LECTURE- 4

PART- I CYTOGENETICS
 DUPLICATIONS

MULTIGENE FAMILIES
Multigene families -definition
Definition:.
A group of genes, linked or unlinked related in both structure and
function, which arose by duplication of a primordial ancestral gene
followed by divergence.

They possess some degree of structural homology and

functional similarities (non-identical).

Note: Some members of the gene family lose their function by

accumulation of mutations and are referred to as pseudogenes.

Note: From the genome projects completed it appears that multigene

families are more the norm than the exception.
Multigene families - types

Gene family

Undispersed gene family Dispersed gene family

(all members linked) ( some linked, some unlinked)

Different arm Unlinked

(syntenic) Different chromosome
Multigene families - types

Gene family

Tandem repeats Dispersed repeats

Satellites

SINES LINES
Short interspersed Long interspersed
sequences sequences
 Multigene families - types
• SINES- sequences which are about 130- 300 bp

• LINES- sequences which are about 500bp or larger

• SINES and LINES are retroposons and account for 34% of

human genome.

• Formed by retrotransposition- retrotransposon "master gene"

is copied into an RNA intermediate, reverse transcribed into
DNA, and inserted into the genome of its host at a new
location.
 Multigene families - types
Central dogma of Biology

LINES and SINES produce a protein that acts as an endonuclease (to initiate the
insertion event), and a reverse transcriptase (to copy the RNA version of a LINE or
SINE into the chromosomal DNA).
Multigene families - types

• SINES and LINES are not tandemly repeated but dispersed

throughout the genome (1000s of copies).

• E.g. SINE: “Alu repeat” found all over the genome, has no function
and through mutations accumulated over time, each repetition is
different. Has taxonomic importance: 50% similar- diff. species;
80% similar- individuals within a species.

• Insertion of Alu into the BRCA2 gene results in inactivation of

tumour suppressing genes- familial breast cancer.

• E.g. LINE insertion into human dystrophin gene can result in

muscular dystrophy.
 Multigene super families - definition
Definition:.
Several sets of multigene families that share some recognizable homology but
have undergone major divergence in function and have often been
relocated in the genome are referred to as a multigene super family.
e.g. Immune system superfamily
- includes immunoglobins (Ig)
- Major histocompatibility complex (MHC)
- T-cell and other receptors.

These are related in structure with some functional similarities. They all
encode proteins that have cell surface functions and protect the cell.
- MHC recognizes foreign antigens, cellular immune response
(phagocytes, T-lymphocytes)
- Ig provides a humoral immune response (anti-body mediated)
Multigene families - origin

1. Duplication and divergence

Divergence occurs by mutation under the influence of natural selection
and random genetic drift. Divergence allows duplicated genes to
assume new but related functions. Some members lose their function
and are referred to a pseudogenes.

2. Homogenisation (molecular drive)

Members of gene family tend to retain more structural similarity than
would be expected by concerted evolution. This is because there are
mechanisms to homogenize sequences within the family
- gene conversion
- unequal cross over
 Multigene families - origin
What is gene conversion?
- Nonreciprocal recombination by which one allele in a heterozygote is converted
into a corresponding allele (e.g. b to B).

- That is, we have nucleotide pairing between two sufficiently homologous genes,
followed by excision of all or part of the nucleotide sequence of one gene and
replacement with parts of the other gene of a multigene family.

In other words the sequence of one gene ‘converts’ the sequence of

the other gene. Occurs in both mitosis and meiosis.

Gene conversion is diff. from crossing over since

only one homologue is altered.
Important for chromosome repair and can
produce new genes with altered functions.
Multigene families - origin

What is gene conversion?

Multigene families - origin

3. Increase or decrease in numbers

Unequal cross over can also lead to increases in the number of
members of the gene family over evolutionary time.

4. Dispersion
Multigene families can become dispersed in the genome
by inversion or translocation or by transposition. Dispersion results in
processed pseudogenes (mediated through an RNA intermediate).

Transposition is mediated through retroviral sequences or

transposons.
 Multigene families – Evolutionary significance

a) Developmental flexibility
Alpha and beta globin gene family

b) Differentiation
Homeobox gene superfamily produces a class of DNA binding proteins
which allow differentiation of organisms. All homeobox genes share a
180 bp homeodomain (HD), which is highly conserved. Once they are
encoded they start a cascade of effects culminating in a fully developed
adult.

Homeobox genes are considered master switches that determine spatial

and temporal patterns of gene expression leading to the development
of organisms.
Multigene families – Evolutionary significance
b) Differentiation
Fruit flies with a particular mutation in one of their many hox genes
(homeobox genes), for example, will develop an anatomically normal
leg - in the spot where an antenna should be.

Homeotic genes are almost identical in every species and have

remained relatively unchanged throughout evolutionary history.
 Multigene families – Evolutionary significance

c) Environmental flexibility

Immune system superfamily

- mounts diverse levels of immune responses against invading
organisms in vertebrates (dispersed over 8 chromosomes in humans)

- Involve Ig, MHC and T-cell receptor families

- Immunoglobin system (Ig). The B lymphocytes circulate in the

blood plasma and secrete antibodies which attack foreign
antigens

- The MHC system enable T-type lymphocytes to recognize proteins of antigens.

They do not secrete antibodies but have receptors on the cell membrane.

- T-cell system is not well understood. Acts like the Ig but does not secrete antibodies.
Multigene families – Evolutionary significance

c) Environmental flexibility

The P450 family of cytochrome oxidases

These are involved in oxidative metabolism of a wide range of
compounds such as prostaglandins, steroids, fatty acids, various plant
products, drugs, environmental toxins, carcinogens, pesticides etc.

The P450 of families have various mono-oxygenase activities ranging

from oxidation of aliphatic compounds, to oxidative deamination, to
sulfoxide formation and hydroxylation of aromatic compounds among
others.
 Multigene families – Evolutionary significance
c) Environmental flexibility

The P450 family of cytochrome oxidases

These enzymes allow the liver to detoxify the different toxic compounds
in the environment. This allows the organism to ingest a wide array of
food and survive in a wide range of environments.

It is a widely dispersed family with genes present in seven chromosomes

in 8 clusters.

Cytochrome mono-oxygenase
Multigene families – Evolutionary significance

c) Environmental flexibility

Amylase gene family

The human alpha amylase family contains five active genes and
one pseudogene.

- two code for pancreatic amylase

- three code for amylases in saliva (parotid glands)

Trypsin gene family

Trypsin is secreted by the pancreas and is cleaved to its active form in
the small intestine.