LEC44: Non-Mendelian Inheritance

Question 1

epigenetics is?

Answer 1

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

Question 2

are epigenetic changes heritable?

mitosis or meiosis related?

Answer 2

yes, heritable

patterns of expression are across cell mitoses, not meiosis

Question 3

how does epigenetic change occur?

Answer 3

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

Question 4

what does epigenetics control?

Answer 4

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

Question 5

what are transcriptional-level molecular mechanisms that mediate epigenetic phenomena?

Answer 5

1) modifications to DNA via methylation at CpG dinucleotides
2) modifications and variations to histones via methylation, acetylation
3) modifying non-coding RNA

Question 6

what is DNA methylation? where usually occur?

Answer 6

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”

Question 7

what does methylation of DNA at CpG islands and gene promoters cause?

what is usual state of CpG islands?

Answer 7

methylation = represses transcription

USUALLY, CpGs are methylated (> 80%)

thus gene is usually OFF

Question 8

if a CpG island or gene promoter is unmethylated, what’s the state of the gene?

Answer 8

unmethylated = active gene

Question 9

what is X-inactivation

Answer 9

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

Question 10

why does x chromosome inactivation occur?

Answer 10

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

Question 11

which X is inactivated and when for X chromosome inactivation?

Answer 11

inactivation occurs randomly in somatic cells during 100-200 cell stage of embryogenesis

Question 12

what is result of X inactivation in offspring?

Answer 12

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

Question 13

what does calico cats’ fur patterning demonstrate?

Answer 13

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

Question 14

what is anhidrotic ectodermal dysplasia? what does it show about X linked inactivation?

Answer 14

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

Question 15

when do X-linked diseases phenotypically manifest?

Answer 15

when cells that have inactivated the wild-type X

explains why X-linked diseases more commonly manifest in males than females

Question 16

how does X-linked inheritance occur?

Answer 16

cannot be male-to-male transmission

female carriers are affected if X-chromosome carrying normal allele is inactive in nearly all cells

Question 17

genomic imprinting?

Answer 17

epigenetic phenomenon where expression status of a gene is dependent on its parental origin

Question 18

when does imprinting occur?

Answer 18

generated in germline cells so chromosomal regions are marked as being maternally or paternally derived and differentially expressed in fertilized zygote

Question 19

what kind of expression do non-imprinted genes show?

Answer 19

bi-allelic expression

Question 20

what kind of expression do imprinted genes exhibit?

Answer 20

mono-allelic expression & epigenetic marks

Question 21

if the same mutation (i.e. deletion) on the maternal and paternal chromosome causes different phenotypes in offspring, what does this suggest?

Answer 21

confirms the presence of imprinted gene(s) influencing phenotype within the mutation (deletion) region

Question 22

what are “imprinted domains”? what do they exhibit?

Answer 22

clusters of imprinted genes

~80% of imprinted genes occur in clusters

Question 23

how many imprinted genes do we know?

Answer 23

~80 in humans, >100 in mouse

there are many unidentified imprinted human genes

Question 24

what genes are imprinted in cancer/BWW syndrome?

in prader-willi/angelman syndrome?

Answer 24

IGF2 and IGF2R - growth regulators - BWW/cancer

UBE3A and MAGEL2 - brain development - PW/angelman

Question 25

what causes both prader-willi and angelman syndrome?

what is difference between them?

Answer 25

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

Question 26

what is the locus effected in P-W/angelman syndromes?

Answer 26

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)

Question 27

what are the possible molecular causes of Prader-Willi syndrome?

Answer 27

15q13 locus mutations:

65-75%: paternal deletion

20-30%: maternal uniparental disomy

2-5%: imprinting defects

Question 28

what are the possible molecular causes of Angelman syndrome?

Answer 28

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

Question 29

parental conflict hypothesis?

Answer 29

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

Question 30

what is relationship between imprinted genes and environmental influences?

Answer 30

environmental cues thought play a role in gene expression patterns via imprinted regions of genes

Question 31

what does agouti mouse hair color experience show?

Answer 31

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

Question 32

what is effect of “methyl donor” diet on agouti expression?

what does this demonstrate?

Answer 32

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

Question 33

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

what does this demonstrate?

Answer 33

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

Question 34

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

Answer 34

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

Question 35

what epigenetic finding is assocaited w/ IVF?

Answer 35

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

Question 36

why might ICSI cause epigenetic changes in embryo?

Answer 36

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

Question 37

are monozygous twins really identical?

Answer 37

no

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

Question 38

what is histone code?

Answer 38

aggregate of histone modifications

causes alterations to chromatin states and conformation

type of epigenetic control

Question 39

what is IMPRINTING

Answer 39

parent of origin-specific gene expression