene mutation causes double-muscling in Belgian Blue cattle?

A coding frame deletion in MSTN (myostatin) that inactivates the muscle growth inhibitor protein.

How does the Texel sheep MSTN mutation increase muscle mass without altering the protein coding sequence?

A $G \to A$ substitution in the 3' UTR creates a target site for miR-1 and miR-206, leading to microRNA-mediated repression of myostatin translation.

How does the pig IGF2 regulatory mutation influence muscle growth?

It increases postnatal IGF2 transcription in muscle specifically when inherited from the sire.

What is the primary purpose of executing a reciprocal cross in genetic research?

To test for parent-of-origin effects by comparing offspring phenotypes when parental genotypes are swapped between mother and father.

Why does finding an offspring phenotype in exposed pregnant female mammals fail to demonstrate multi-generational epigenetic inheritance?

Because both the developing fetus ($F_1$) and its germ cells ($F_2$) are directly exposed to the maternal treatment environment during pregnancy.