Human Genetics
Mariam55Ch 11: Gene Expression and Epigenetics
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Temporal and spatial gene expression
changes in gene expression
over time
in different cell types/areas
molecular, tissue, or organ/gland level
epigenetic changes
changes to chromatin
chemical groups that associate with DNA
transmitted to daughter cells after cell division
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Epigenetics is change in gene expression
”outside the gene”
do not alter the base sequence
reversible
modifiers of gene expression
sequence remains unchanged
chromatin can be opened or closed
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Temporal Globin Chain Switching
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Spatial gene expression in pancreas
pancreas is a dual gland
exocrine: releases digestive enzymes into ducts
endocrine: secretes polypeptide hormones into bloodstream
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Spatial expression in pancreas
differential gene expression
either endocrine or exocrine cells
transcription factor pdx-1 exocrine
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Proteomics: temporal and spatial
“-omics”
groups of genes that encode proteins made in a cell, tissue, gland, organ, pathway, or entire body
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Control of Gene Expression
structural genes contain some controls
promoter/ regulatory sequence
transcription factors and mutations
gene duplication
eukaryotic gene structure includes regulatory elements for gene expression
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Control of Gene Expression
transcriptional control
post-transcriptional control
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Control of Gene Expression
most control of gene expression
chromatin remodeling
open or closed chromatin (no transcription)
microRNAs
loss of transcript (no translation)
open chromatin allows transcription
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Remodeling opens or closes chromatin
histone core of nucleosomes
can hide or expose DNA
controls transcription
small molecules bind to histones to control expression
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Acetylated histone tails allow transcription
acetyl groups bind via histone acetylase (HAT)
interferes with tight association of DNA/histone
lysine residues interact with phosphates in backbone
loosens DNA from nucleosome
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Methylated histone tails stop transcription
methyl groups attached to
lysines in histone tails
methyl spreading due to methylases
cytosines in CpG islands
methylome of 16,000 sites
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Control of epigenome
euchromatin
can be remodeled to open or closed
heterochromatin
permanently closed
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Control of epigenome
facultative heterochromatin
closed, but reversible
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MicroRNAs control translation
noncoding RNAs 21-22 bases long
Human genome about 1,000 distinct microRNAs
regulate at least 1/3rd of protein-encoding genes
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MicroRNAs control translation
alternate mechanisms
double-stranded RNA is abnormal and degraded
double-stranded RNA physically blocks initiation
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MicroRNAs control translation
mRNA degradation pathway
uses miRNA processed through DICER
sequence-specific “anti-RNA”
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MicroRNAs control translation
translational repression
uses miRNA processed through DICER
sequence-similar “anti-mRNA”
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MicroRNAs control translation
gene silencing using siRNA
engineered transcripts trigger pathway
transgenic manipulation not needed
reversible, “switchable”
can “knock-out” gene function
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Genome expression
proteins outnumber genes nearly 50 times
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Maximizing Genetic Information
gene structure in complex eukaryotes
pattern of exons and introns
alternative splicing increases transcripts
exons encode amino acids
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Maximizing Genetic Information
gene structure in complex eukaryotes
splicing of exons in spliceosome
DNA sequence at splice sites is conserved within introns:
GU at beginning/AG at end
branch point A in center
splicing cannot occur without these sequences
branch point mutations
splice site mutations
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Alternative splicing produces different mRNA
new combinations of codons = new protein
regulated splicing
weak or strong splice sites, branch sites
interference with loop formation
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Introns interrupt mRNA
intron is usually noncoding
in same direction as gene
can include
alternative splice site
alternate promoter
alternate polyadenylation site
coding region
microRNA
etc.
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Introns interrupt mRNA
intron is usually noncoding
in same direction as gene
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Introns interrupt mRNA
intron on one gene’s template strand
encode protein in reverse (coding strand)
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Post-translational modifications
change or activate protein function
glycoproteins and lipoproteins
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Proteolytic processing
pre-protein cut to yield products
e.g., dentinogenesis imperfecta
deficiency in proteolysis
DSPP pre-protein DPP and DSP
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1.5 % of Human genome encodes protein
only exon DNA encodes protein
rest of genome
viral DNA
noncoding RNA
introns
promoters and other control sequences
repeated sequences
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Viral DNA from ancestral infections
8% of our genome derived from retroviruses
sequences tend to duplicate over time
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Noncoding RNAs function as RNA
transcripts folded into useful molecules
rRNAs and tRNAs for translation
microRNAs for gene regulation
snRNAs for splicing
snoRNAs for rRNA processing
ribozymes
other transcripts
100,000’s other ncRNAs (function?)
pseudogene transcripts
not translated into protein, gene regulation?
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Repeat DNA
transposons
sequences that can move within the genome
e.g., Alu repeats can copy themselves
comprise about 2-3% of the genome
telomeres, centromeres, rRNA gene clusters
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Genome expression
proteins outnumber genes nearly 50 times
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