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About what percent of mutations are not adaptive?

About what percent of mutations are not adaptive?


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Many popular texts that discuss evolution and natural selection often mention that many (or most) mutations are bad (not adaptive).

Have there been any studies on what the rough percentages are? (E.g. Is it 90%? 99%? 99.9%? If this number varies by species, an answer could just focus on one particular species.)


As suggested by the McGrew comment, this is dramatically dependent on the shape of the fitness landscape. It will vary quite a bit from situation to situation.

More precisely, you are interested in the distribution of fitness effects (DFE) of mutations, and the upper tail specifically.

Wikipedia has a section on this. In there, they note one study of a virus that suggests that ~4% of mutations are beneficial. That may be an overestimate, and many of those are probably only very slightly beneficial. Probably the number is lower in non-viral organisms.

For a review on the DFE of new mutations, see here. They write in their section "Advantageous mutations":

As expected, relatively few of the mutations that are not effectively neutral are advantageous.In three mutagenesis experiments, the proportion of advantageous mutations was 4% in the RNA virus vesicular stomatitis virus (VSV)15 (FIG. 1), 0% in Escherichia coli(14), 0-15% in the bacteriophage φX174 (REF. 40), 0% in φ6 (REF. 13) and 6% in Saccharomyces cerevisiae (16).


It is necessary to distinguish mutations from substitutions: assuming for simplicity that a mutation can happen at any place in the genetic sequence, most mutations are bound to result in non-functional genomes. Substitutions, on the other hand, are mutations that resulted in viable organisms - they can still have negative fitness effect, but not outright deleterious.

Note also that non-adaptive mutations are not necessarily bad - the neutral theory of evolution tells us that, due to randomness effects, substitutions may fix in the population without having a direct fitness advantage.

In viruses the quantity of substitutions can be very high - tens of percents, to the point that one has to introduce ad-hoc thresholds to distinguish viral strains, e.g., viruses that differ by 30% of their genetic content. How much of this is adaptive depends on the shape of the fitness landscape, as noted by @MaximilianPress. E.g., for HIV it has been found that up to a third of the sequence changes tend to revert to the ancestral HIV sequence, i.e., constitute host-specific adaptation.

Clarification
In view of the discussion that followed, I would like to add some precisions to my answer:

  • My distinction between mutations and substitutions is essentially distinction between the actual and the observed mutations. This is different from the more common usage, where substitution means point mutation, with mutation being a more general term.
  • Since I mentioned the neutral theory, it is necessary to remark that the entirety of its claims is not generally accepted and/or supported by data. Moreover, its validity depends on the organisms in question. My use of the neutral theory is therefore limited to the fact that being adaptive/non-adaptive is not the only factor that determines that a mutation fixes in the population.

Harvard Molecular Geneticist Vindicates Michael Behe’s Main Argument in Darwin Devolves

When Michael Behe’s book Darwin Devolves came out last year, critics were quick to pounce. Skeptic Magazine wrote that “In Darwin Devolves, Michael Behe continues to dig himself further into the hole he opened 20 years ago with Darwins Black Box.” Three Quarks Daily stated that Behe’s central thesis in the book, “is clickbait, the book title misleading, and the argument long since rebutted.”

That thesis is what Behe calls the “first rule of adaptive evolution,” namely that Darwinian processes tend to “Break or blunt any functional gene whose loss would increase the number of a species’s offspring.” A review in the journal Science called Behe’s arguments “quixotic” and charged that “[t]here are indeed many examples of loss-of-function mutations that are advantageous, but Behe is selective in his examples” — so much so that Behe “misrepresents theory and avoids evidence that challenges him.”

A response in the journal Evolution had this to say:

Concise, catchy and matter-of-fact, Behe’s First Rule makes for a quality sound bite, but it is overly simplistic and untruthful to the data. Darwin Devolves overemphasizes loss-of-function mutations, and brushes off countervailing examples as nothing more than a “sideshow.”

You can find many responses to the critics here, but it’s still worth revisiting some relevant questions: Did Behe mislead readers in emphasizing the importance of loss-of-function mutations? Did Behe misrepresent evolutionary theory and ignore evidence by claiming that adaptations tend to involve degradative mutations? Did Behe dig himself into a hole by claiming that constructive mutations are less common than those that break or diminish functions? If a new article Current Biology means anything, the critics are not just rude but plain wrong:

In laboratory-based experimental evolution of novel phenotypes and the human domestication of crops, the majority of the mutations that lead to adaptation are loss-of-function mutations that impair or eliminate the function of genes rather than gain-of-function mutations that increase or qualitatively alter the function of proteins. Here, I speculate that easier access to loss-of-function mutations has led them to play a major role in the adaptive radiations that occur when populations have access to many unoccupied ecological niches.

Andrew W. Murray, “Can gene-inactivating mutations lead to evolutionary novelty?” Current Biology, 30(10) R465-R471 emphasis added.

Adaptive Mutations That Occurred during Circulation in Humans of H1N1 Influenza Virus in the 2009 Pandemic Enhance Virulence in Mice

During the 2009 H1N1 influenza pandemic, infection attack rates were particularly high among young individuals who suffered from pneumonia with occasional death. Moreover, previously reported determinants of mammalian adaptation and pathogenicity were not present in 2009 pandemic H1N1 influenza A viruses. Thus, it was proposed that unknown viral factors might have contributed to disease severity in humans. In this study, we performed a comparative analysis of two clinical 2009 pandemic H1N1 strains that belong to the very early and later phases of the pandemic. We identified mutations in the viral hemagglutinin (HA) and the nucleoprotein (NP) that occurred during pandemic progression and mediate increased virulence in mice. Lethal disease outcome correlated with elevated viral replication in the alveolar epithelium, increased proinflammatory cytokine and chemokine responses, pneumonia, and lymphopenia in mice. These findings show that viral mutations that have occurred during pandemic circulation among humans are associated with severe disease in mice.

Importance: In this study, novel determinants of 2009 pandemic H1N1 influenza pathogenicity were identified in the viral hemagglutinin (HA) and the nucleoprotein (NP) genes. In contrast to highly pathogenic avian influenza viruses, increased virulence in mice did not correlate with enhanced polymerase activity but with reduced activity. Lethal 2009 pandemic H1N1 infection in mice correlated with lymphopenia and severe pneumonia. These studies suggest that molecular mechanisms that mediate 2009 pandemic H1N1 influenza pathogenicity are distinct from those that mediate avian influenza virus pathogenicity in mice.

Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Figures

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Virulence of recombinant 2009 pH1N1 influenza viruses in C57BL/6J mice. C57BL/6J mice were…

Lung tropism of recombinant 2009…

Lung tropism of recombinant 2009 pH1N1 influenza viruses in C57BL/6J mice. C57BL/6J mice…

2009 pH1N1 viral polymerase activity…

2009 pH1N1 viral polymerase activity and replication in mammalian cells. The tertiary structure…

Cytokine response in recombinant 2009…

Cytokine response in recombinant 2009 pH1N1-infected human lung cells. Human lung cells (A549)…

Lymphocyte counts in recombinant 2009…

Lymphocyte counts in recombinant 2009 pH1N1 virus-infected C57BL/6J mice. C75BL/6J mice were either…

Virus lung titers in recombinant…

Virus lung titers in recombinant 2009 pH1N1 virus-infected C57BL/6J mice. C57BL/6J mice were…


Author summary

Mutation is of central importance in biology. It creates genetic variation, the raw material of evolution by natural selection, It can improve traits and organisms, but can also lead to phenomena like cancerous cells and antibiotic resistant pathogens. Increasing the mutation rate can accelerate evolutionary adaptation, even over many thousands of generations in a constant environment. Our study describes the laboratory evolution of asexual Escherichia coli strains with a range of mutation rates at levels found in the wild (from wild type to strong mutator). Unexpectedly, evolutionary adaptation was most limited in the populations with the highest mutation rate. Our work suggests that deleterious mutations can begin to limit adaptation at lower mutation rates than previously thought.

Citation: Sprouffske K, Aguilar-Rodríguez J, Sniegowski P, Wagner A (2018) High mutation rates limit evolutionary adaptation in Escherichia coli. PLoS Genet 14(4): e1007324. https://doi.org/10.1371/journal.pgen.1007324

Editor: Ivan Matic, Université Paris Descartes, INSERM U1001, FRANCE

Received: July 7, 2017 Accepted: March 21, 2018 Published: April 27, 2018

Copyright: © 2018 Sprouffske et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All files are available from the Dryad database (doi:10.5061/dryad.mh206).

Funding: KS acknowledges support through the Forschungskredit program of the University of Zurich, grant K-74301-03-0. AW acknowledges support by ERC Advanced Grant 739874, by Swiss National Science Foundation grant 31003A_146137, by an EpiphysX RTD grant from SystemsX.ch, as well as by the University Priority Research Program in Evolutionary Biology at the University of Zurich. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.


Organic Selection, Organic Choice, Plasticity

In 1897, H. F. Osborn published an article with the title ‘Organic selection’, in which we read: ‘Organic selection is the term proposed by Professor Baldwin and adopted by Professor Morgan and myself for this process in nature which is believed to be one of the true causes of definite or determinate variation. The hypothesis is briefly as follows: That ontogenic adaptation is of a very profound character. It enables animals and plants to survive very critical changes in their environment. Thus all the individuals of a race are similarly modified over such long periods of time that very gradually congenital or phylogenetic variations, which happen to coincide with the ontogenetic adaptive variations, are selected. Thus there would result an apparent but not real transmission, of acquired characters. This hypothesis, if it has no limitations, brings about a very unexpected harmony between the Lamarckian and Darwinian aspects of evolution, by mutual concessions upon the part of the essential positions of both theories. While it abandons the transmission of acquired characters, it places individual adaptation first, and fortuitous variations second, as Lamarckians have always contended, instead of placing survival conditions by fortuitous variations first and foremost, as selectionists have contended’ ( Osborn, 1897: 584).

Organic plasticity – the ability to solve unexpected problems, to accommodate one's behaviour during the lifetime, according to circumstances – is a universal feature of all living beings. This feature does not require an additional evolutionary explanation because it is as universal as life itself ( West-Eberhard, 2003: 34). Once alive, organisms cannot avoid fulfilling their organic needs and, by doing so, they cannot completely avoid learning. [Thus, learning can be seen as a means for achieving adaptation. There exist several different mechanisms of learning. One may assume that ontogenetic learning is based on a mechanism that is analogous to natural selection at the intraorganismal or histological level however, this is not generally the case (see, for example, Watson et al., 2010 Kirby, 2000).] Organic plasticity (as different from transformations in non-living systems) should be understood as a change that has alternatives – it should be possible also to behave in the ways that do not meet the needs, it should be possible to make errors. In this case we can say that organic selection – or rather, organic choice made by organisms – is inevitable. Where a population of organisms is facing a shared change of conditions, all organisms in the population may respond simultaneously and in a similar way. However, the role of organic plasticity in evolution depends on the mechanisms that may make the results of organic choice irreversible.

In fact, Osborn, in the article about organic selection, continues: ‘This hypothesis has been endorsed by Alfred Wallace. It appears to me, however, that it is subject to limitations and exceptions which go far to nullify its universal application. This is especially seen in the fact that the law of determinate variation is observed to operate with equal force in certain structures, such as the teeth, which are not improved by individual use or exercise, as in structures which are so improved’ ( Osborn, 1897: 584–585). To understand this hesitation (which has been continuously used in the interpretations of the Baldwin effect), I should point out that there was almost no knowledge about the dynamics of gene expression patterns until recent decades.

The organic selection mechanism is a mechanism that is different from the natural selection mechanism. They are probably both at work in evolution, but their relative roles have to be discovered by empirical studies. If so, then it is theoretically possible that on some occasions an adaptive evolutionary change can take place without natural selection.

Organic selection is a possible constituent part of the evolutionary mechanism, the other part of the same mechanism being natural selection. In this case it may be that natural selection is never absent in an adaptive evolutionary change.

Indeed, the advocates of organic selection mostly could not completely avoid involvement of natural selection in the mechanism they proposed. This is true for most interpretations of organic selection, or the Baldwin effect, by H. F. Osborn and his contemporaries (see also Bowler, 1983), of genetic assimilation as described by C. H. Waddington ( Waddington, 1953a, b, 1956), of niche-construction as described by Odling-Smee, Laland & Feldman (2003), or of epigenetic evolution by Jablonka & Lamb (2005). Thus, they all seem to accept (2), but not (1). [However, there exists some work that makes the radical claim, similar to the view expressed here, that natural selection is not necessary for adaptation – see, for example, Jablonka & Lamb (2008), Margulis & Sagan (2002), and Watson et al. (2010).] Let me now argue for the possibility of accepting (1).


About what percent of mutations are not adaptive? - Biology

Mutations can be beneficial, neutral, or harmful for the organism, but mutations do not "try" to supply what the organism "needs." Factors in the environment may influence the rate of mutation but are not generally thought to influence the direction of mutation. For example, exposure to harmful chemicals may increase the mutation rate, but will not cause more mutations that make the organism resistant to those chemicals. In this respect, mutations are random — whether a particular mutation happens or not is unrelated to how useful that mutation would be.

For example, in the U.S. where people have access to shampoos with chemicals that kill lice, we have a lot of lice that are resistant to those chemicals. There are two possible explanations for this:

Hypothesis A: Hypothesis B:
Resistant strains of lice were always there — and are just more frequent now because all the non-resistant lice died a sudsy death. Exposure to lice shampoo actually caused mutations for resistance to the shampoo.

Scientists generally think that the first explanation is the right one and that directed mutations, the second possible explanation relying on non-random mutation, is not correct.

Researchers have performed many experiments in this area. Though results can be interpreted in several ways, none unambiguously support directed mutation. Nevertheless, scientists are still doing research that provides evidence relevant to this issue.

In addition, experiments have made it clear that many mutations are in fact random, and did not occur because the organism was placed in a situation where the mutation would be useful. For example, if you expose bacteria to an antibiotic, you will likely observe an increased prevalence of antibiotic resistance. Esther and Joshua Lederberg determined that many of these mutations for antibiotic resistance existed in the population even before the population was exposed to the antibiotic — and that exposure to the antibiotic did not cause those new resistant mutants to appear.

The Lederberg experiment
In 1952, Esther and Joshua Lederberg performed an experiment that helped show that many mutations are random, not directed. In this experiment, they capitalized on the ease with which bacteria can be grown and maintained. Bacteria grow into isolated colonies on plates. These colonies can be reproduced from an original plate to new plates by "stamping" the original plate with a cloth and then stamping empty plates with the same cloth. Bacteria from each colony are picked up on the cloth and then deposited on the new plates by the cloth.

Esther and Joshua hypothesized that antibiotic resistant strains of bacteria surviving an application of antibiotics had the resistance before their exposure to the antibiotics, not as a result of the exposure. Their experimental set-up is summarized below:

When the original plate is washed with penicillin, the same colonies (those in position X and Y) live — even though these colonies on the original plate have never encountered penicillin before.


Impact of mutations

Most often, mutations come to mind as the cause of various diseases. Though there are several such examples (some listed below), according to the Genetics Home Reference Handbook, disease-causing mutations are usually not very common in the general population.

Fragile X syndrome is caused by a dynamic mutation and occurs in 1 in 4,000 men and 1 in 8,000 women. Dynamic mutations are rather insidious since the severity of disease can increase as the number of nucleotide repeats increase. In those with fragile X syndrome, the nucleotide sequence CGG repeats more than 200 times within a gene called FMR1 (for which the normal number is anywhere between 5 and 40 repeats). This high number of CGG repeats leads to delayed speech and language skills, some level of intellectual disability, anxiety and hyperactive behavior. However, in those with fewer numbers of repeats (55-200 repeats), most are considered to have normal intellect. Since the FMR1 gene is on the X chromosome, this mutation is also heritable.

A variant of adult hemoglobin, known as hemoglobin S can occur due to a missense mutation, which causes the amino acid valine to take the place of glutamic acid. If one inherits the aberrant gene from both parents, it leads to a condition known as sickle cell disease. The disease gets its name from the fact that red blood cells, which are usually disc-shaped, contract and resemble a sickle. Those with the condition suffer from anemia, regular infections and pain. Estimates suggest that the condition occurs in 1 in 500 African Americans and about 1 in 1,000 to 1,400 Hispanic Americans.

Mutations can also occur due to environmental factors. For example, according to a 2001 article published in Journal Biomedicine and Biotechnology, the UV rays from the sun, particularly UV-B waves, are responsible for causing mutations in a tumor suppressor gene calledp53. The mutated p53 gene has been implicated in skin cancer.

Mutations have other important implications. They create variation within the genes in a population. According to the Genetics Home Resource Handbook, genetic variants seen in more than 1 percent of a population are called polymorphisms. The different eye and hair colors, and the various blood groups that can occur, are all due to polymorphisms.

In the broad scheme of things, mutations can also function as tools of evolution, aiding in the development of new traits, characteristics, or species. &ldquoThe accumulation of multiple mutations in a single pathway or in genes participating in a single developmental program are likely to be responsible for speciation [the creation of a new species],&rdquo said Boekhoff-Falk.

According to the resource Understanding Evolution published by the University of California Museum of Paleontology, only germline mutations play a role in evolution, since they are heritable. It is also important to note that mutations are random, that is to say, they do not occur to fulfill any requirements for a given population.


Not Entirely Random

What is more, since Darwinism cannot have a specific goal or plan, it has generally been assumed that mutations must be random. At least they must be random in their usefulness if not in their DNA location. Mutations would not occur because the organism needs them. Rather, they can have no intended purpose or deliberate advantage. Mutations will randomly alter the organism’s traits, and natural selection determines if the altered trait is useful to the organism. This is classic neo-Darwinism.

Randomness was also a necessary tenet to separate neo-Darwinism from Lamarckian evolution, which predicted that organisms can develop traits based upon environmental factors—and these traits can be inherited by subsequent generations. Furthermore, randomness was considered necessary to exclude any suggestion of Divine guidance or intelligent programming. However, this was more a philosophical than scientific paradigm, as there has always been an absence of direct evidence that all mutations are fully random.4

Recent studies have found distinct patterns in the location of mutations on the DNA, rather than a random scattering.5 Far fewer mutations occur in areas of high gene expression, the opposite of what would be predicted since Darwinism requires dramatic changes to gene expression.6 It has long been recognized that DNA contains “hotspots”—locations where mutations are more likely to occur.7 However, the precise and predictable locations of many mutations indicate involvement of more than just “hotspots.”

Also, since the DNA location of many mutations is not random, this challenges an assumption frequently made by evolutionary biologists. When two organisms share nearly identical mutations, biologists often assume this is evidence of shared evolutionary history. The identical mutations must have been inherited from a common ancestor. The shared mutational pattern presumably shows a Darwinian lineage.

However, this reasoning assumes mutations are randomly scattered throughout the DNA. Thus, the only way two organisms can share identical mutations is through shared ancestry. Yet because many mutations are not randomly located, shared mutations could result from shared mutational hotspots rather than shared evolutionary history. Thus, identical mutations do not verify Darwinian descent.


Genes Are Not Destiny

Genes influence every aspect of human physiology, development, and adaptation. Obesity is no exception. Yet relatively little is known regarding the specific genes that contribute to obesity and the scale of so-called “genetic environment interactions” the complex interplay between our genetic makeup and our life experiences.

A 2014 study found that consumption of fried food could interact with genes related to obesity, underscoring the importance of reducing fried food consumption in individuals genetically predisposed to obesity. (21)The search for human obesity genes began several decades ago. Rapid advances in molecular biology and the success of the Human Genome Project have intensified the search. This work has illuminated several genetic factors that are responsible for very rare, single-gene forms of obesity. Emerging research has also begun to identify the genetic underpinnings of so-called “common” obesity, which is influenced by dozens, if not hundreds, of genes. In addition, research into the relationship between certain foods and obesity is shedding more light on the interaction between diet, genes, and obesity.

What’s increasingly clear from these early findings is that genetic factors identified so far make only a small contribution to obesity risk-and that our genes are not our destiny: Many people who carry these so-called “obesity genes” do not become overweight, and healthy lifestyles can counteract these genetic effects. This article briefly outlines the contributions of genes and gene-environment interactions to the development of obesity.

Rare Forms of Obesity Caused by Mutations in a Single Gene (Monogenic Obesity)

Several rare forms of obesity result from spontaneous mutations in single genes, so-called monogenic mutations. Such mutations have been discovered in genes that play essential roles in appetite control, food intake, and energy homeostasis-primarily, in genes that code for the hormone leptin, the leptin receptor, pro-opiomelanocortin, and the melanocortin-4 receptor, among others. (1)

Obesity is also a hallmark of several genetic syndromes caused by mutation or chromosomal abnormalities, such as Prader–Willi and Bardet-Biedl syndromes. In these syndromes, obesity is often accompanied by mental retardation, reproductive anomalies, or other problems. (2)

“Common Obesity” Caused by Mutations in Multiple Genes

In the 21st century, obesity is a health problem affecting rich and poor, educated and uneducated, Westernized and non-Westernized societies. Body fat level varies from person to person, however, and some people have always tended to carry a bit more body fat than others. Evidence from animal models, human linkage studies, twin studies, and association studies of large populations suggests that this variation in our susceptibility to obesity has a genetic component. But rather than being controlled by a single gene, susceptibility to common obesity is thought to be affected by many genes (polygenic).

Twin studies offer some insight into the genetics of common obesity. Based on data from more than 25,000 twin pairs and 50,000 biological and adoptive family members, the estimates for mean correlations for body mass index (BMI) are 0.74 for monozygotic (“identical”) twins, 0.32 for dizygotic (“fraternal”) twins, 0.25 for siblings, 0.19 for parent-offspring pairs, 0.06 for adoptive relatives, and 0.12 for spouses. (3) The strong correlation for BMI between monozygotic twins and its attenuation with lesser degrees of shared genes suggest a strong genetic influence on BMI. However, this conclusion is based on the assumption that identical and fraternal twins have the same degree of shared environment-and it’s an assumption that may not hold in practice.

Using Genome-Wide Association Studies to Identify Obesity-Related Genes

A genome-wide association study scans hundreds of thousands of genetic markers across thousands of individuals’ complete sets of DNA to find gene variations that may be related to a particular disease. These studies can be used to find gene variations that play a role in common, complex diseases such as obesity. Often, a change in just one small section of the DNA that encodes for a gene can make a difference in the gene’s action. These tiny DNA variations, called “gene variants” or “single-nucleotide polymorphisms” (SNPs), are often related to disease risk.

In 2007, researchers using genome-wide association studies identified the first obesity-related gene variants in the so-called “fat mass and obesity-associated” (FTO) gene on chromosome 16. (4, 5) These gene variants are fairly common, and people who carry one have a 20 to 30 percent higher risk of obesity than people who do not. The second obesity-associated gene variant that researchers identified lies on chromosome 18, close to the melanocortin-4 receptor gene (the same gene responsible for a rare form of monogenic obesity). (6, 7)

To date, genome-wide association studies have identified more than 30 candidate genes on 12 chromosomes that are associated with body mass index. (8󈝶) It’s important to keep in mind that even the most promising of these candidate genes, FTO, accounts for only a small fraction of the gene-related susceptibility to obesity. (11)

Gene-Environment Interactions: Why Heredity Is Not Destiny

Genetic changes are unlikely to explain the rapid spread of obesity around the globe. (1) That’s because the “gene poolthe frequency of different genes across a population-remains fairly stable for many generations. It takes a long time for new mutations or polymorphisms to spread. So if our genes have stayed largely the same, what has changed over the past 40 years of rising obesity rates? Our environment: the physical, social, political, and economic surroundings that influence how much we eat and how active we are. Environmental changes that make it easier for people to overeat, and harder for people to get enough physical activity, have played a key role in triggering the recent surge of overweight and obesity. (12)

Work on obesity-related gene-environment interactions is still in its infancy. The evidence so far suggests that genetic predisposition is not destiny-many people who carry so-called “obesity genes” do not become overweight. Rather, it seems that eating a healthy diet and getting enough exercise may counteract some of the gene-related obesity risk.

In 2008, for example, Andreasen and colleagues demonstrated that physical activity offsets the effects of one obesity-promoting gene, a common variant of FTO. The study, conducted in 17,058 Danes, found that people who carried the obesity-promoting gene, and who were inactive, had higher BMIs than people without the gene variant who were inactive. Having a genetic predisposition to obesity did not seem to matter, however, for people who were active: Their BMIs were no higher or lower than those of people who did not have the obesity gene. (15)

Subsequent work on the relationship between the FTO gene, physical activity, and obesity yielded contradictory results. (16󈝾) To arrive at a more definitive answer, investigators recently combined and re-analyzed the data from 45 studies in adults and 9 studies in children-nearly 240,000 people in all. (19) They found that people who carried the obesity-promoting FTO gene variant had a 23 percent higher risk of obesity than those who did not. But once again, being physically active lowered the risk: Active adults who carried the obesity-promoting gene had a 30 percent lower risk of obesity than inactive adults who carried the gene.

Most people probably have some genetic predisposition to obesity, depending on their family history and ethnicity. Moving from genetic predisposition to obesity itself generally requires some change in diet, lifestyle, or other environmental factors. Some of those changes include the following:

  • the ready availability of food at all hours of the day and in places that once did not sell food, such as gas stations, pharmacies, and office supply stores
  • a dramatic decrease in physical activity during work, domestic activities, and leisure time, especially among children
  • increased time spent watching television, using computers, and performing other sedentary activities and
  • the influx of highly processed foods, fast food, and sugar-sweetened beverages, along with the ubiquitous marketing campaigns that promote them.

The Bottom Line: Healthy Environments and Lifestyles Can Counteract Gene-Related Risks

Having a better understanding of the genetic contributions to obesity-especially common obesity-and gene-environment interactions will generate a better understanding of the causal pathways that lead to obesity. Such information could someday yield promising strategies for obesity prevention and treatment. But it’s important to remember that overall, the contribution of genes to obesity risk is small, while the contribution of our toxic food and activity environment is huge. As one scientist wrote, “Genes may co-determine who becomes obese, but our environment determines how many become obese.” (20) That’s why obesity prevention efforts must focus on changing our environment to make healthy choices easier choices, for all.

References

1. Hu F. Genetic predictors of obesity. In: Hu F, ed. Obesity Epidemiology. New York City: Oxford University Press, 2008 437-460.

2. Farooqi S, O’Rahilly S. Genetics of obesity in humans. Endocr Rev. 2006 27:710-18.

3. Maes HH, Neale MC, Eaves LJ. Genetic and environmental factors in relative body weight and human adiposity. Behav Genet. 1997 27:325-51.

4. Dina C, Meyre D, Gallina S, et al. Variation in FTO contributes to childhood obesity and severe adult obesity. Nat Genet. 2007 39:724-6.

5. Frayling TM, Timpson NJ, Weedon MN, et al. A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science. 2007 316:889-94.

6. Loos RJ, Lindgren CM, Li S, et al. Common variants near MC4R are associated with fat mass, weight and risk of obesity. Nat Genet. 2008 40:768-75.

7. Qi L, Kraft P, Hunter DJ, Hu FB. The common obesity variant near MC4R gene is associated with higher intakes of total energy and dietary fat, weight change and diabetes risk in women. Hum Mol Genet. 2008 17:3502-8.

8. O’Rahilly S. Human genetics illuminates the paths to metabolic disease. Nature. 2009 462:307-14.

9. Speliotes EK, Willer CJ, Berndt SI, et al. Association analyses of 249,796 individuals reveal eighteen new loci associated with body mass index. Nat Genet. 2010 42:937-48.

10. Heid IM, Jackson AU, Randall JC. Meta-analysis identifies 13 novel loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution. Nat Genet. 2010 42:949-60.

11. Walley AJ, Asher JE, Froguel P. The genetic contribution to non-syndromic human obesity. Nat Rev Genet. 2009 10:431-42.

12. Qi L, Cho YA. Gene-environment interaction and obesity. Nutr Rev. 2008 66:684-94.

15. Andreasen CH, Stender-Petersen KL, Mogensen MS, et al. Low physical activity accentuates the effect of the FTO rs9939609 polymorphism on body fat accumulation. Diabetes. 2008 57:95-101.

16. Rampersaud E, Mitchell BD, Pollin TI, et al. Physical activity and the association of common FTO gene variants with body mass index and obesity. Arch Intern Med. 2008 168:1791-7.

17. Ruiz JR, Labayen I, Ortega FB, et al. Attenuation of the effect of the FTO rs9939609 polymorphism on total and central body fat by physical activity in adolescents: the HELENA study. Arch Pediatr Adolesc Med. 2010 164:328-33.

18. Jonsson A, Renstrom F, Lyssenko V, et al. Assessing the effect of interaction between an FTO variant (rs9939609) and physical activity on obesity in 15,925 Swedish and 2,511 Finnish adults. Diabetologia. 2009 52:1334-8.

19. KilpelinenTO, Qi L, Brage S, et al.Physical activity attenuates the influence of FTO variants on obesity risk: a meta-analysis of 218,166 adults and 19,268 children. PLoS Med. 20118:e1001116. Epub 2011 Nov 1.

20. Veerman JL. On the futility of screening for genes that make you fat. PLoS Med. 2011 Nov8(11):e1001114. Epub 2011 Nov 1.

21. Qi, Q, Chu, AY, Kang, JH, Huang, J, Rose, LM, Jensen, MK, Liang, L, Curhan, GC, Pasquale, LR, Wiggs, JL, De Vivo, I, Chan, AT, Choi, HK, Tamimi, RM, Ridker, PM, Hunter, DJ, Willett, WC, Rimm, EB, Chasman, DI, Hu, FB, Qi, L. (2014). Fried food consumption, genetic risk, and body mass index: gene-diet interaction analysis in three US cohort studies. BMJ 19348:g1610.

22. Asai M Ramachandrappa S Joachim M Shen Y Zhang R Nuthalapati N Ramanathan V Strochlic, DE Ferket P Linhart K, Ho C Novoselova, TV Garg S Ridderstr


Persistence of Deleterious Mutations

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Despite their harmful nature, why do deleterious genes persist in the genome of organisms? This could be due to a number of reasons, such as the rate of elimination of these mutations may be low compared to the rate at which they appear. Other probable reasons are as follows.

Heterozygote Advantage

This is the condition where the possession of two different copies of a gene (wild-type and mutant) is beneficial to the organism, rather than detrimental. An example of this is the mutation that occurs in the hemoglobin gene, resulting in the condition called sickle cell anemia (SCA). In this case, the homozygote for the mutant allele will show a deleterious effect, i.e, the individual will suffer from SCA (all RBCs will be sickle-shaped). However, if the individual is a heterozygote, the recessive nature of the condition will render him a carrier (Partial sickling of RBCs) of the condition. This is beneficial, since the malarial parasite P. falciparum that infects red blood cells and deprives them of oxygen will be unable to infect the sickled cells and lead to a malarial infection. In other words, the partial sickling of RBCs of a carrier render that person immune to malaria. On the other hand, a wild-type homozygote individual would be susceptible to the malarial infection.

No Effect on Reproductive Fitness

In some cases, the deleterious effect of the mutation is exhibited at a later stage in life, by when the reproductive stage of the organism has already elapsed. Hence, the mutations are passed on despite their harmful nature, as the effect does not interfere or exhibit itself during the reproductive stage. An example of this is the trinucleotide repeat mutations seen in the HD gene that causes Huntington’s disease. In this case, the effects of the disease are seen after the age of 40, and till then, the individual has already reproduced and passed this deleterious mutation onto the offspring. Despite this affecting the fitness of the individual, it persists, since it does not affect the reproductive fitness of the individual, but merely shortens the lifespan.

Maintained by Mutations

Some mutations may keep arising in certain genes despite the elimination efforts taken by the organisms genome. This may be due to the hyper-mutable nature of the gene, and also because the gene maybe too vital to tamper with (to prevent the induction of other accidental errors). An example of this is the NF gene, which when mutated, gives rise to a condition called neurofibromatosis, that causes tumors of the nervous system. Here, it may be difficult to remove the mutation, since any unwanted disruption in the gene sequence will only cause further damage. Also, even in case this mutation is eliminated, the gene does have a high tendency to mutate almost 1 in every 4,000 gametes possesses new mutations of this gene.

Maintained by Gene Flow

This refers to the prevalence of a mutated gene copy in a population to its introduction by another population that has migrated to the same location. As mentioned above, the SCA mutation is beneficial to areas with rampant malaria, as is the case with the regions of the African continent. However, when the carriers residing in this area migrated to other countries with a low incidence of malaria, the SCA mutation was introduced into the populations of those countries. Therefore, human migration brought about the flow of genetic material from Africa to other countries, where this mutation, in the absence of malarial incidence, was purely detrimental.

Polyploidy of Genome

Deleterious mutations are usually recessive in nature. If a haploid organism possesses a deleterious mutation, the effect can be readily observed, crippling the organisms fitness, and resulting in its demise. However, in case the organism is a diploid or polyploid with multiple alleles of a gene, the detrimental effect can be silenced or overridden by the presence of a fully functional wild-type allele. While this prevents the expression of the mutated allele, it does not eliminate it, causing it to persist in the population, till two individuals with the same allele reproduce and give rise to an offspring that will suffer the deleterious effects of the mutation.

Although the cellular repair machinery, along with the proofreading mechanisms, try to eliminate the mutations, certain mutations are not rectified or are actively conserved (as explained above). The accumulation of mutations, by this way, over the course of several generations, leads to an effect called Muller’s ratchet, which may lead to the extinction of the species of that organism. This effect is a principle studied in reference to the extinction of species, and the effort to conserve those on the brink of extinction.

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