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Homologous genes
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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. 05-06 prof S. Presciuttini
Similarity of nucleotide sequences
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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:
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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. 05-06 prof S. Presciuttini
Reconstructing extinct gene sequences
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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. 05-06 prof S. Presciuttini
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. 05-06 prof S. Presciuttini
Which individual’s DNA have to be compared?
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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.
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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 intraspecies 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. 05-06 prof S. Presciuttini
A mosaic of small DNA pieces
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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. 05-06 prof S. Presciuttini
Functional Constraint
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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.
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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. 05-06 prof S. Presciuttini
Differences among nucleotide substitution rates
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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. 05-06 prof S. Presciuttini
Effect of functional constraints
Length of
Region (bp) in
Human
Average Pairwise
Number of
Changes
Standard
Deviation
Substitution Rate
(substitutions/
site/109 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
Region
Average pairwise divergence among different regions of the human,
mouse, rabbit, and cow beta-like globin genes
Genetica per Scienze Naturali
a.a. 05-06 prof S. Presciuttini
The ancestor sequence
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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.
Genetica per Scienze Naturali
a.a. 05-06 prof S. Presciuttini
On men and mice
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The human and chimpanzee genomes are much more alike than are,
say, the human and mouse genomes.
Although the size of mouse and human/chimp genomes is
approximately the same and the sets of genes is nearly identical, there
has been a much longer time period over which changes have had a
chance to accumulate—approximately 100 million years versus 5
million years.
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It may also be that rodents have significantly higher mutation rates than
primates; in this case the great divergence of the human and mouse
genomes would be dominated by a high rate of sequence change in the
rodent lineage. Lineage-specific differences in mutation rates are,
however, difficult to estimate reliably, and their contribution to the
patterns of sequence divergence observed among contemporary
organisms remains controversial.
Genetica per Scienze Naturali
a.a. 05-06 prof S. Presciuttini
Mouse and human leptin genes
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Comparison of a portion of the mouse and human leptin genes.
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Positions where the sequences differ by a single nucleotide substitution
are boxed in green, and positions that differ by the addition or deletion of
nucleotides are boxed in yellow.
Note that the coding sequence of the exon is much more conserved
than the adjacent intron sequence.
Genetica per Scienze Naturali
a.a. 05-06 prof S. Presciuttini
Purifying selection at work
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As indicated by the DNA sequence comparison, mutation has led to
extensive sequence divergence between humans and mice at all sites
that are not under selection—such as the nucleotide sequences of
introns.
Indeed, human-mouse-sequence comparisons are much more
informative of the functional constraints on genes than are humanchimpanzee comparisons.
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In the latter case, nearly all sequence positions are the same simply
because not enough time has elapsed since the last common ancestor for
large numbers of changes to have occurred.
In contrast, because of functional constraints in human-mouse
comparisons the exons in genes stand out as small islands of
conservation in a sea of introns.
The sequence conservation found in genes of human and mouse is
largely due to purifying selection, rather than to inadequate time for
mutations to occur. As a result, protein-coding sequences and regulatory
sequences are often remarkably conserved. In contrast, most DNA
sequences in the human and mouse genomes have diverged so far that it
is often impossible to align them with one another.
Genetica per Scienze Naturali
a.a. 05-06 prof S. Presciuttini