Medical Genetics

Genome & Gene

Medical Genetics

Genome

A genome is the entirety of an organism's hereditary

information.

The genome includes both the genes and the non-

coding sequences of the DNA/RNA.
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• Unique DNA
• that is DNA whose nucleotide sequence is
represented only once (or at most a few times) in the
genome.

• repetitive DNA
• DNA whose nucleotide sequence is repeated
hundreds to millions of times in the genome.
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• Genome composition is used to describe the contents

of a haploid genome,

• which should include genome size,

• proportions of non-repetitive DNA and repetitive
DNA in details.
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• In prokaryotes,

• most of the genome (85-90%) is non-repetitive

DNA,
• which means coding DNA mainly forms it, while
non-coding regions only take a small part.
•
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• On the contrary,
• the variation of repetitive DNA content in eukaryotes
is also extremely high.

• When refer to mammalians and plants, the major part

of genome is composed by repetitive DNA.
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• Unique DNA

• The proportion of non-repetitive DNA

• is calculated by using length of
• non-repetitive DNA divided by genome size.

• Protein-coding genes and RNA-coding genes are

generally non-repetitive DNA.
• single-copy or unique DNA
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• Bigger genome does not mean more genes,

• and the proportion of non-repetitive DNA decreases

along with the increase of genome size in higher
eukaryotes.
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• Repetitive DNA

• The proportion of repetitive DNA

• is calculated by using length of
• repetitive DNA divided by genome size.
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• There are two categories of repetitive DNA in

genome:

• tandem repeats and

• interspersed repeats.
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• Tandem repeats
• repeated sequences (repeats) are clustered in one or a
few locations

• Tandem repeats are usually caused by

• slippage during replication,
• unequal crossing-over and
• gene conversion,
•
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• Satellite DNA, short repeats in head to tail

fashion
•
• minisatellite DNA
• microsatellite DNA.
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• The size of a satellite DNA ranges from 100 kb to

over 1 Mb.

• The size of a minisatellite ranges from 1 kb to 20 kb.

usually minisatellite DNA is a short region (1-5kb) of
20-50 repeats.

• Microsatellites are also known as short tandem

repeats (STR), because a repeat unit consists of only
1 to 6 bp and the whole repetitive region spans less
than 150 bp.
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• Although tandem repeats count for a significant

proportion in genome,
• the largest proportion in mammalian is the other
type, interspersed repeats.
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• Interspersed repeats

• interspersed throughout the genome, with single copy

sequences along the chromosome.

• Interspersed repeats are mainly from

• transposable elements (TEs),
• it also include some protein coding gene families and
pseudogenes.
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• Transposable elements are able to integrate into the

genome at another site within the cell.

• It is believed that TEs is an important driving force

on genome evolution of higher eukaryotes.
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•
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The gene

• A gene is a molecular unit of heredity of a living

organism.
• It is a name given to some stretches of DNA and
RNA that code for a polypeptide or for an RNA chain
that has a function in the organism.
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• Genes hold the information to

• build and maintain an organism's cells and
• pass genetic traits to offspring,
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the triplets
• The genetic code is the set of rules by
which information encoded within genetic
material (DNA or mRNA sequences) is
translated into proteins by living cells.
• transfer RNA molecules,
• each specific for one amino acid and
• for a particular triplet of nucleotides in
mRNA called a codon.
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Gelehrter, Collins and Ginsburg: Principles of Medical Genetics 2E; Figure 6.5
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• Coding sequence
• Open reading frame
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• The eukaryotes have the feature of exon-intron

organization of protein coding genes;

• The majority of genes are interrupted by one or

more noncoding regions.
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• An exon is a coding region of a gene that contains the

information required to encode a protein
• stretches of DNA translated into amino acids and
proteins.

• Intron is the noncoding sequence intervened in a gene

sequence.
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Synthesis of globin
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Gene Structure

• Gene is consists of

• coding sequences
• regulatary sequences
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• Promoters and enhancers determine

what portions of the DNA will be
transcribed into the precursor mRNA (pre-
mRNA).
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• A regulatory region shared by almost all genes is

known as the promoter,

• which provides a position that is recognized

by the transcription machinery when a gene is about
to be transcribed and expressed.
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• Other possible regulatory regions include

enhancers, which can compensate for a weak
promoter.

• Most regulatory regions are "upstream"—that is,

before or toward the 5' end of the transcription
initiation site.
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Gene Expression

The majority of genes are expressed as the

proteins they encode.

The process occurs in two steps:

Transcription = DNA → RNA

Translation = RNA → protein
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• The central dogma of molecular biology

• describes the way genetic information is expected to

be transferred in a single direction through a
biological system.
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• as Marshall Nirenberg said,

• "DNA makes RNA makes protein."
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• transcription.

• The DNA codes for the production of

messenger RNA (mRNA).

• In eucaryotic cells, the mRNA is processed

and migrates from the nucleus to the
cytoplasm.
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Gene Transcription: DNA → RNA

DNA serves as the template for the

synthesis of RNA much as it does for its
own replication.
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Here is an overview
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RNA Processing:
pre-mRNA → mRNA

All the primary transcripts produced in

the nucleus must undergo processing
steps to produce functional RNA molecules
for export to the cytosol. We shall confine
ourselves to a view of the steps as they
occur in the processing of pre-mRNA to
mRNA.
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• The pre-mRNA is then spliced into

messenger RNA (mRNA) which is later
translated into protein.
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• translation

• Messenger RNA carries coded information

to ribosomes.
• The ribosomes "read" this information
and use it for protein synthesis.
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Gene Translation: RNA -> Protein

By means of transfer RNA molecules,

each specific for one amino acid and for a
particular triplet of nucleotides in mRNA
called a codon.
The family of tRNA molecules enables
the codons in a mRNA molecule to be
translated into the sequence of amino
acids in the protein.
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The Steps of Translation

1. Initiation
2. Elongation
3. Termination
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• Posttranslational modification

• Protein amino acid sequence can be edited

after translation by various enzymes.
• This is a case of protein affecting protein
sequence, not explicitly covered by the
central dogma.
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• Many proteins undergo extensive

posttranslational modification.
• The polypeptide chain that is the primary
translation product is folded and bonded
into a specific three-dimensional structure
that is determined by the amino acid
sequence itself.
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• Two or more polypeptide chains, products

of the same gene or of different genes,
may combine to form a single mature
protein complex.
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• The protein products may also be modified

chemically by, for example, addition of
methyl groups, phosphates, or
carbohydrates at specific sites.
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• Other modifications may involve cleavage

of the protein,

• either to remove specific amino-terminal

sequences after they have functioned to
direct a protein to its correct location
within the cell or
• to split the molecule into smaller
polypeptide chains.
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• Regulation of gene expression

• The β-globin chain is a 146-amino acid

polypeptide,
• encoded by a gene that occupies
approximately 1.6kb on the short arm of
chromosome 11.
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• The β-globin gene has three exons and two
introns.
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• DNA sequence required for the accurate

initiation of transcription of the β-globin
gen are located in the promoter within
approximately 200 base pairs upstream
from the transcription start site.
• The promoter consists of a series of
relatively short functional elements that
interact with specific transcription factors.
•
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• One important promoter sequence is the

TATA box,
• a conserved region rich in adenines and
thymines that is approximately 25 to 30
base pairs upstream of the start site of
transcription.
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• A second conserved region, the so-called

CAT box (actually CCAAT)

• is a few dozen base pairs farther

upstream.
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• In particular genes that are constitutively

expressed in most or all tissues (called
housekeeping genes) often lack the
CAT and TATA boxes that are more
typical of tissue –specific genes.
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• Promoters of many housekeeping genes often

contain a high proportion of cytosines and guanines
in relation to the surrounding DNA.

• Such CG-rich promoters are often located in regions

of the genome called CpG islands.
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• Some of the CG-rich sequence elements

found in these promoters are thought to
serve as binding sites for specific
transcription factors.

• CpG islands are also important because

they are targets for DNA modification by
the addition of a methyl group to one of
the available carbons in cytosine.
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• Extensive DNA methylation at CpG islands

is usually associated with repression of
gene transcription.

• This type of gene inactivation is seen in

many cancers and is a hallmark of several
important developmental regulatory
events, such as genomic imprinting and X
chromosome inactivation.
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• Enhancers are sequence elements that

can act at a distance from a gene to
stimulate transcription.
• Unlike promoters, enhancers are both
position and orientation independent and
can be located either 5’ or 3’ of the
transcription start site.
• The interaction of enhancers with
particular proteins leads to increased
levels of transcription.
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• RNA splicing

• The process of RNA splicing is exact and

highly efficient;
• 95% of β-globin transcripts are thought to
be accurately spliced to yield functional
globin mRNA.
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• Alternative splicing

• For many genes, the primary transcript

can follow multiple related but different
mRNAs,
• each of which can be subsequently
translated to generate different protein
products.
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• Polyadenylation

• Polyadenylation is the addition of a

poly(A) tail to an RNA molecule. The
poly(A) tail consists of multiple adenosine
monophosphates;
• in other words, it is a stretch of RNA that
has only adenine bases.
•
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• In eukaryotes, polyadenylation is part of

the process that produces mature
messenger RNA (mRNA) for translation.
• It, therefore, forms part of the larger
process of gene expression.
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summary
• Gene ， exon ， intron
• Promoter ， enhancer
• Genome ， genome composition
• Unique DNA ， Repetitive DNA
• tandem repeats ， interspersed repeats
• central dogma of molecular biology
• triplet ， codon
• RNA Processing
• Steps of Translation
• Posttranslational modification
• TATA box ， CAT box ， CpG island
• RNA splicing ， Alternative splicing
• Polyadenylation
Medical Genetics Questions
• What is genome composition?
• What are the differences between the two
categories of repetitive DNA in genome?
• What different types of satellite DNA are there in
the genome?
• What components does a typical gene contain?
• What regulatory elements are there on a gene?
• Give a brief introduction to the process of gene
expression.
• What possible ways does the posttranslational
modification usually contain?