LEC44: Non-Mendelian Inheritance Flashcards Preview

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Flashcards in LEC44: Non-Mendelian Inheritance Deck (40)
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epigenetics is?

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?

yes, heritable 

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?

cell development

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


genomic imprinting?

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?

bi-allelic expression 



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


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


what does agouti mouse hair color experience show?

normally, Agouti gives brown expression 

can insert a transgenic IAP element upstream of Agouti gene 

but expression from IAP element in TRANSGENIC mice gives YELLOW color + diabetes, obesity, tumors 

when IAP region is hypermethylated, so IAP is off, causes INCREASED agouti expression, BROWN FUR



what is effect of "methyl donor" diet on agouti expression?

what does this demonstrate?

feeding mother "Methyl Donors" - folic acid, vitamin B, during prengnacy, results in skewed coat color distribution in offspring 

methylation of IAP element allows increased agouti expression = brown coat in progeny

example of how epigenetics can be impacted by diet, environment during pregnancy


what persistent epigenetic differences have been observed w/ offspring of those who lived during Dutch famine in 44-45? 

what does this demonstrate?

those who were prenatally exposed to famine have less DNA promoter methylation of imprinted IGF2 gene 

contributed to later disease states in these chidlren

shows that early mammalian development is crucial pd for establishing, maintaining epigenetic marks and can occur via environmental influences such as diet



what do we know about maternal diet during pregnancy re: obesity? 

preliminary studies show how much carbs a mother eats during pregnancy is assocaited w/ altered gene methylation 

this impacts child's level of obesity, BMI at adolescence


what epigenetic finding is assocaited w/ IVF?

see increased frequency of imprinting disorders in babies conceived by IVF 

especially, 4x increase in proportion of babies suffering from Beckwith-WIedermann syndrome, caused by defects in imprinted gene cluster 11p15.5

see abnormal methylation in IVF children 

suggests epigenetic disturbances are caused by method of IVF


why might ICSI cause epigenetic changes in embryo?

ICSI: inject complete head of a sperm into the oocyte by brute force 

is physically disruptive 

could affect subsequent events in early embryo, such as proper methylation of the genome


are monozygous twins really identical?


monozygous twins are formed from single embryo that splits during very early cell division into 2 separate embryos 

genetically identical, HOWEVER epigenome likely differs given that epigenome is responsive to environment, and individuals will be exposed to different environmental factors over lifetime


what is histone code?

aggregate of histone modifications 

causes alterations to chromatin states and conformation

type of epigenetic control



parent of origin-specific gene expression


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