MOLECULAR EVOLUTION

MOLECULAR EVOLUTION 

Questo documento è pubblicato sotto licenza Creative Commons 

Attribuzione – Non commerciale – Condividi allo stesso modo 

http://creativecommons.org/licenses/by-nc-sa/2.5/deed.it 

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. 



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 



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. 



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. 



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 



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? 



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. 



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. 



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 



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. 



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. 



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 



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 



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

MOLECULAR EVOLUTION

Create successful ePaper yourself

Delete template?

Save as template?