study of reverisble heritable changes in gene fxn that occur w/o a change in sequence of nuclear DNA
gene-regulatory info that isn't expressed in DNA sequences but can be trasmitted from 1 generation to the next
are epigenetic changes heritable?
mitosis or meiosis related?
patterns of expression are across cell mitoses, not meiosis
how does epigenetic change occur?
series of structural modifications to the DNA, or to underlying chromatin that packages DNA, that can affect gene expression without changing primary DNA sequence
through: DNA methylation, genomic imprinting, X-inactivation, environemnt/nutrition and EWAS, IVF
what does epigenetics control?
thus explains tissue-specific patterns of gene expression that're critical for appropriate development to occur despite cells all having same genomic complement
what are transcriptional-level molecular mechanisms that mediate epigenetic phenomena?
1) modifications to DNA via methylation at CpG dinucleotides
2) modifications and variations to histones via methylation, acetylation
3) modifying non-coding RNA
what is DNA methylation? where usually occur?
methyl group added at at CpG nucleotide islands or gene promotoers
if added to C of CpG island, forms methylcytosine, the "5th base of DNA"
what does methylation of DNA at CpG islands and gene promoters cause?
what is usual state of CpG islands?
methylation = represses transcription
USUALLY, CpGs are methylated (> 80%)
thus gene is usually OFF
if a CpG island or gene promoter is unmethylated, what's the state of the gene?
unmethylated = active gene
what is X-inactivation
females inactivate 1 copy of X in each somatic cell by random process during embryogenesis
gene-dose compensation strategy mammals use to equalize trascript abundance btwn females who have 2 copies of X-linked genes and males who have single copy
why does x chromosome inactivation occur?
b/c there's an inequality of gene content between males and females, since females are 46,XX and males are 46,XY
X chrom is large, ~1000 genes, Y is small, ~50 genes
females thus "compensate" by inactivating 1 X chromosome to make a single "dosage" of X-linked genes
which X is inactivated and when for X chromosome inactivation?
inactivation occurs randomly in somatic cells during 100-200 cell stage of embryogenesis
what is result of X inactivation in offspring?
progeny cells all have same inactivated X chromosome as their ancestor
this creates mosaic females with some cells having paternal X inactive, other cells have maternal X inactive
what does calico cats' fur patterning demonstrate?
all calico cats are female and heterozygous for an X-linked gene that codes for either black or orange fur
2 colors represent skin cells that've inactivated different X chromosomes
X-linked inactivation results in mosaic coloration
what is anhidrotic ectodermal dysplasia? what does it show about X linked inactivation?
an X-linked recessive disease caused by mtuations in the EDA gene
disease severity in females is dependent on proportion of cells that've inactivated the normal EDA copy
if female has the mutant EDA allele, X with the mutant EDA allele is active some places; X without mutant is active elsewhere; thus have normal skin in some areas and regions without sweat glands in others
this is mosaicism
when do X-linked diseases phenotypically manifest?
when cells that have inactivated the wild-type X
explains why X-linked diseases more commonly manifest in males than females
how does X-linked inheritance occur?
cannot be male-to-male transmission
female carriers are affected if X-chromosome carrying normal allele is inactive in nearly all cells
epigenetic phenomenon where expression status of a gene is dependent on its parental origin
when does imprinting occur?
generated in germline cells so chromosomal regions are marked as being maternally or paternally derived and differentially expressed in fertilized zygote
what kind of expression do non-imprinted genes show?
what kind of expression do imprinted genes exhibit?
mono-allelic expression & epigenetic marks
if the same mutation (i.e. deletion) on the maternal and paternal chromosome causes different phenotypes in offspring, what does this suggest?
confirms the presence of imprinted gene(s) influencing phenotype within the mutation (deletion) region
what are "imprinted domains"? what do they exhibit?
clusters of imprinted genes
~80% of imprinted genes occur in clusters
how many imprinted genes do we know?
~80 in humans, >100 in mouse
there are many unidentified imprinted human genes
what genes are imprinted in cancer/BWW syndrome?
in prader-willi/angelman syndrome?
IGF2 and IGF2R - growth regulators - BWW/cancer
UBE3A and MAGEL2 - brain development - PW/angelman
what causes both prader-willi and angelman syndrome?
what is difference between them?
both: inheritance of deletion of proximal chr15, causing absence of genes expressed from maternal or paternal allels, causing disease b/c of functional nullisomy
ANGELMAN: MATERNAL deletion
P-W: PATERNAL deletion
what is the locus effected in P-W/angelman syndromes?
imprinted genes in 15q11-q13
occurs b/c some genes are only expressed from paternally-derived allele, some from maternal; thus where deletion occurs determines if you get prader willi (PATERNAL deletion) or Angelman (MATERNAL deletion)
what are the possible molecular causes of Prader-Willi syndrome?
15q13 locus mutations:
65-75%: paternal deletion
20-30%: maternal uniparental disomy
2-5%: imprinting defects
what are the possible molecular causes of Angelman syndrome?
all result in loss of the maternally-expressed imprinted gene UBE3A
65-75%: maternal deletion
3-7%: paternal uniparental disomy (UPD)
5-11%: UBE3A mutation
3%: imprinting defects
parental conflict hypothesis?
hypothesis: inequality btwn parental genomes due to imprinting is a result of differing interests of each parent in terms of evolutionary fitness
PATERNAL genes: promote offspring growth, at expense of mother
MATERNAL genes: limit growth, to conserve resources for survival, to produce more offspring
what is relationship between imprinted genes and environmental influences?
environmental cues thought play a role in gene expression patterns via imprinted regions of genes