Homologous genes

Genetica per Scienze Naturalia.a. 05-06 prof S. Presciuttini

Homologous genes Genes with similar functions can be found in a diverse range of living Genes with similar functions can be found in a diverse range of living

things.things. The great revelation of the past 20 years has been the discovery that The great revelation of the past 20 years has been the discovery that

the actual nucleotide sequences of many genes are sufficiently well the actual nucleotide sequences of many genes are sufficiently well conserved that homologous genes—that is, genes that are similar in conserved that homologous genes—that is, genes that are similar in their nucleotide sequence because of a common ancestry—can often their nucleotide sequence because of a common ancestry—can often be recognized across vast phylogenetic distances.be recognized across vast phylogenetic distances.

For example, unmistakable homologs of many human genes are easy For example, unmistakable homologs of many human genes are easy to detect in such organisms as nematode worms, fruit flies, yeasts, and to detect in such organisms as nematode worms, fruit flies, yeasts, and even bacteria.even bacteria.


Similarity of nucleotide sequences Homologous genes are ones that share a common evolutionary Homologous genes are ones that share a common evolutionary

ancestor, revealed by sequence similarities between the genes. These ancestor, revealed by sequence similarities between the genes. These similarities form the data on which molecular phylogenies are based. similarities form the data on which molecular phylogenies are based. Homologous genes fall into two categories:Homologous genes fall into two categories: Orthologous genes are those homologs that are present in different organisms Orthologous genes are those homologs that are present in different organisms

and whose common ancestor predates the split between the species.and whose common ancestor predates the split between the species. Paralogous genes are present in the same organism, often members of a Paralogous genes are present in the same organism, often members of a

recognized multigene family, their common ancestor possibly or possibly not recognized multigene family, their common ancestor possibly or possibly not predating the species in which the genes are now found.predating the species in which the genes are now found.

A pair of homologous genes do not usually have identical nucleotide A pair of homologous genes do not usually have identical nucleotide sequences, because the two genes undergo different random changes sequences, because the two genes undergo different random changes by mutation, but they have similar sequences because these random by mutation, but they have similar sequences because these random changes have operated on the same starting sequence, the common changes have operated on the same starting sequence, the common ancestral gene. ancestral gene.

Two DNA sequences with 80% sequence identity


Reconstructing extinct gene sequences For closely related organisms such as humans and chimpanzees, it is For closely related organisms such as humans and chimpanzees, it is

possible to reconstruct the gene sequences of the extinct, last common possible to reconstruct the gene sequences of the extinct, last common ancestor of the two species.ancestor of the two species.

The close similarity between human and chimpanzee genes is mainly The close similarity between human and chimpanzee genes is mainly due to the short time that has been available for the accumulation of due to the short time that has been available for the accumulation of mutations in the two diverging lineages, rather than to functional mutations in the two diverging lineages, rather than to functional constraints that have kept the sequences the same.constraints that have kept the sequences the same.

Evidence for this view comes from the observation that even DNA Evidence for this view comes from the observation that even DNA sequences whose nucleotide order is functionally unconstrained — sequences whose nucleotide order is functionally unconstrained — such as the third position of “synonymous” codons — are nearly such as the third position of “synonymous” codons — are nearly identical.identical.


Human and chimpanzee leptin genes

For convenience, only the first 300 For convenience, only the first 300 nucleotides of the leptin coding nucleotides of the leptin coding sequences are given.sequences are given.Only 5 codons (of 441 nucleotides Only 5 codons (of 441 nucleotides total) differ between these two total) differ between these two sequences, and in only one does the sequences, and in only one does the encoded amino acid differ. The encoded amino acid differ. The corresponding sequence in the corresponding sequence in the gorilla is also indicated. In two gorilla is also indicated. In two cases, the gorilla sequence agrees cases, the gorilla sequence agrees with the human sequence, while in with the human sequence, while in three cases it agrees with the three cases it agrees with the chimpanzee sequence.chimpanzee sequence.

Leptin is a hormone that regulates food intake and energy utilization in Leptin is a hormone that regulates food intake and energy utilization in response to the adequacy of fat reserves.response to the adequacy of fat reserves.


Which individual’s DNA have to be compared? In comparisons between two species that have diverged from one In comparisons between two species that have diverged from one

another by millions of years, it makes little difference which another by millions of years, it makes little difference which individuals from each species are compared.individuals from each species are compared. For example, typical human and chimpanzee DNA sequences differ from one 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 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 from two different humans, the differences are typically less than 0.1%. For more distantly related organisms, the inter-species differences overshadow more distantly related organisms, the inter-species differences overshadow intra-species variation even more dramatically.intra-species variation even more dramatically.

However, each “fixed difference” between the human and the However, each “fixed difference” between the human and the chimpanzee (i.e., each difference that is now characteristic of all or 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 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 a single individual. How does such a rare mutation become fixed in the population, and hence become a characteristic of the species rather the population, and hence become a characteristic of the species rather than of a particular individual genome?than of a particular individual genome?


A mosaic of small DNA pieces The answer to the previous question depends on the functional The answer to the previous question depends on the functional

consequences of the mutation. If the mutation has a significantly consequences of the mutation. If the mutation has a significantly deleterious effect, it will simply be eliminated by purifying selection deleterious effect, it will simply be eliminated by purifying selection and will not become fixed. (In the most extreme case, the individual and will not become fixed. (In the most extreme case, the individual carrying the mutation will die without producing progeny.) carrying the mutation will die without producing progeny.)

Conversely, the rare mutations that confer a major reproductive Conversely, the rare mutations that confer a major reproductive advantage on individuals who inherit them will spread rapidly in the advantage on individuals who inherit them will spread rapidly in the population. Because humans reproduce sexually and genetic population. Because humans reproduce sexually and genetic recombination occurs each time a gamete is formed, the genome of recombination occurs each time a gamete is formed, the genome of each individual who has inherited the mutation will be a unique each individual who has inherited the mutation will be a unique recombinational mosaic of segments inherited from a large number of recombinational mosaic of segments inherited from a large number of ancestors.ancestors.

The selected mutation along with a modest amount of neighboring The selected mutation along with a modest amount of neighboring sequence — ultimately inherited from the individual in which the sequence — ultimately inherited from the individual in which the mutation occurred — will simply be one piece of this huge mosaic.mutation occurred — will simply be one piece of this huge mosaic.


Functional Constraint Changes to genes that diminish an organism's ability to survive and Changes to genes that diminish an organism's ability to survive and

reproduce are typically removed from the gene pool by the process of reproduce are typically removed from the gene pool by the process of natural selection.natural selection.

Portions of genes that are especially important are said to be under Portions of genes that are especially important are said to be under functional constraint and tend to accumulate changes very slowly over functional constraint and tend to accumulate changes very slowly over the course of evolution.the course of evolution.

Different portions of genes do accumulate changes at widely differing Different portions of genes do accumulate changes at widely differing rates that reflect the extent to which they are functionally constrained.rates that reflect the extent to which they are functionally constrained. Changes at the nucleotide level of coding sequence that do not change Changes at the nucleotide level of coding sequence that do not change

the amino acid sequence of a protein are called synonymous the amino acid sequence of a protein are called synonymous substitutions.substitutions.

In contrast, changes at the nucleotide level of coding sequence that do In contrast, changes at the nucleotide level of coding sequence that do change the amino acid sequence of a protein are called nonsynonymous change the amino acid sequence of a protein are called nonsynonymous substitutions.substitutions.


Differences among nucleotide substitution rates Nucleotide substitution Nucleotide substitution

rates differ among rates differ among different portions of the different portions of the genesgenes

Highest rates are typical Highest rates are typical of pseudogenes, lowest of pseudogenes, lowest rates are characteristic rates are characteristic of non-synonymous of non-synonymous substitutionssubstitutions


Effect of functional constraints

Average pairwise divergence among different regions of the human, Average pairwise divergence among different regions of the human, mouse, rabbit, and cow beta-like globin genesmouse, rabbit, and cow beta-like globin genes

3.6014.376.33003' Flanking sequence

3.0011.533.01323' Untranslated sequence

3.488.141.8131Intron 1



1.5816.769.2441Coding, overall

3.3314.167.9913Noncoding, overall

Substitution Rate (substitutions/ site/109 year)

Standard Deviation

Average Pairwise Number of Changes

Length of Region (bp) in

HumanRegion



3.488.141.8131Intron 1



1.5816.769.2441Coding, overall

3.3314.167.9913Noncoding, overall

Substitution Rate (substitutions/ site/109 year)

Standard Deviation

Average Pairwise Number of Changes

Length of Region (bp) in

HumanRegion


The ancestor sequence What was the sequence of the leptin gene in the last common ancestor What was the sequence of the leptin gene in the last common ancestor

of human and chimpanzee?of human and chimpanzee? We know from other evidences that human and chimpanzee are more We know from other evidences that human and chimpanzee are more

closely related one to each other than any of them to gorillaclosely related one to each other than any of them to gorilla An evolutionary model that seeks to minimize the number of An evolutionary model that seeks to minimize the number of

mutations postulated to have occurred during the evolution of the mutations postulated to have occurred during the evolution of the human and chimpanzee genes would assume that the leptin sequence human and chimpanzee genes would assume that the leptin sequence of the last common ancestor was the same as the human and of the last common ancestor was the same as the human and chimpanzee sequences when they agreechimpanzee sequences when they agree

When they disagree, it would use the gorilla sequence as a tie-breaker.When they disagree, it would use the gorilla sequence as a tie-breaker.


On men and mice The human and chimpanzee genomes are much more alike than are, The human and chimpanzee genomes are much more alike than are,

say, the human and mouse genomes.say, the human and mouse genomes. Although the size of mouse and human/chimp genomes is Although the size of mouse and human/chimp genomes is

approximately the same and the sets of genes is nearly identical, there 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 has been a much longer time period over which changes have had a chance to accumulate—approximately 100 million years versus 5 chance to accumulate—approximately 100 million years versus 5 million years.million years. It may also be that rodents have significantly higher mutation rates than It may also be that rodents have significantly higher mutation rates than

primates; in this case the great divergence of the human and mouse 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 genomes would be dominated by a high rate of sequence change in the rodent lineage. Lineage-specific differences in mutation rates are, rodent lineage. Lineage-specific differences in mutation rates are, however, difficult to estimate reliably, and their contribution to the however, difficult to estimate reliably, and their contribution to the patterns of sequence divergence observed among contemporary patterns of sequence divergence observed among contemporary organisms remains controversial.organisms remains controversial.


Mouse and human leptin genes Comparison of a portion of the mouse and human leptin genes.Comparison of a portion of the mouse and human leptin genes.

Positions where the sequences differ by a single nucleotide substitution Positions where the sequences differ by a single nucleotide substitution are boxed in green, and positions that differ by the addition or deletion of are boxed in green, and positions that differ by the addition or deletion of nucleotides are boxed in yellow.nucleotides are boxed in yellow.

Note that the coding sequence of the exon is much more conserved Note that the coding sequence of the exon is much more conserved than the adjacent intron sequence.than the adjacent intron sequence.


Purifying selection at work As indicated by the DNA sequence comparison, mutation has led to As indicated by the DNA sequence comparison, mutation has led to

extensive sequence divergence between humans and mice at all sites extensive sequence divergence between humans and mice at all sites that are not under selection—such as the nucleotide sequences of that are not under selection—such as the nucleotide sequences of introns.introns.

Indeed, human-mouse-sequence comparisons are much more Indeed, human-mouse-sequence comparisons are much more informative of the functional constraints on genes than are human-informative of the functional constraints on genes than are human-chimpanzee comparisons.chimpanzee comparisons. In the latter case, nearly all sequence positions are the same simply In the latter case, nearly all sequence positions are the same simply

because not enough time has elapsed since the last common ancestor for because not enough time has elapsed since the last common ancestor for large numbers of changes to have occurred.large numbers of changes to have occurred.

In contrast, because of functional constraints in human-mouse In contrast, because of functional constraints in human-mouse comparisons the exons in genes stand out as small islands of comparisons the exons in genes stand out as small islands of conservation in a sea of introns.conservation in a sea of introns.

The sequence conservation found in genes of human and mouse is The sequence conservation found in genes of human and mouse is largely due to largely due to purifying selectionpurifying selection, rather than to inadequate time for , rather than to inadequate time for mutations to occur. As a result, protein-coding sequences and regulatory mutations to occur. As a result, protein-coding sequences and regulatory sequences are often remarkably conserved. In contrast, most DNA sequences are often remarkably conserved. In contrast, most DNA sequences in the human and mouse genomes have diverged so far that it sequences in the human and mouse genomes have diverged so far that it is often impossible to align them with one another.is often impossible to align them with one another.

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Homologous genes