Genetics

Introduction
DR I.F. EZEJIOFOR
MBBS, FWACP, FMCPath
CONSULTANT HISTOPATHOLOGIST NAUTH, NNEWI
NONCODING DNA
• Regulatory sequences=promoters, enhancers
DEFINITIONS OF SOME KEY WORDS
• Gene; is the functional unit of inheritance controlling the transmission
and expression of one or more traits OR a sequence of nucleotides in
DNA or RNA, located usually on a chromosome that encodes either
RNA or protein.

• Three nucleotides is a codon or each codon consists of 3 nucleotides

DEFINITION OF SOME KEY WORDS
• Chromosomes= is a threadlike structure of a nucleic acid (DNA or
RNA) found in the nucleus of most living cells carrying genetic
information in forms of genes.
• Chromatids = are paired chromosomes connected at centromere
during meiosis. It has short(p) & long(q) arms
DEFINITION OF SOME KEY WORDS
• Telomeres are repetitive nucleotide sequences that cap the termini of
chromatids and permit repeated chromosomal replication without
loss of DNA at the chromosome ends.
Slide showing location of Genes in the
chromosome
STRUCTURE OF A GENE
THE STRUCTURE
NUCLEOTIDE (Composed of sugar, base and phosphate)

SEQUENCE OF NUCLEOTIDES (1000 &1000 OF NUCLEOTIDES)

DNA OR RNA (NUCLEIC ACIDS)

SEQUENCE OF DNA OR RNA

GENE (FUNCTIONAL UNIT OF INHERITANCE)

CHROMOSOME
DEFINITIONS OF SOME KEY WORDS
• DNA(deoxyribose nucleic acid) or RNA (Ridoxynucleic acid) are defined as
nucleic acids which are composed of thousands and thousands of nucleotides
join together by phosphodiester bond.

• Nucleotides are the building blocks of DNA or RNA, is composed of a sugar,

base and phosphate.
• Base =PURINE (2rings e.g adenine,guanine) PYRIMIDINE (1ring e.g cytosine,
uracil & thymine)
• Sugar= The nucleotide of DNA is different from that of RNA b/c the sugar
(ribose) component in DNA lacks oxygen at position 2 and therefore is called
deoxyribose. (FIG 1)
SUGAR PART OF THE NUCLEOTIDE
STRUCTURE OF NUCLEOTIDE OF DNA
DEFINITIONS OF SOME KEY WORDS
• Nucleoside = unlike nucleotide, nucleoside is made of only a
nitrogenous base and a sugar (5 carbon sugar) and lacks phosphate.
• The base is bound to either ribose or deoxyribose via a beta-
glycosidic linkage at 1 position.
Structure of nucleoside
DEFINITIONS OF SOME KEY WORDS
• Nucleosomes/chromatin =is when DNA is package around octameric
histone cores—with the nucleosomes connected via DNA linkers.
• NOTE; proteins are normally negatively charged BUT Histone is the
only positively charged protein that contain arginine and lysine. It has 4
paired subtypes (H1,H2A, H2B, H3, & H4)
• The DNA are packaged into 2 forms
(1) Euchromatin= is loosely packed, dispersed & transcriptionally active
DNA which lack H1 histone and is 10nm in size.
(2) Heterochromatin= densely packed, transcriptionally inactive and has
H1 histone that condenses the DNA tightly together. It is 30nm in size.
NUCLEOSOME
(EUCHROMATIN/HETEROCHROMATIN)
EUCHROMATIN/HETEROCHROMATIN
DEFINITIONS OF SOME KEY WORDS
• Hereditary disorders, means disorders derived from one’s
parents.
• When this disorders are transmitted in the germ line through
the generations is said to be familial.
• Congenital simply implies “born with.”
• Some congenital diseases are not genetic;(e.g congenital
syphilis) & not all genetic diseases are congenital (Huntington
disease which manifest only after 20s or 30 years.
DIVERSITY OF PHENOTYPES IN HUMAN
POPULATIONS
• Majority of difference b/w individuals lies in the 98.5% non coding human genome.
• Two individuals have >99.5% similarity in their DNA sequences but vary only in less
than 0.5% of their DNA (15 million base pairs.)

• The two most common forms of DNA variation in the human genome are
(1) Single-nucleotide polymorphisms(SNPs) = variation at the single nucleotide
position are almost always biallelic (A or T/ G or C). It occurs across the genome both
in coding (1%) and non coding region.
(2)Copy number variations (CNVs)= duplication or deletion of large contiguous
stretches of DNA from 1000 base pairs to millions of base pairs & 50% of CNVs
involve gene-coding sequences.
Diversity of phenotypes in human
populations
• The diversity in human phenotypes also involve the third culprit known as
epigenetic variation (literally means factors that are “above genetics”).
(3) Epigenetics= is defined as heritable changes in gene expression that are
not caused by alterations in DNA sequence(ie DNA number) but rather on
modifications of histone /or modification of DNA (DNA methylation
resulting in transcriptional silencing)
• Histone can be modified through its amino acid(arginine & lysine) in form
of Histone methylation, Histone acetylation,& Histone phosphorylation
which can either cause DNA to open up or to condense into inactive form.
Diversity of phenotypes in human
populations
• In summary; Person-to-person variation, including differential
susceptibility to diseases, in response to environmental agents and
drugs, is encoded in less than 0.5% of our total DNA and majority of it
is occurs in the non-coding genome.
• Single-nucleotide polymorphisms(SNPs)
• Copy number variations (CNVs)
• Epigenetics
GENES & HUMAN DISEASES
• Genetic disorders are far more common than we imagined; what we
see in medical practice is only the tip of the iceberg.
• The lifetime frequency of genetic diseases is estimated to be 670 per
1000. ie those that permit full embryonic development or live birth.
• Fifty percent (50%) of spontaneous abortuses during the early months
of gestation have chromosomal abnormality.
• Note 7.5% of all conception have chromosomal abnormality but only
0.5% to 1% of cases are seen in live-born infants & about 5% of those
children are born by mothers < 25 years.
• Majority (>75%) are therefore born by mother above 40 years of age
3 CATEGORIES OF HUMAN GENETIC
DISORDER
• Human genetic disorders are broadly classified into three categories
(1) Disorders related to mutations in single genes /Monogenic disorder
(2) Chromosomal disorders
(3) Complex multigenic disorders (MOST COMMON)

• Single gene mutations are further divided into 2

• (A) Classic Mendelian pattern of inheritance ie single gene mutation with large effects (also called
Mendelian disorders) MOST COMMON.
• (B) Single-gene disorders with non-classic patterns of inheritance EXAMPLES
= triplet-repeat mutations
= mitochondrial DNA (mtDNA) mutations
=& genomic imprinting or gonadal mosaicism.
CHROMOSOMAL DISORDERS
• Chromosomal disorders; These disorders occur when there is
structural or numerical alteration (deletion/duplications) in the
autosomes and sex chromosomes.
• They are also associated with high penetrance
COMPLEX MULTIGENIC/POLYGENIC DISORDERS
(MULTIFACTORIAL DISORDERS).

• They are caused by interactions b/w multiple genes & environmental

factors.
• Each of these genes disorder is not enough to cause dx rather they produce
small increase in disease risk (small effect), it is only when multiple of these
genes are present that dx is produced. It is therefore called
multigenic/polygenic
• Unlike monogenic disorder, polygenic disorder have; Small effect and low
penetrance but like monogenic disorder, complex multigenic disorder
show high variability (polymorphisms=different physical forms within a
population)
COMPLEX MULTIGENIC/POLYGENIC
DISORDERS (MULTIFACTORIAL
DISORDERS).
• Examples; atherosclerosis, diabetes mellitus, hypertension,
autoimmune diseases, & normal traits or normal phenotypic
characteristics such as hair color, eye color, skin color, height,
intelligence & weight.
• Environmental factors usually unmasks these disorders e.g diabetes
mellitus is unmasked by obesity while Nutrition can cause
monozygous twins to achieve different heights.
• Again culturally deprived child cannot achieve his or her full
intellectual capacity.
SINGLE GENE MUTATION WITH LARGE
EFFECTS
• Single gene mutation with large effect is highly penetrant.

• Large effect; means with a single gene mutation there is wide varieties of
symptoms like in SSDx.

• High penetrant; meaning that the presence of the mutation must be

associated with the symptoms in a large proportion of individuals.

• Examples; hemoglobinopathies, cholesterol transport, chloride secretion

(cystic fibrosis)
MUTATIONS IN SINGLE GENE DISORDERS

• A mutation is defined as a permanent change in the DNA.

• Mutations that affect germ cells (sex cells) will give rise to inherited
diseases WHILE Mutations that arise in somatic cells will cause
cancers.
• E.G of these mutations; Point mutations within coding sequences,
Point Mutations within noncoding sequences, Deletions and
insertions, Trinucleotide-repeat mutations
(1)Point mutations within coding
sequences
• Definition; A point mutation is a change in which a single base is substituted
with a different base, resulting in alteration of the code in a Codon & lead to
the replacement of one amino acid by another in the gene product.
• Because the mutation alters the meaning of the encoded protein it is called
missense mutations (e.g=glutamic acid CTC is substituted with valine CAC in
SSDx)
• If the substituted amino acid is biochemically similar to the original, & causes
little change in the function of the protein; the mutation is called a
“conservative” missense point mutation.
• But if mutation replaces the normal amino acid with a biochemically different
one it is called a “nonconservative” missense point mutation = e.g in SSDX.
Point mutations within coding sequences
• If the substitution of a single base in amino acid codon leads to a
chain terminator, or stop codon, it is called nonsense point mutation.
• Example; When glutamine acid codon (CAG) creates a stop codon
(UGA,UAG, UAA,) in β-globin gene of haemoglobin by
substituting C base with U base.
• This stop codon will result in sudden termination of β-globin gene
translation leading to production of short peptide which are rapidly
degraded, & thereby resulting in deficiency of β-globin chains. This
will give rise to a severe form of anemia called β0-thalassemia
Nonsense  mutation  leading  to  premature  chain termination.  A  point 
mutation  changes  a  glutamic acid (Glu)  codon  to  a  stop  codon &
hence  stops protein  synthesis 
(2)Point Mutations within noncoding sequences
• Abnormalities also occur when mutation involves noncoding regions
e.g=regulatory sequences (promoter and enhancer), introns etc.
• If mutations occur in these regulatory sequences it will lead to lack of
binding of transcription factors to these regions resulting in marked
reduction or total lack of transcription as seen in some forms of
thalassemias
• Likewise mutations within introns may lead to its defective splicing
resulting in failure of production of mature mRNA from initial mRNA
transcripts. Therefore, translation cannot take place, and the gene
product is not synthesized. (FIG 1)
FIGURE 1
(3)Deletions and insertions
• Three-base deletion in the common cystic fibrosis (CF) allele results in
synthesis of a protein that lacks amino acid 508 (phenylalanine).
• When the number of deletion involves 3base pair or multiple of 3 it is
not a frameshift mutation but a 3-base pair deletion.
• In 3base deletion, frameshift is intact/is not altered
FRAMESHIFT MUTATIONS
• Frameshift mutations are insertions or deletions in the genome that
are not in multiples of three nucleotides/3bases (i.e deletion or
insertion of one, two or four but never 3 bases
FRAMESHIFT MUTATIONS
• When a Single-base is deleted as in ABO (glycosyltransferase) locus.
FRAMESHIFT MUTATIONS
• Four-base insertion in the hexosaminidase A gene in Tay-Sachs dx,
leading to a frameshift mutation
FRAMESHIFT MUTATIONS
Thanks