MUTATION

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

You are a mutant. Genetic changes occurred in the production of the gametes which led to your conception that are not present in the somatic cells throughout the bodies of your parents. Not only are you a mutant, but you are a mutant more than a hundred times over. Everyone you know is a mutant. Every figure in history ranging from the founding fathers of the U.S. to ancient religious prophets were mutants. Your great-grandchildren will be mutants.
How should we view mutation?

 

 

EVOLUTIONARY MODEL

If the evolutionary model of life's diversity is true, then mutations, although often deleterious, are the ultimate biological source of the great diversity of the biological world. Mutations and the variation which results from them are the reason that every person, every dog, every fly, and every flower is unique. (Even twins, if we were to examine the DNA of every cell in their bodies, could be distinguished by unique mutations.) When reproductively isolated, populations of a species will vary depending upon which mutations become fixed. Eventually, mutations can lead to new species and new adaptations. The first fish were chordates which accumulated millions of mutations over millions of years. The first amphibians were fish which accumulated millions of mutations. In the same way, the first reptiles were mutant amphibians, the first mammals were mutant reptiles, and the first hominids were apes. The first Bantu, Cheyenne, Celts, Hindi, and Ainu possessed mutations which distinguished them from other populations of humans. The mutations which were generated by you, your parents, and your grandparents may someday become the standard variants in the human genome and may someday contribute to future generations' ability to adapt to the challenges of their world.

CREATIONISM MODEL

If the creationist model is true, mutation is a curse. When the original progenitors of every kind of organism appeared a few thousand years ago, they were genetically perfect and through some unknown genetic mechanism, stored all the genetic variation within them which would lead to any positive change which would develop in the billions upon billions of descendants which might arise from their lineage. When Adam and Eve ate an apple, every single type of organism ranging from bacteria to fruit flies to mice to people (and even apples) were genetically modified so that their genomes would gradually degrade from its initial perfect state. Even though countless mutations would occur during the history of life, not a single one would contribute a single positive attribute to future generations. The many mutations which arose in your cells and the cells of every person that you know will lead to no positive result and have removed you farther from the perfect human state. As mutations accumulate over time, every species on earth is doomed to a gradual degeneration.

INTELLIGENT DESIGN

If intelligent design is true, then mutations can actually lead to novel developments in modern species-just nothing complicated. Any anatomical or physiological change involving multiple interacting parts is potentially "irreducibly complex" and mutations in any part would be utterly incapable of producing a modification of the whole. While natural processes could result in small modifications of life, any significant modification would require supernatural intervention into genomic restructuring.

 

 

 

 

Which of these three models is most consistent with genetic analysis of mutations?


MUTATION RATES

The average mutation rate in humans is thought to be about 2.5 x 10-8 mutations per nucleotide per generation, resulting in 175 new mutations per diploid genome generation Of these175 new mutations per diploid generation,10 are deleterious (Reed, 2006; Nachman, 2000). Thus, every human is a mutant (and the host of well over 100 new mutations, at that). Given that the average spontaneous generation rate would produce multiple mutations per male gamete, a man who makes the average of 300 million gametes in a day will generate more separate changes to the human genome in one day than separate the human genome from that of chimps. In fact, given that the human genome contains 3 billion nucleotides, each man could potentially mutate every single nucleotide of the human genome in at least one sperm every single day.

Humans are not the only organisms which undergo frequent mutations. Viruses undergo mutations. The mutation rates in RNA viruses vary from an average of 1 per replication in lytic viruses to 1 per every 10 replications in retroviruses and retrotransposons (Drake, 1998). Mutation and shuffling of genetic information produces new viruses such as the H5N1 virus (which has a 50% mortality), the flu viruses of 1957 and 1968 (which were produced by reassorting genes from separate strains and which killed 70,000 and 34,000 people in the U.S. respectively), and the Spanish Flu virus (which mutated from an avian strain and killed 40 million people worldwide and 675,000 in the U.S.) (Skeik, 2007).
Bacteria undergo frequent mutations. Given that bacteria possess thousands of genes (almost 4300 in E.coli), the mutation rates in bacteria are high enough that a researcher who inoculated a broth culture with one bacterium could produce millions of new mutations in a day. [Bacteria such as E.coli and Y. pestis vary in the number of mutations at a specific gene per generation (8.5 × 10-6 to 3.7 × 10-4 mutations/generation in Yersinia and 4.0 × 10-4 to 3.4 × 10-6 mutations/generation in E. coli (Vogler, 2007).] Under certain conditions, bacteria undergo increases in spontaneous mutation rates (such after mutator mutations) which can increase the rate more than 1000 times (Drake, 1998).

With a mutation rate of 1.7 x 10-10 and a genome size of 15 million bases, more than 0.2% of yeast possess new mutations. In general, it is thought that mutation rates in higher eukaryotes vary from 0.1 to 100 per sexual generation (Drake, 1998). In the plant Zea mays the average mutation rate per locus per gamete is 7.7 x 10-5 (Drake, 1998). If the mutation rate (the number of mutations per base pair per genome replication) is estimated 1.5 × 10-10 in nematodes which have 110 million base pairs in their genome, then almost 2% of nematodes are mutant. (Given that each nematode can produce up to 1000 offspring within 3 days of their conception, new mutations are common.) (Vieira, 2006; Hartwell, 2000). In flies, a mutation rate of 8.5 x 10-9 mutations per base per generation and genome size of 1.8 x 108 base pairs would result in every fly possessing a new mutation (Drake, 1998). The fruit fly species Drosophila sechellia is a specialist, feeding on the byproducts of the fruit of one shrub in the Seychelles archipelago (in the Indian Ocean). Mutations are causing the loss of functional olfactory and gustatory genes at a rate ten times faster than the related species Drosophila simulans (McBride, 2007).

Because male spermatogonia undergo more cell divisions than female oogonia in a given generation, more mutations arise in the male germ line than the female germ line (which can be demonstrated by comparing the number of point mutations of paternal origin to those of maternal origin) (Li, 2002; Ellegren, ). Human males, for example, can produce 300 million gametes a day. Mutations accumulate in the spermatogonia which initiate spermatogenesis and, as a result, the percentage of sperm which carry mutations increase over the course of a man's life. A number of studies have indicated that the overwhelming majority of new mutations are of male origin. Increased paternal age is correlated with a higher percentage of the mutations. Increased maternal age is correlated with a number of chromosomal mutations (Huttley, 2007; Crow, 1997).

One of the most important aspects of sexual reproduction is the recombination between maternal and paternal chromosomes which creates such an enormous diversity of potential gametes. Because of the recombination between independently assorting chromosomes in meiosis I, each human couple has the genetic potential to engender more genetically different children than there have ever been human children. There is some evidence in yeast to suggest that this recombination may itself be mutagenic. Some have estimated that one in 1 in every 7 recombination events results in a mutation (Hellman, 2005). Areas of the genome which experience higher degrees of recombination also experience higher numbers of mutations and a faster divergence from ancestral sequences (Hellman, 2005).
Of course, the majority of mutations are not beneficial and many are dangerous. The average fruit fly has one slightly deleterious mutation. Because of the larger human genome, the rate in humans is greater (Crow, 1997). In industrialized human populations, all individuals have a better chance of surviving to reproductive age even when possessing mutations which are slightly deleterious. As a result, the negative effects of the accumulation of deleterious mutations will increase in the future (Crow, 1997). However, there are natural processes which attempt to limit the number of harmful mutations which are passed down to the next generation. Of the hundreds of millions of sperm which are released by the male, only one can fertilize the ova. The processes of swimming a great distance and interacting with surface proteins on the ova provide opportunities to weed out sperm which are less viable. During spermatogenesis, the level of gene transcription of genes is much higher than that of oocytes giving a mutation a greater chance of affecting a sperm's phenotype. Many genes (such as brain-specific genes) also have alternative testis promoters which allows the function of important genes throughout the body to be relevant in sperm as well (Reed, 2006).

Of the potential oocytes possessed in the fetal ovary, only a fraction will ever be ovulated. Of the 7 million potential oocytes in fetal ovary at 5 months, only 1 million will exist at birth and a few hundred thousand at puberty. Each menstrual cycle, about 20 to 25 oocytes will continue development for each single secondary oocyte which is ovulated. After conception, about 10 to 30% of human pregnancies are spontaneously aborted. Many mutations will reduce the likelihood that an individual will live long enough to reproduce. Although the background rate of mutations are high, many deleterious mutations are selected against (Reed, 2006).

NUCLEOTIDE DIVERSITY
Although many mutations are negative and selected against, many increase in frequency and become a natural aspect of normal diversity. In order to measure the evolutionary potential of mutations, one must consider the gradual accumulation of mutations in the genome. When analyzing DNA sequences, it is obvious that each individual's genome is unique (excepting twins). There are differences in nucleotide sequences which distinguish individuals-where one individual possesses a guanine, another possesses and adenine. Where one individual possesses a cytosine, another possesses a thymine. All species possess a measurable nucleotide diversity.

The average nucleotide diversity within D. melanogaster populations (about 0.011 for non-coding sections of the genome) is about 10 time greater than the average nucleotide diversity within humans (0.001) and is within the range of the average divergence between human, chimp, and gorilla genomes (0.01-0.02) (Aquadro, 2001).
Nucleotide diversity increases in areas with greater recombination (Aquadro, 2001).

Your genetic sequence is more than 99% identical to that of other people. There are differences however-variations which make you unique and set you apart from others. About 95% of human sequences have a nucleotide diversity of between 0.02% and 0.16%. In other words, if you wanted to find a person who had a nucleotide different from the one you possess at a specific nucleotide position in the genome, you could find someone with a variant after studying between 625 and 5,000 people, depending on which area of the genome it was. For 5% of human sequences, variations would either be harder to find (becoming almost impossible for some sites) or so easy that a variant could be found in one in every 10 people. The nucleotide diversity in the MHC regions of the genome which are so important for immunity can surpass 10%; (Gaudieri, 2000; Nachman, 2001). Only about 9% of this human variation is variation between races; most human variation results from variation within each population (Tobin, 2001). The genetic diversity observed between ape subspecies is comparable to that observed between human populations (Fischer, 2006).

Given the recent date of the sequencing of the human genome, the enormous variation in the DNA sequences of human populations will not be fully known for quite some time. More than 1.4 million single nucleotide polymorphisms were known in 2001 when the human genome was sequenced (International Human Genome Sequencing Consortium, 2001). As of 2006, more than 10 million single nucleotide polymorphisms were known in the human genome (Jiang, 2006).


This level of nucleotide diversity would simply be impossible without the gradual accumulation of mutations. The current human population of 6.5 billion people is descended from much smaller ancestral populations. Genes affecting antigen presentation at these MHC loci can have tens to hundreds of alleles (Raymond, 2005). The number of variations in modern human populations can only be accounted for by mutation.
As multiple possible nucleotides are incorporated into a the genome of a species, the percentage of an individual's genes which are heterozygous increases, given that the maternally and paternally inherited forms are more likely to be different. The rates of heterozygosity for the genes of invertebrates, vertebrates, and outcrossing plants are about 15%, 5-8%, and 8% respectively. In most populations of plants and insects, more than half of the enzyme-coding genes are polymorphic (which means there are multiple alleles which represent more than 5% of the total alleles of the population) (Raven, 2002). Within fruit fly genomes, the average heterozygosity of nucleotide positions varies from 0.4% to 2%, being greater in some species (Such as Drosophila pseudoobscura and D. simulans) than others (such as D. melanogaster) and varying in different regions of the genome. The variation at noncoding sites can reach 4%. As a result, it can be said that statistically virtually every fly is heterozygous at every locus in the genome. (This would not be as true of closely inbred flies or at regions of the genomes which have atypically low levels of nucleotide diversity) (Moriyama, 1996).

HUMAN POPULATIONS
Variations not only exist in human genomic sequences, they form patterns. Many patterns reflect recent diversification of ethnic groups and can even be of clinical significance in identifying the differing predisposition to disease in different groups. Comparisons of genetic sequences indicates that mutations have accumulated gradually in human populations and the study of genetic similarities can indicate the degrees of relatedness between various human populations. In general, the greatest genetic difference in human populations occur between sub-Saharan African populations. This is consistent with the conclusion that humanity evolved in Africa and some African lineages have had the greatest length of time to accumulate variations compared to other lineages, African and non-African (Zischler, 1995; Waddle, 1994; Vigilant, 1991; Wood, 1997; Preworski, 2000; Goldstein, 1995; Bonatto, 1997). Some East Africans possess a sequence on their X chromosomes which seems to predate the emergence of modern humans and would have resulted from interbreeding between older populations of the genus Homo which predate the rise of Homo sapiens (Garrigan, 2005b).


Humans were once more diverse than they are now with multiple anatomically distinct species/subspecies existing throughout the world and even coexisting in the same region. Some genetic analysis indicates that although modern humans originated Africa over 100,000 years ago, they interbred with older hominid populations which were already present on other continents (Homo erectus in Asia, Homo neanderthalis in Europe) to produce many of the regional differences in modern humans. The discovery of apparently ancient DNA sequences in Asian and Australian populations which are not found anywhere else in the world supports the model of regional continuity (Harding, 1997; Holden 2001). Some anthropologists conclude that a number of fossil finds of Homo erectus and Homo neanderthalis have physical traits which correspond to the modern humans from those regions from much later dates (Wolpoff, 1993; Thorne, 1992; Thorne, 1981).


Some modern Asians possess a segment on the X chromosome which includes more variation than samples from Africa, unlike what is usually observed. This segment is estimated to have had a common ancestral sequence about 2 million years ago and seems to represent a genetic sequence which resulted from interbreeding between modern humans (Homo sapiens) who migrated out of Africa and older populations (Homo erectus) which had already inhabited Asia (Garrigan, 2005a).


Modern humans were very different from those older populations of the genus Homo. For example, the craniofacial differences between Neanderthals and modern Europeans are greater than those observed between all modern human populations (and also greater than that observed between the two species of chimpanzee). This suggests that Neanderthals were a separate species (Harvati, 2003; Harvati, 2004). Genetic evidence also supports this conclusion. Mitochondrial DNA was successfully isolated from neanderthal bone and the sequence was unlike any living human. Its variation from modern humans is roughly half of the difference between humans and chimps. A second lab repeated this with identical results. Analysis of Cro-Magnon DNA of about the same age identified a sequence which was well within the variations of modern humans. Mitochondrial DNA from several Neanderthals has identified DNA sequences which predate the origin of the mitochondrial strains which are known in modern living humans (Caramelli, 2003; Adcook, 2001; Ward, 1997; Kahn, 1997; Mellars, 1998). Studies of nuclear genes are underway and indicate that Neanderthals did contribute to the genes of Europeans and a separate lineage of Africans (separate from the main lineage of modern Africans) did contribute to the genes of the modern inhabitants of West Africa (estimated at 5% of the gene pools in each case) (Wall, 2006).


Obviously, the accumulation of genetic differences in isolated populations is not unique to humans. The branching points in the ancestry of a species' populations can be traced through the accumulation of genetic differences in species ranging from fruit flies to dogs. This variation continues as populations of one species diverge and become separates species (which may still be capable of interbreeding). For example, the average mitochondrial sequence variation between domesticated horses and a wild population is 2.6% and between horses and donkeys 16.1% (Vila, 2001). Mutations have resulted in the different genetic sequences between dogs, wolves, and coyotes. On average, a dog DNA sequence possesses a different nucleotide compared to a coyote every 420 base pairs, every 580 base pairs when compared to a wolf, and every 900 base pairs on average when compared to other breeds of dog (Lindblad-Toh, 2005). The great genetic and anatomical differences between orangutans from Sumatra and Borneo are close to the range which is often used to define separate species. Some researchers feel they should be classified as separate species (Zhi, 1996).