MOLECULAR EVOLUTION

MOLECULAR EVOLUTION
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Genetica per Scienze Naturali
a.a. 08-09 prof S. Presciuttini

1. Homologous genes
Genes with similar functions can be found in a diverse range of living
things.
The great revelation of the past 20 years has been the discovery that
the actual nucleotide sequences of many genes are sufficiently well
conserved that homologous genes—that is, genes that are similar in
their nucleotide sequence because of a common ancestry—can often
be recognized across vast phylogenetic distances.
For example, unmistakable homologs of many human genes are easy
to detect in such organisms as nematode worms, fruit flies, yeasts, and
even bacteria.
Genetica per Scienze Naturali
a.a. 08-09 prof S. Presciuttini

2. Similarity of nucleotide sequences
Homologous genes are ones that share a common evolutionary
ancestor, revealed by sequence similarities between the genes. These
similarities form the data on which molecular phylogenies are based.
Homologous genes fall into two categories:
Orthologous genes are those homologs that are present in different organisms
and whose common ancestor predates the split between the species.
Paralogous genes are present in the same organism, often members of a
recognized multigene family, their common ancestor possibly or possibly not
predating the species in which the genes are now found.
A pair of homologous genes do not usually have identical nucleotide
sequences, because the two genes undergo different random changes
by mutation, but they have similar sequences because these random
changes have operated on the same starting sequence, the common
ancestral gene.
Two DNA sequences with 80% sequence identity
Genetica per Scienze Naturali
a.a. 08-09 prof S. Presciuttini

3. Reconstructing extinct gene sequences
For closely related organisms such as humans and chimpanzees, it is
possible to reconstruct the gene sequences of the extinct, last common
ancestor of the two species.
The close similarity between human and chimpanzee genes is mainly
due to the short time that has been available for the accumulation of
mutations in the two diverging lineages, rather than to functional
constraints that have kept the sequences the same.
Evidence for this view comes from the observation that even DNA
sequences whose nucleotide order is functionally unconstrained —
such as the third position of “synonymous” codons — are nearly
identical.
Genetica per Scienze Naturali
a.a. 08-09 prof S. Presciuttini

4. Human and chimpanzee leptin genes
Leptin is a hormone that regulates food intake and energy utilization in
response to the adequacy of fat reserves.
For convenience, only the first 300
nucleotides of the leptin coding
sequences are given.
Only 5 codons (of 441 nucleotides
total) differ between these two
sequences, and in only one does the
encoded amino acid differ. The
corresponding sequence in the
gorilla is also indicated. In two
cases, the gorilla sequence agrees
with the human sequence, while in
three cases it agrees with the
chimpanzee sequence.
Genetica per Scienze Naturali
a.a. 08-09 prof S. Presciuttini

5. The ancestor sequence
What was the sequence of the leptin gene in the last common ancestor
of human and chimpanzee?
We know from other evidences that human and chimpanzee are more
closely related one to each other than any of them to gorilla
An evolutionary model that seeks to minimize the number of
mutations postulated to have occurred during the evolution of the
human and chimpanzee genes would assume that the leptin sequence
of the last common ancestor was the same as the human and
chimpanzee sequences when they agree
When they disagree, it would use the gorilla sequence as a tie-breaker.
Therefore, the sequence of the common ancestor underwent three
substitutions (at position 2, 4 and 5 of the five differences) in the
human lineage, and two substitutions (at positions 1 and 3) in the
chimpanzee lineage
Genetica per Scienze Naturali
a.a. 08-09 prof S. Presciuttini

6. Which individual’s DNA have to be compared?
In comparisons between two species that have diverged from one
another by millions of years, it makes little difference which
individuals from each species are compared.
For example, typical human and chimpanzee DNA sequences differ from one
another by 1%. In contrast, when the same region of the genome is sampled
from two different humans, the differences are typically less than 0.1%. For
more distantly related organisms, the inter-species differences overshadow
intra-species variation even more dramatically.
However, each “fixed difference” between the human and the
chimpanzee (i.e., each difference that is now characteristic of all or
nearly all individuals of each species) started out as a new mutation in
a single individual. How does such a rare mutation become fixed in
the population, and hence become a characteristic of the species rather
than of a particular individual genome?
Genetica per Scienze Naturali
a.a. 08-09 prof S. Presciuttini

7. A mosaic of small DNA pieces
The answer to the previous question depends on the functional
consequences of the mutation. If the mutation has a significantly
deleterious effect, it will simply be eliminated by purifying selection
and will not become fixed. (In the most extreme case, the individual
carrying the mutation will die without producing progeny.)
Conversely, the rare mutations that confer a major reproductive
advantage on individuals who inherit them will spread rapidly in the
population. Because humans reproduce sexually and genetic
recombination occurs each time a gamete is formed, the genome of
each individual who has inherited the mutation will be a unique
recombinational mosaic of segments inherited from a large number of
ancestors.
The selected mutation along with a modest amount of neighboring
sequence — ultimately inherited from the individual in which the
mutation occurred — will simply be one piece of this huge mosaic.
Genetica per Scienze Naturali
a.a. 08-09 prof S. Presciuttini

8. Functional Constraint
Changes to genes that diminish an organism's ability to survive and
reproduce are typically removed from the gene pool by the process of
natural selection.
Portions of genes that are especially important are said to be under
functional constraint and tend to accumulate changes very slowly over
the course of evolution.
Different portions of genes do accumulate changes at widely differing
rates that reflect the extent to which they are functionally constrained.
Changes at the nucleotide level of coding sequence that do not change
the amino acid sequence of a protein are called synonymous
substitutions.
In contrast, changes at the nucleotide level of coding sequence that do
change the amino acid sequence of a protein are called nonsynonymous
substitutions.
Genetica per Scienze Naturali
a.a. 08-09 prof S. Presciuttini

9. The molecular clock
The integrated phylogenetic trees support the basic idea that changes
in the sequences of particular genes or proteins occur at a constant
rate, at least in the lineages of organisms whose generation times and
overall biological characteristics are quite similar to one another.
This apparent constancy in the rates at which sequences change is
referred to as the molecular-clock hypothesis.
Molecular clocks have a finer time resolution than the fossil record
and are a more reliable guide to the detailed structure of phylogenetic
trees than are classical methods of tree construction, which are based
on comparisons of the morphology and development of different
species. For example, the precise relationship among the great-ape
and human lineages was not settled until sufficient molecularsequence
data accumulated in the 1980s to produce the tree that was
shown
Genetica per Scienze Naturali
a.a. 08-09 prof S. Presciuttini

10. Rate of molecular evolution
The constant rate of neutral substitution predicts that, if the number of
nucleotide differences between two species is plotted against the time
since their divergence from a common ancestor, the result should be a
straight line with a slope equal to μ.
That is, evolution should proceed according to a molecular clock that
is ticking at the rate μ.
Because molecular clocks run at rates that are determined both by
mutation rates and by the amount of purifying selection on particular
sequences, a different calibration is required for genes replicated and
repaired by different systems within cells.
Most notably, clocks based on functionally unconstrained
mitochondrial DNA sequences run much faster than clocks based on
functionally unconstrained nuclear sequences because of the high
mutation rate in mitochondria.
Genetica per Scienze Naturali
a.a. 08-09 prof S. Presciuttini

11. Nucleotide substitutions in the β-globin gene
A plot of synonymous and nonsynonymous substitutions for the β-
globin gene. The slope for nonsynonymous substitutions is much
lower than that for synonymous changes, which means that the
mutation rate to nonsynonymous substitutions is much lower than that
to synonymous ones.
Genetica per Scienze Naturali
a.a. 08-09 prof S. Presciuttini

12. Differences among nucleotide substitution rates
Nucleotide substitution
rates differ among
different portions of the
genes
Highest rates are typical
of pseudogenes, lowest
rates are characteristic
of non-synonymous
substitutions
Genetica per Scienze Naturali
a.a. 08-09 prof S. Presciuttini

13. Effect of functional constraints
Region
Length of
Region (bp) in
Human
Average Pairwise
Number of
Changes
Standard
Deviation
Substitution Rate
(substitutions/
site/10 9 year)
Noncoding, overall
913
67.9
14.1
3.33
Coding, overall
441
69.2
16.7
1.58
5' Flanking sequence
300
96.0
19.6
3.39
5' Untranslated sequence
50
9.0
3.0
1.86
Intron 1
131
41.8
8.1
3.48
3' Untranslated sequence
132
33.0
11.5
3.00
3' Flanking sequence
300
76.3
14.3
3.60
Average pairwise divergence among different regions of the human,
mouse, rabbit, and cow beta-like globin genes
Genetica per Scienze Naturali
a.a. 08-09 prof S. Presciuttini

14. Different clok rates in different proteins
Another prediction of neutral evolution is that different proteins will have different
clock rates, because the metabolic function of some proteins will be much more
sensitive to changes in their amino acid sequence. Proteins in which every amino acid
makes a difference will have smaller values of the neutral mutation rate than will
proteins that are more tolerant of substitution.
A comparison of the clocks for
fibrinopeptides, hemoglobin, and
cytochrome c. That fibrinopeptides
have a much higher proportion of
neutral mutations is reasonable
because these peptides are merely a
nonmetabolic safety catch, cut out of
fibrinogen to activate the blood-
clotting reaction. From a priori
considerations, why hemoglobins are
less sensitive to amino acid changes
than is cytochrome c is less obvious
Genetica per Scienze Naturali
a.a. 08-09 prof S. Presciuttini