POSITIVE SELECTION

 

EVOLUTIONARY MODEL

If the evolution model is correct, mutations can lead to adaptive changes in the genome. Beneficial changes to the ancestral genome should be evident (although the specific environment often determines what is beneficial). In comparing human and chimp genomes, positive selection should be evident in the sequences which were preferentially modified to derive humans from their ape ancestors.

CREATIONISM MODEL

If creationism is correct, then mutations are not capable of causing an adaptive change.

INTELLIGENT DESIGN

If intelligent design is correct, then complex mechanisms cannot be modified by the gradual accumulation of mutations.

Are all mutations bad? The best studied mutations are those which have a deleterious affect. A person whose health is worse than average for unknown reason is more likely to investigate than a person whose health is better than average for unknown reasons. Researchers requesting grants are more likely to be approved if they are studying the causes of illness. Many researchers who study mutations in animals simply find it easier to identify a mutation which causes a large-scale negative change than a small-scale positive one. Often, mutations are specifically generated so that a gene no longer functions and, by studying the deficits a researcher can study the normal function of the gene. Not all mutations are negative. Of the 175 mutations estimated to occur in any one individual's original genome, only about 10 are thought to be harmful. Mutations are ultimately the source of variation which make one person different from another, one dog different from another, a dog different from a wolf, and a human different from a chimp.

By definition, any allele of a gene which is found in less than 1% of the population is a mutant allele. However, if a mutation has a positive effect, natural selection will increase its frequency. Eventually, the once mutant allele may become fixed in a population. It is estimated that an adaptive change in protein sequence is fixed in Drosophila species once every 45 years (Smith, 2002). When comparing human and chimp genomes, it is evident that some genes in each lineage have undergone positive selection because their rate of change is higher than that predicted by chance (Ellegren, ;Lu, 2005). Of the amino acid differences between human and chimp proteins, it is estimated that between 10 and 13% are adaptive and were fixed by positive selection (Gojobori, 2007).

The genes which have undergone a positive selection in the human lineage since its divergence from the lineage of chimps include genes for olfactory receptors, skeletal development (TLL2, ALPL, BMP4, SDC2, MMP20, and MGP), the development of the nervous system (*NLGN3, SEMA3B, PLXNC1, NTF3, WNT2, WIF1, EPHB6, NEUROG1, and S1M2), and homeodomain transcription factors (CDX4, HOXA5, HOXD4, MEOX2, POU2F3, MIXL1, and PHTF). A gene required for speech, forkhead-box P2 and a gene involved in hearing, tectorin, have also undergone selection in the human lineage (Clark, 2003). In addition to microcephalin and ASPM, two additional genes whose mutations cause microcephaly have undergone positive selection in primates in general and the human lineage, specifically (Evans, 2006).

Beneficial genes in humans include lactase persistence, chemokine receptors variants which reduce HIV infection (and may have been selected for in Europeans as an adaptation against smallpox infection), Duffy negative alleles (whose percentage approaches fixation in central Africa and which offers close to complete protection from vivax malaria), The alleles for cystic fibrosis may have originally been selected for as a protection from typhoid fever whose infection utilizes the CFTR protein (Harpending, 2006; OMIM).

Immune defenses are improved by mutations which produce greater variability in the antigen binding capabilities of the MHC complex. One of the many interesting features of the MHC complex is the polymorphism which exists at many of the loci. Unlike most genes in the genome, there appears to be a selective pressure to create variation in these genes and most alleles differ by multiple nucleotides. Individual MHC genes may exist with more than 100 alleles in some species and are the most polymorphic vertebrate genes known (Penn, 1998). Some MHC genes have more than 400 alleles (Anzai, 2003). More than 1500 alleles of the HLA genes in the MHC and the most common changes from ancestral alleles are in the peptide binding regions where there are more nonsynonomous substitutions than synonomymous (OMIM; Reche, 2003).

The region of the human genome which includes the MC1R gene is one of the most variable nucleotide sequences in humans. The activity of this gene affects pigmentation of skin and hair which not only affects susceptibility to skin cancer (especially in tropical regions), it also has produced many of the normal variations which contribute to human diversity (such as hair color; Makova, 2005).

Within human populations, there are three major alleles for the Duffy blood group locus, which encodes the Fy chemokine receptor on a variety of cell types throughout the body. The FY*O allele represents a mutation in the GATA1 regulatory element which prevents transcription in red blood cells, although the gene is still active in other cells. This change prevents infection by the malarial parasite Plasmodium vivax which requires the receptor for infection of red blood cells. This allele is essentially fixed in Sub-Saharan Africa as a result of natural selection. If this allele had existed prior to the migration of early humans out of Africa 100,000 years ago, its frequencies outside Africa would be expected to be higher (Hamblin, 2000).

The chimpanzee Apolipoprotein E gene sequence is closest to the sequence of the human E4 allele. The frequency of the E4 allele varies from .05 in Sardiaians to .41 in Pygmies. The E2 and E3 alleles seem to be recent changes. E2 and E3 alleles are not associated with the increased risk of heart disease and Alzheimer's which has been reported for E4 alleles. The high frequency of E3 alleles in many human populations seems to be the result of positive natural selection (Fullerton, 2000).

Beneficial mutations are known in many species. Obviously, the environmental conditions often determine what is beneficial. Farmers and animal breeders have been fostering gene combinations which they have defined as beneficial in organisms as diverse as corn, potatoes, wheat, dogs, cattle, horses, and doves. After maintaining Escherichia coli evolving in the laboratory for 10,000 generations, populations have been shown to increase their fitness, evolved a number of noticeable changes, and develop unique DNA fingerprints (Papadopoulos, 1999). There are a number of mutations which are known in animals which affect their muscle in ways which are either advantageous to humans who eat them or for athletic ability (as in racehorses) (Harpending, 2006). Forty years of selection in silver foxes produced docile populations (Raven, 2002). Evidence for targets of positive selection are known in fruit flies (Aquadro, 2001).

The ability of some yeasts (flor yeasts) to form a biofilm which sustains them at a liquid surface is controlled by two adaptive changes in an ancestral FLO11 gene. A deletion in a repressor region increases gene expression and rearrangements make the gene product more hydrophobic (Fidalgo, 2006).

Similar mutations can occur independently in separate lineages. For example, modifications of the gene Pitx was a factor in the reduction of the pelvic girdle in unrelated lineages of stickleback fish and manatees (Shapiro, 2006).

NUCLEOTIDE SUBSTITUTION
If the creationism and intelligent design models are correct, simple mutations that change the amino acid order of a protein shouldn't yield significant changes which are potentially adaptive.


All sodium and calcium channels are formed by a single protein which is formed by four tandem regions composed of 6 transmembrane regions (Anderson, 2001). Single amino acid substitutions can change the specificity of the ion channel from sodium to calcium (Plummer, 1999).

Serine proteases represent an ancient gene family, including eubacterial digestive enzymes (and the vertebrate digestive enzymes trypsin and chymotrypsin). Most of these proteins have the amino acid proline at residue 225 in the protein. However, in vertebrates, some of these proteins possess the amino acid serine at residue 225. This enabled the binding of sodium and novel protein function. Some serine proteases in blood (such as plasmin and clotting factor XIa) possess a proline at site 225 while others such as thrombin, clotting factor Xa (involved in clotting), and complement protein C1r (involved in immunity) possess a serine. Mutations at site 225 drastically affect the function of thrombin (affecting ligand recognition up to 60,000 times). The change in some of the serine proteases needed to acquire a function in coagulation seems to stem from one ancestral mutation changing the amino acid at residue 225 (Guinto,1998; Dang, 1996).

POSITIVE SELECTION

Adaptive changes in genes are evident when the genomes of related species (such as Drosophila melanogaster and D. simulans) are compared and amino acid substitutions in specific genes are significantly higher than the number expected under neutral drift (Shapiro, 2007). Comparisons of human and chimp genomes reveal regions that have undergone modifications at rates much higher than background rates, indicative of positive selection (Hawks, 2007). Using mice as an outgroup, more changes can be identified in chimp genomes than in human genomes indicating that the chimp lineage has undergone a greater amount of positive selection than the human lineage (Bakewell, 2007).