Can genes change as we age?

Let's say you're a 23-year-old man who impregnates a woman. Will your genes be the same if you were to impregnate another woman at age 35? Will your genes in those 12 years have changed/mutated/become smarter?

Yes, there are some differences between the gametes that a parent produces at different ages!

Mutations in the germline during mitosis

Every time a cell replicates some mutations may occur (even through mitosis). Of course, any mutation that occurs in cells are located in your hand or in your brain, for example, will not be transmitted to the offsprings. Only mutations occurring in the germline (cells in the testis and in the ovaries whose descendent or themselves go through meiosis) are possibly passed to the offsprings. Interestingly, because of the developmental pathways of sperm cells and ovules, sperm cells go through a lot more mitosis than ovules do, resulting in more mutations in the sperms than in the ovules. Therefore, if you look at a mutation in an individual and assuming you know that the mutation occurred during the lifetime of the parents, then you are more likely that the mutation comes from the father than from the mother.

As reviewed by Cochran and Harpending (2013), mothers transmit on average a number x of new mutations to their offspring. This number x is independent of the age of the Mother. Fathers, however, transmit a number of new mutations to their offsprings that is very much dependent on the age of the father for developmental reasons.

Of course, as it has been pointed out there are various environmental factors that may increase or diminish the mutation rate (such as the mutagens (Tobacco, X-ray,… ))

Note on the process of adaptation

It is important to know that a vast majority of mutations are deleterious (impact negatively the reproductive success and survival of the individual carrying it). If we assume that no selection occurs between the cells of the germline, then no adaptation is possible. And in average sperm cells of an old guy should have lower fitness than the sperm cells of the same guy when he was younger. This process is referred to as mutation accumulation (mutation accumulation is not a concept that is specific to somatic lines mutations). However, one may argue the opposite! One might think that the cells that carry the new mutations (the mutation that occurred during the lifetime of the man) may be selected for or counter-selected. In such a case, the few beneficial mutations might be enough to make our cell lineages more fit with age. Whether the fitness of cells increase or decrease through our lifetime is dependent on the effective population size, the mutation rate and distribution of mutational effects. One can calculate the critical parameters yielding to one (mutation accumulation and fitness decrease) or the other (fitness increase through age) thanks to the mutational meltdown literature.

It is important to note however that what increase the fitness of a cell might decrease the fitness of its carrier. Knowing the joint distribution of mutational effect for both the carrier and the cells should allow us to calculate if reproducing late in life allows transmitting better genes than reproducing early in life. Intuitively, I would expect that reproducing early in life would allow a parent to transmit better genes.


We have to talk about epigenetics also. Epigenetics refers to all the modification that occur "around" or "on" the DNA but which are not the modification of the sequence of nucleotides. It is possible that the transmission of epigenetic modification is dependent on the age of the parents. But I have never heard of any case where this happens.

Pre-sperm cells divide constantly, and will have more mutations in 12 years. Unfortunately, neither the genes (nor the father) are likely to be smarter. There is some evidence that children from older fathers are more prone to diseases like autism and schizophrenia.

A very nice, short overview of the current research is in this (open-source) Nature article.

Genes can get mutated in one's lifetime. They gene altering agents are mutagens. Some common mutagens are X-ray, UV-ray, tobacco.

Recent studies have yielded results which state that some behavioral actions may cause gene mutations.

So, yes in twelve years gene can mutate. Moreover as a man ages his efficiency of meiosis division is affected. So, genes may differently get expressed in his progenies.

Your Childhood Experiences Can Permanently Change Your DNA

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DNA is the genetic material that makes us who we are, determining our physical characteristics and even helping to shape our personality. There are many ailments that have a strong hereditary component—Alzheimer’s, Huntington’s Disease, cancers and diabetes among others—and the risk of suffering them is passed down from our parents through our DNA.

But we’re finding out that our DNA isn’t always set in stone. Now, a team of researchers from Northwestern University led by anthropology professor Thom McDade have shown that DNA can also be modified by your environment during childhood. What’s more, the authors conclude in the journal Proceedings of the National Academy of Sciences, those modifications can affect how or when you develop certain illnesses during adulthood.

Their investigation followed more than 500 children in the Philippines and found that certain childhood situations can create modifications in genes associated with inflammation, which affects how prone we are to suffer from certain illnesses. Specifically, these factors included socioeconomic status, the prolonged absence of a parent, the duration of breastfeeding, birth during the dry season, and exposure to microbes in infancy.

But what exactly do the findings mean?

DNA is, in essence, a really long text made up of a 4-letter alphabet that our cells use as an instruction manual for making proteins. The order in which the letters are arranged (the DNA sequence) defines the genes that a person has, which remain the same throughout that person’s body. Despite that, only some genes (or sentences in the DNA text) are necessary for each cell type to function.

If genes are sentences within the DNA text, epigenetic marks are like differently colored highlighters that indicate which genes a cell should express (importantly, they do not change the sequence of the DNA). The most important of these marks is methylation, or the addition of a methyl group to the DNA molecule, which promotes or inhibits the expression of certain proteins depending on which gene it is on and where on the gene it is located.

“We could have genes in our bodies that might lead to some bad outcomes or adverse health outcomes, but if those genes are silent, if they’re turned off due to epigenetic processes, that can be a good thing,” explains McDade, principal author of the PNAS study.

McDade adds that, for the most part, once a gene is methylated it remains permanently methylated. Although it is not quite clear how a person’s childhood environment causes the methylation of some genes, it is possible to investigate its effect.

How environment impacts health

Inflammation—the body’s reaction to infections and wounds—plays a central role in human health. It is an important player in many fatal diseases related to old age, like diabetes, cardiovascular diseases and dementia. What’s more, there is increasing evidence that inflammation levels during pregnancy can affect the baby’s weight, or influence whether a baby is born prematurely.

The body must be able to mount an inflammatory response against different threats and threat levels. McDade compares the job of inflammation to the job of firefighters.

Let’s assume the fire is an infection or an injury and the fire department is the inflammatory response. You want the fire department to come as fast as possible and to use the least amount of water to put out any fire, and then you want them to leave. You don't want them to come into your house with more firefighters than needed and to hose everything down to put out a small fire nor do you want them to show up to a massive fire with just a bucket of water. Think of the potential damage in either scenario.

The researchers focused on this bodily function for two reasons. First, previous research has shown that childhood environments can cause improper regulation of inflammation during adulthood. Second, they had access to literally lifetimes’ worth of data from a cohort of babies in the Philippines that they could mine for methylation and inflammation data.

This cohort comprised over 3,000 pregnant women recruited in the Philippines in 1983. These women came from all different walks of life: They differed in access to clean water or a roof over their heads, whether they lived in an urban or a rural area, and whether they came into frequent contact with animals. From the data, they looked at over 500 of those women in order to figure out if their child’s environment growing up led to epigenetic modifications to their DNA—and later to a change in inflammatory proteins in their blood in adulthood.

Once their children were born, the investigators kept track of them and of the environments they were exposed to throughout their lives. Once they turned 21, the investigators took a blood sample that they used to measure the DNA methylation throughout their genome, as well as inflammation-related proteins that have been previously associated with cardiovascular diseases and other aging-related diseases.

The authors determined that the childhood environment of these youths affected the level of inflammation-related proteins (biomarkers) in their blood during adulthood, likely as a result of methylation of some of their inflammation-related genes. The dysregulation of these proteins can affect health and risk of disease.

The nutritional, microbial, psychological and social environments that children are exposed to growing up are critical for their physiology and health later in life, says McDade. As to the effects of specific childhood environments, he pointed to prolonged breastfeeding, exposure to microbes, and an abundance of family assets that led to better regulation of the inflammatory proteins.

In turn, the prolonged absence of a parent, the lack of exposure to microbes, and the lack of family assets were predictive of a higher dysregulation of the inflammatory proteins.

This is not the first time research has shown that a child’s environment growing up can help determine his or her future health. This isn’t even the first time that scientists have linked environment to DNA methylation and methylation to health (these studies have been done in mice). This is, however, one of the first and most complete investigations that show that epigenetic modifications created by the environment have lasting effects on human health.

What is DNA?

DNA (Photo Credit : Forluvoft / Wikimedia Commons)

DNA is the abbreviated name for deoxyribonucleic acid, a biomolecule. Adenine (A), Thymine (T), Cytosine (C), and Guanine (G) are the 4 monomers (nucleotides) that combine to form DNA. What holds all these monomers in the sequence is the phosphate backbone structure. Now, unless you&rsquore familiar with biology, you might not really understand what I&rsquom rambling on about.

Putting it in even simpler words, DNA is why you got your mother&rsquos eye color or your dad&rsquos hair color, because DNA stores all the genetic information. Heredity exists because you have the DNA that stores all the features of your parents!

Theories of Aging

There are two primary categories of aging theories which differ fundamentally in what can be referred to as the "purpose" of aging. In the first category, aging is essentially an accident an accumulation of damage and wear and tear to the body which eventually leads to death. In contrast, programmed aging theories view aging as an intentional process, controlled in a way that can be likened to other phases of life such as puberty.

Error theories include several separate theories including:

    of aging   of aging
  • Protein cross-linking theory of aging  
  • Free radical theory of aging of aging  

Programmed theories of aging are also broken down into different categories based on the method by which our bodies are programmed to age and die.

  • Programmed longevity - Programmed longevity claims that life is determined by a sequential turning on and off of genes.  
  • Endocrine theory of aging of aging  

There is significant overlap between these theories and even categories of aging theories.

Understanding the effect of aging on the genome

Credit: CC0 Public Domain

Time may be our worst enemy, and aging its most powerful weapon. Our hair turns gray, our strength wanes, and a slew of age-related diseases represent what is happening at the cellular and molecular levels. Aging affects all the cells in our body's different tissues, and understanding its impact would be of great value in fighting this eternal enemy of all ephemeral life forms.

The key is to first observe and measure. In a paper published in Cell Reports, scientists led by Johan Auwerx at EPFL started by asking a simple question: how do the tissues of aging mice differ from those of mice that are mere adults?

To answer the question, the researchers used the multiple techniques to measure the expression of everyone one of the thousands of mouse's genes, and to identify any underlying epigenetic differences. The researchers not only measured different layers of information, but they did it across three different tissues: liver, heart, and muscle.

The data collectively allowed them to define an aging 'footprint' that can serve as a field for investigation. But while many of the known aging manifestations were recovered, different tissues behaved differently.

"We will never have a thorough understanding of aging by studying a single tissue, and this applies to many other processes and diseases," says lead author Maroun Bou Sleiman. "Data, whether freshly produced or reused, is the key to understanding complex systems, and we are just scratching the surface."

Through multiple bioinformatics analyses, the scientists identified certain genes and proteins that may be controlling the complex aging process. By including human population data, they also showed that many of the "players" they identified in the mouse genome may be also relevant in human aging.

Finally, the researchers used human genetic data to show that some of the 'players' may also explain why some humans live longer than others. "Our final goal is not to stop aging, but to age better and disease-free, and to do that, we will need to characterize this system," says Johan Auwerx. "This is a perfect example of cross-species integration starting from the laboratory mouse and ending in human population data that takes us one step closer to understanding one of the most complex processes in biology."

In Your Genes?

Aging itself is not a disease. Instead, it’s a slow deterioration of the whole body—beginning with our DNA and cells and affecting every part of the body. However, aging increases our body’s vulnerability to many ailments, such as heart disease, stroke, diabetes, cancer, pneumonia, or Alzheimer’s. Thanks to these age-associated diseases, our risk of dying increases each year until we hit 80. Interestingly, after 80, the yearly odds of dying diminish, plateauing at 105.

The predictability of the aging process suggests it is somehow internally controlled. But how much of aging is “in our genes”? To determine this, doctors have studied aging twins. They’ve learned that about 20–30% of the variation in human life expectancy is under genetic control.

That’s huge. No matter how well you take care of yourself, your genes may have the final say.

Then which genes are to blame? Scientists have found that no single gene controls aging. As a person ages, various genes switch on and off, affecting a complex web of biochemical and physiological processes.

Biological events, not the calendar, trigger the changes associated with aging. In other words, our genes don’t dictate a specific day on which we’ll die. Instead, the body gradually makes subtle changes throughout our lives, timing these changes in response to many internal and external factors. So where does aging start?

Genes can 'influence' personality and behaviour

Genetics plays a role in the age a person first has sex, according to a new study from the Medical Research Council (MRC).

The study, published in the journal Nature Genetics, identifies 38 different genes that are linked to the age of first birth and the age of puberty – as well as the age of first sex.

There is a "reasonably sizeable genetic component" influencing these areas, according to Felix Day from Cambridge University, who worked on the study. But he stressed that cultural and social factors also determine their outcomes.

A wider implication of the study, Day claimed, was an understanding of how genetics may affect a person's behaviour. "We're starting to find genes that have an influence on personality and behaviour," he told WIRED. "I think that people have often become comfortable with the idea that genes determine, or help to determine, various particular characteristics. But the idea that there might be a genetic component of personality is not something that people have particularly looked at before."

CADM2, a gene that controls brain activity and cell connections, the researchers explained, has a genetic variant that leads to a more risk-taking personality. The gene, along with ESR1, is also linked to the number of children a woman has. An irritable temperament was linked to the MSRA gene.

We're starting to find genes that have an influence on personality and behaviour Felix Day , Cambridge University

Researchers from the MRC and Cambridge studied the genetic data of 59,357 men and 66,310 women, all of whom were aged between 40 and 69-years-old. The data came from the UK BioBank, a charity that collected health information from 500,000 people around the country.

Using a regression model the scientists analysed the DNA of people who had provided information on when they lost their virginity and when their first child was born. Day said that this selection process left researchers with around 10 million DNA sites and of these "38 of them came out as statistically significant".

The idea that there might be a genetic component of personality is not something that people have particularly looked at before Felix Day, Cambridge University

is due to genetic factors, which likely act through a variety of biological mechanisms, many of which influence either physical traits, such as puberty timing, or personality characteristics, such as risk-taking propensity," the research paper reads.

Previous research by the team found that entering puberty at an earlier age was linked to increased long-term risks for diabetes, heart disease and some types of cancer.

Dr Ken Ong, one of the lead authors on the paper, said: "We have already shown that early puberty and rapid childhood growth adversely affect disease risks in later life, but we have now shown that the same factors can have a negative effect at a much younger age, including earlier sexual intercourse and poorer education attainment."

Everything starts to sag

Your skin can be a dead giveaway that you've passed the half-century mark. With aging, the skin's outer layer, called the epidermis, thins. At the same time, the skin becomes less elastic and facial fat in the deeper layers of the skin wanes. The result: a loose, saggy façade marked by lines and crevices.

While injections of fillers can help plump up a face, researchers are now finding such cosmetic procedures might not be enough.

That's because jaw, cheek and eye-socket bones also wear down with the march of time, according to research led by Dr. Robert Shaw, Jr., of the University of Rochester. The loss of this "scaffolding" results in upper eyelid droop, plummeting cheeks and jowls that sway in the breeze. The study researchers suggest bone implants might be in order, though as with any surgery there are risks, such as infection and numbness.

Evidences for Evolution: The Whales’ Tale

A really fun family outing in San Diego is to visit Sea World and see the many fascinating and exciting marine exhibits. But the unquestioned main attraction is Shamu, the killer whale. If you are a real bona-fide thrill-seeker, you sit in the first few rows next to the tank, virtually guaranteeing that when the sleek but massive animal breaches the water and then falls back, you will be inundated by a huge wave and soaked to the skin! How did such marvelous creatures arise in the first place? It has taken many years of patient work by scientists operating in very different specialties, but we are now at the point where we can relate the “Whales’ Tale.” It is a story of evolution over a critical period of about ten million years, which is supported by three main types of evidence. We will consider the first two types of evidence in this essay: molecular and fossil.

If evolution is true, then modern whales and other mammals should be related to previously living ancestral species, through a process of “descent with modification.” It should therefore be true that the living organisms and ancestral ones (now extinct) should form a sort of “family tree.” If you have taken an interest in your family genealogy, then you know right away what this means. You, your siblings, parents, aunts, uncles, grandparents, and so forth, can be arranged in a diagram that passes from one generation to the next. If we visualize this going deep into the past, we can use the “tree analogy” even further – the most recent generation of members of the family can be said to lie at the tips of the branches, while very early generations of the family would lie deeper in the tree, at branching points.

The metaphor of using a tree to represent ancestry comes in other varieties too—not just families. Consider, for example the growth and diversification of the historic Christian church – from its roots in ancient history to the tips of its branches—the various denominations still in existence today. As shown below, the Christian traditions which are especially closely related to each other are located near one another at the branch tips. The more distant the relationship, the further away they are in the tree of Christian traditions.

So how can one derive the family tree for organisms like whales—how can one determine the tale of the whale? Cetaceans, after all, have such a dramatically different body plan compared to all other mammals deciphering their family tree presents a fascinating challenge. If evolution is true though, there is one group of organisms to which whales are more closely related than any other. Furthermore, if evolution is true, independent ways of deriving tree structure ought to produce very similar results.

In today’s essay we will show two methods that have enabled biologists to trace the lineage of the whale family: two somewhat independent methods that allow us to explore the structure of the whale’s family tree. In our next post, we will examine a third.

The instructions on how to build an organism are contained within the four letter DNA code: A, G, C, and T. Each gene is a short stretch of this code and the specific order of the 4 letter code is called its “sequence.” The cells of the organism read the code, gene-by-gene, working in concert with one another in constructing the body. Because it is very different than that of other living mammals, understanding the origin of the whale body presents an interesting challenge. Whales are mammals though, so if evolution is true they must have a family tree which shows how they are connected to other groups of mammals.

One useful source of information in whale family tree construction is the sequence of the DNA code-letters (bases) in a particular gene in whales compared to the sequence of that same gene in other mammals. Why would this information help us? Both whales and their related mammalian “sibling and cousin” species will each possess a version of whatever gene we look at that was inherited from their common ancestor. Random mutation will have changed each version of the gene slightly, so that the descendant organisms will generally each have a distinct sequence. More closely related species will have a more recent common ancestor, and will, therefore, have more similar sequences. This means they will tend to lie closer together in our reconstructed family tree.

We can put this DNA gene sequence information from whales and comparison mammals into a tree-building computer program. The living organisms form the tips of the branches and the interior branch points represent extinct predicted ancestral organisms. It turns out that whales sit closest in the tree to a set of hoofed mammals including cows, sheep, pigs, camels, and hippopotamuses. 1 This entire group of hoofed mammals is technically called the “Artiodactyla” (Greek for “even toed”). If evolution is true, this means that whales and these even-toed hoofed mammals share a common ancestral species that existed much more recently than the ancient common ancestral species that gave rise to all mammals. Indeed, even before that there would have been a common ancestral species that gave rise to all mammals and all reptiles. All of this can be represented on the metaphorical tree of life.

There are other independent ways in which DNA analysis can be used to test whether we have correctly positioned whales on the tree of life. Scientists are always eager to obtain different sorts of data. If all independent methods lead to the same conclusion, if “all roads lead to Rome” to use the analogy introduced in an earlier essay, then we can become increasingly convinced that our model is correct. So what is another DNA feature that can be used to determine the whale family history? There are certain chunks of DNA which, on rare occasions in the history of life, move to a new location in a chromosome. These mobile chunks of DNA are sometimes called “jumping genes” although it should be emphasized that they don’t “jump” very often. The location at which a jumping gene inserts itself into a chromosome is quite random. When such an element inserts itself into a particular place in the chromosome, it will reside at that location for many generations. Indeed since “jumping” is so rare, it generally stays at the same location for millions of years. 2 Since the insertion process is almost random, and the element almost never moves out once it is in a chromosome at a particular position, the chance that a “jumping gene” will be in precisely the same place in the chromosome of unrelated organisms is vanishingly small—(essentially zero). In other words, the “jumping gene” makes an ideal “marker” to trace the ancestry of living species. If you examine a set of such “jumping genes,” each inserted into a particular place in the chromosome, only related organisms will share a particular insertion, since they inherited it from their common ancestor. If one of a pair of organisms lacks this insertion at this site, it supports the conclusion that those two organisms do not share a recent common ancestor.

The figure below shows a set of chromosomes, and then enlarges one part of one chromosome to show the DNA molecule. Imagine a “jumping gene” moving in precisely between two of the millions of units of DNA in a chromosome. Since DNA replicates each generation, the chromosome with its inserted “jumping gene” gets passed on faithfully through millions of years. Once a piece of DNA has moved into a chromosome between two bases, it is a great marker to identify species that descend from a common ancestor.

One of the very nice things about this type of DNA information is that it can be tabulated, and is simple enough that you can do a little head scratching and puzzle out the relationships of the organisms involved. The data either consists of a particular “jumping gene” being present (call that a “1”), or if it is absent (call that a “0”). In practice we need a third category, and that is “we don’t know if the “jumping gene” was there or not” (call that a “?”). This third category is necessary because sometimes a random genetic event will result in the loss (deletion) of the entire region which might have contained the jumping gene insertion. Now with this background, take a look at the following figure. 3 For this somewhat simplified example, we show 20 “jumping genes.” If two species share a “jumping gene” at exactly the same position, this means those species are derived from the same ancestral species. This tree confirms the prediction made based on DNA sequence data previously, that is, that whales should be closely related to the group of even-toed hoofed mammals. For example, whales share “jumping genes” 10,12, and 18 with a broad assortment these animals. This means that they all share a common ancestor with insertions in these exact same positions. No other living organisms will share this group of common insertions, or this common ancestor. In addition, these data show that whales are most closely related to hippos (note that they each share “jumping genes” 4, 5, 6, and 7). (In fact, DNA gene sequence studies also support such a relationship, so this is not an aspect of using “jumping gene” data alone). 4

Now we come to the bottom line: so far we have two roads (DNA sequence data and “jumping gene” data), both of which lead to “Rome.” Both point to exactly the same conclusion. Whales, despite their highly specialized body form, can now be confidently predicted to lie within the group of even-toed hoofed mammals. Furthermore, of that group of living mammals, hippos are predicted to be the most closely related to whales. There is agreement between two types of DNA data, and more confidence in our result.

Therefore, if evolution is true, we would expect that living whales and living hoofed mammals should share extinct common ancestors, from which they descended with modification. Or, put another way, we should be able to find “transitional fossil forms” which we can identify by their structural features as being ancestral to both living hoofed mammals and also whales. But about how long ago would we expect such extinct forms to have been alive? It turns out that application of DNA data once again can give us a time estimate with which to start.

We mentioned above that random mutational changes to DNA in an ancestor are passed on to descendant organisms. It turns out that for a particular gene, this sort of change acts as a sort of “molecular clock.” That is, for a particular gene, the rate of change over time is approximately constant. If we can “calibrate” how fast a particular molecular clock for a particular gene is ticking, then we can use it to determine how long ago in the past two species last shared a common ancestor. For example, we know from the fossil record (which has been dated by radioactive isotope clocks, as discussed in a previous essay), that cows and pigs last shared a common ancestor about 55-60 million years ago. We can measure the total number of changes in the DNA of a particular gene in cows and pigs, divide that by the age of a fossil from an ancient species believed to be ancestral to both of them, and determine an average rate of DNA change. Our molecular clock for this gene is now calibrated. If we want to determine when whales last shared a common ancestor with cows, and then pigs, we can measure the total DNA change in our clock gene between whales and cows, and between whales and pigs. We can then divide by the rate of “ticking” of the clock, and determine when in the past these ancestors should have lived. When we do this, it turns out that such common ancestors should have lived about 45 to 50 million years ago.1 So if evolution is true, we should expect to find fossil “transitional forms” showing evidence of common ancestry of hoofed mammals and whales, dating from about this period.

Previously, we learned that a tree summarizing species relationships can be built using DNA information, and how we can use DNA as a “molecular clock” to date ancient events. Both of these methods have made specific predictions about the origin of whales. If evolution is true: whales are related to the even-toed hoofed mammals and should share common ancestors with them transitional fossil forms dating from about 45 to 50 million years ago should be found which can be shown to be related to both the even-toed hoofed mammals and modern whales whales are most closely related to modern hippos, and should share a common ancestor with them.

What other types of information might we be able to use to construct a phylogenetic tree (i.e. a family tree) of species relationships? It turns out that characteristics of body structure also can be used—for example, the presence or absence of certain bones, or the specific shapes of those bones. An advantage of using bony features is that they can be recovered from fossils, whereas DNA (with only certain limited exceptions) must come from living organisms.

We can also derive functional information from an examination of bony features. The various protrusions, bumps and knobs found on bones usually have important implications. For example, smooth rounded areas at the ends of bones allow them to fit together and move easily. The shapes of such surfaces determine which bone motions are “allowed” or “disallowed.” Consider, for example, the motion of the forearm against the upper arm at the elbow. This is a “hinge” joint, whose normal motion is defined by the shapes of the upper arm bone and one of the forearm bones, where they meet each other. You might normally exercise the action of this hinge joint when you pick up a cup of coffee, bring it to your mouth, then set it back down again. Let’s try to imagine another motion. For this exercise we first need to get our arm into the proper starting position. Place your arm at your side, bent at the elbow at a ninety degree angle, with your palm up. Now, while keeping your palm up, let’s attempt to move your arm only at the elbow (no shoulder motion – that’s cheating!). Now swing your forearm out to the side and attempt to end up with your fingers pointed directly away from your side. Most of you will not be able to do this. If you can, it’s because your shoulder is rotating in spite of yourself. This motion at the elbow is normally not allowed. Hence a careful analysis of bone shapes can allow us to infer how the bones were used. This in turn can assist us in the task of phylogenetic (evolutionary) classification of organisms. That is, we will have more confidence in the grouping together of animals in our tree diagram if corresponding bones are used functionally in the same way.

Therefore we would expect that we could use various bony features to help us examine the predictions generated by our previous look at different types of DNA data. Are there any bony features that are particularly relevant to the even-toed hoofed mammals? Well, it turns out that there are. These are mainly running animals, and there are several features of their ankle bones, which taken together define the “allowed” motions which make them efficient runners. If one takes the various ankle bones of a large group of mammals, examines them carefully to note their shapes, scores that information into a table, then uses a computer program to build a phylogenetic tree, it turns out that all the even-toed hoofed mammals are placed together. So far, so good. But what about whales? Well, now we have an obvious problem. Modern whales are very specialized—they have flippers which correspond to the forelimbs, and they have almost no hind limbs! I say “almost” because they do have small pelvic bones, which are not attached to the rest of their skeletons. But they certainly have no ankles. This is where the fossils should come in—if evolution is true, we should expect to be able to identify transitional fossils which are ancestral to whales which contain the characteristic ankle bony features of the even-toed hoofed mammals.

Now let’s look at bony features from the whale perspective. We have already mentioned the almost complete loss of hind limbs, and the presence of forelimbs modified into flippers. In addition, as air breathers, whales have a blowhole at the top of their skull. And as powerful swimmers, which use a large tail fluke in vertical motions, whales have enormous sets of muscles which attach to enlarged projections from their vertebral column. So if evolution is true, we should begin to see fossil forms which manifest changes in bony features which correspond to the gradual accumulation of these whale-like characteristics. However, we still need more, because these various bony features all would be expected to occur in largely or exclusively aquatic forms. We might expect this to correspond to the later stages of a transition from terrestrial even-toed hoofed mammals. But what about the earlier stages? It would be very helpful if we had some “defining” characteristic of whales, similar to the ankle structure of even-toed hoofed mammals.

It turns out that the structure of the bones of the skull and ear apparatus of whales are highly modified to allow efficient hearing underwater. The mechanical aspects of efficiently receiving sound through water are somewhat different than receiving sound traveling through air. If evolution is true, we should expect to be able to find key transitional fossil forms with a progressive series of modifications of the skull and ear bones, features which would not be found in any other mammals.

Now that we know what we should expect to see, if evolution is true, let’s look at what has actually been found in the fossil record. Over the last fifteen years or so, a series of fossils, many of them discovered in the Indian subcontinent, have fulfilled nearly all of our predictions. 1,2 The entire fossil progression illustrated occurs from a little over 50 million years ago to about 40 million years ago. So a remarkable alteration in general body form occurred in a little over 10 million years. This time frame agrees well with the previous prediction from the DNA “clock” that we discussed earlier. Second, the general change in body shape corresponds to what we predicted in our discussion of whale bony features above. That is, there is a gradual elongation and streamlining, there is a modification of the forelimb into flippers and progressive reduction of the hindlimb, the nostrils for breathing move toward the top of the skull to form a blowhole, and the vertebrae develop enlarged projections to support the attachment of swimming muscles.

There is probably little question that the fossil species Dorodon is well on the way to becoming a modern whale. However, it might be argued by a skeptic that the earlier species (like Rhodocetus, Ambulocetus, or Pakicetus), despite the “cetus” (whale) part of their names, are not so obviously “whale-like” that they deserve to be considered as fossil whale ancestors. However, remember the characteristic whale skull modifications for hearing? It has been shown very clearly that throughout this series of fossil species, the various bony changes necessary to support efficient hearing in water were being acquired in a stepwise fashion. Organisms earlier in the sequence had skeletal characteristics consistent with them being able to hear well in both air (using the “classic” mammalian hearing apparatus), and newly acquired changes to also allow better hearing in water. Later organisms in the sequence become increasingly specialized for hearing in water only. 4

What of the earliest fossil shown in this diagram—Pakicetus? Careful examination shows that it has the features we would predict for an early whale ancestor. It has the ankle bone characteristics of the even-toed hoofed mammals (in fact these features are also found in several of the later fossil forms as well, ensuring their continuity). This confirms one of the predictions made by the DNA evidence we discussed earlier. Furthermore, it has some of the modifications of the skull bones necessary for more efficient underwater hearing, which were previously documented only for modern whales and their later (more obvious) ancestors. 4 These features are also shared with the “whale cousin” Indohyus. 5 Preservation of more of the skeleton of this latter species has allowed detailed analysis indicating characteristics likely shared with whale ancestors. Indohyus was probably a wading animal, which spent much of its time in the water. It appears to have fed mostly on land, so it is suggested that resort to the water was made to escape predators. 5

Finally, we need to look back at the last prediction from our previous DNA evidence, namely that modern whales are most closely related to hippos. If evolution is true, we should expect to find fossil forms linking these two modern groups. This has proven to be a tougher nut to crack, mainly because the ancestral whales first appear about 50 million years ago in what is now south Asia, and the hippo family first appears about 15 million years ago, in Africa. The most recent tree diagram, produced by using a combination of skeletal features and DNA data, still supports this family connection, as shown by the following figure (Figure 2). 6

Figure 2: Phylogenetic Tree Showing the Relationship of Modern Whales to Living and Extinct Even-Toed Hoofed Mammals
This tree is based on both bony features and DNA data. The organisms presented in blue are semi-aquatic or aquatic forms. Organisms shown in green are terrestrial even-toed hoofed mammals (Artiodactyls). In black is shown a member of the odd-toed hoofed mammals. In red is an extinct fossil ancestor group. (This figure is adapted from Fig 1a in Reference 6).

The blue lines in the diagram show species in which the skeleton is specially thickened, and the bone structure more dense. This is an adaptation which allows wading animals (like modern hippos and the fossil Indohyus) to be good “bottom-walkers” (it prevents them from floating due to lighter body tissues), and allows fully marine organisms (like modern whales) to have “neutral buoyancy” (so they don’t always tend to pop up to the water surface, like a cork). There has also been progress in clarifying the relationships between fossil ancestors of hippos and those of modern whales. A recent study of hippo evolution, based only on skeletal characteristics, has conclusively shown that the hippo family are descended from an extinct group of fossil Artiodactyls, known to go back more than 40 million years, and whose fossils are from southern Asia. Furthermore, this study produced a phylogenetic tree predicting that this extinct hippo ancestor group also shared a common ancestor with the fossil whales. 7 Thus the investigation of hippo origins is independently leading us back toward the origin of whales. However, in this study the statistical support for predicted common ancestor of the ancient hippo group and the ancient whale group is not as strong as scientists would like to consider this “case closed.” What is necessary is more fossils, of the appropriate age in order to complete the story of hippo evolution. We still need that to fill in the details of the predicted relationship of hippos to modern whales.

Thus the “Whales’ Tale” is not yet complete. It is a story of scientific discovery in progress. As we finish, let’s briefly summarize what we have found out. Different types of DNA evidence agree that modern whales are most closely related to the even-toed hoofed mammals, despite the obvious great changes in limb anatomy of the modern whales. This prediction has been amply confirmed by the fossil record. The DNA sequence evidence predicted a time frame during which critical early events in evolution of whale ancestors should occur. This prediction has also been amply confirmed. Finally, DNA evidence predicts that modern whales are most closely related to hippos. There is some fossil evidence supporting a predicted common ancestor, but more data is needed. A final caution to possible sceptics—this state of “unfinished business” is precisely how the scientific process works. There is no “crisis.” There is no indication that evolution is not true. There is simply the ongoing work of mapping out of various lines of evidence. A scientific conclusion is considered well supported if “all roads lead to Rome.” In the case of whale evolution it might be prudent to say that the evidence has not quite converged in Rome yet, but that we are now in the suburbs. That is precisely what makes science interesting and fun. Stay tuned!

Notes & References

Part One Notes:

1. Grauer D. and Higgins D.G. 1994. Molecular Evidence for the Inclusion of Cetaceans within the Order Artiodactyla. Molecular Biology and Evolution 11(3):357-364.

2. Very often, in fact, inserted “jumping” elements are “paralyzed” and unable to jump out, but that’s another story.

3. Data from: Nikaido M., Rooney A.P., Okada N. 1999. Phylogenetic relationships among cetartiodactyls based on insertions of short and long interpersed elements:Hippopotamuses are the closest extant relatives of whales.Proceedings of the National Academy of Sciences U.S.A. 96:10261-10266.
Figure adapted from: Freeman S. and Herron J.C. 2007. Evolutionary Analysis, 4th Ed. Pearson, Upper Saddle River, NJ, Pg. 128.

4. Gatesy J., Milinkovitch M., Waddell V., Stanhope M. 1999. Stability of Cladistic Relationships between Cetacea and Higher-Level Artiodactyl Taxa. Systematic Biology. 48(1):6-20.

Part Two Notes:

1. Thewissen J.G.M., Williams E.M., Roe L.J. and Hussain S.T. 2001. Skeletons of terrestrial cetaceans and the relationship of whales to artiodactyls. Nature. 413: 277-281.

2. Gingerich P.D., ul Haq M., Zalmout I.S., Khan I.H., Malkani M.S. 2001. Origin of Whales from Early Artiodactyls: Hands and Feet of Eocene Protocetidae from Pakistan. Science. 293:2239-2242.

3. Numella S., Thewissen J.G.M., Bajpai S.,Hussain T., Kumar K. 2007. Sound Transmission in Archaic and Modern Whales: Anatomical Adaptations for Underwater Hearing. The Anatomical Record. 290:716-733.

4. Thewissen J.G.M., Cooper L.N., Clementz M.T., Bajpai S., Tiwari B.N. 2007. Whales originated from aquatic artiodactyls in the Eocene epoch of India. Nature. 450:1190-1194.

5. Geisler J.H. and Theodor J.M. 2009. Hippopotamus and whale phylogeny. Nature. 458:E1-E4.

6. Boisserie J.-R., Lihoreau F., Brunet M. 2005. The position of Hippopotamidae within Cetartiodactyla.Proceedings of the National Academy of Sciences U.S.A. 102(5):1537-1541.

About the Authors

Darrel Falk

David Kerk

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Slim people have a genetic advantage when it comes to maintaining their weight

In the largest study of its kind to date, Cambridge researchers have looked at why some people manage to stay thin while others gain weight easily. They have found that the genetic dice are loaded in favour of thin people and against those at the obese end of the spectrum.

More than six in ten adults in the UK are overweight, and one in four adults is obese. By age five, almost one in four children is either overweight or obese. Excess weight increases the risk of related health problems including type 2 diabetes and heart disease.

While it is well known that changes in our environment, such as easy access to high calorie foods and sedentary lifestyles, have driven the rise in obesity in recent years, there is considerable individual variation in weight within a population that shares the same environment. Some people seem able to eat what they like and remain thin. This has led some people to characterise overweight people as lazy or lacking willpower.

With support from Wellcome and the European Research Council, a team led by Professor Sadaf Farooqi at the Wellcome-MRC Institute of Metabolic Science, University of Cambridge, established the Study Into Lean and Thin Subjects -- STILTS -- to examine why and how some people find it easier to stay thin than others. Studies of twins have shown that variation in body weight is largely influenced by our genes. To date studies have overwhelmingly focused on people who are overweight. Hundreds of genes have been found that increase the chance of a person being overweight and in some people faulty genes can cause severe obesity from a young age.

Professor Sadaf Farooqi's team were able to recruit 2,000 people who were thin (defined as a body mass index (BMI) of less than 18 kg/m2) but healthy, with no medical conditions or eating disorders. They worked with general practices across the UK, taking saliva samples to enable DNA analysis and asking participants to answer questions about their general health and lifestyles. It is thought to be the only cohort of its kind in the world and the researchers say that the UK's National Institute for Health Research -- the National Health Service's research infrastructure -- strongly enabled and supported their research.

In a study published today in the journal PLOS Genetics, Professor Farooqi's team collaborated with Dr Inês Barroso's team at the Wellcome Sanger Institute to compare the DNA of some 14,000 people -1,622 thin volunteers from the STILTS cohort, 1,985 severely obese people and a further 10,433 normal weight controls.

Our DNA comprises of a sequence of molecules known as base pairs, represented by the letters A, C, G and T. Strings of these base pairs form genetic regions (which include or make up our genes). Our genes provide the code for how our body functions and changes in the spelling -- for example, a C in place of an A -- can have subtle or sometimes dramatic changes on features such as hair colour and eye colour but also on a person's weight.

The team found several common genetic variants already identified as playing a role in obesity. In addition, they found new genetic regions involved in severe obesity and some involved in healthy thinness.

To see what impact these genes had on an individual's weight, the researchers added up the contribution of the different genetic variants to calculate a genetic risk score.

"As anticipated, we found that obese people had a higher genetic risk score than normal weight people, which contributes to their risk of being overweight. The genetic dice are loaded against them," explains Dr Barroso.

Importantly, the team also showed that thin people, had a much lower genetic risk score -- they had fewer genetic variants that we know increase a person's chances of being overweight.

"This research shows for the first time that healthy thin people are generally thin because they have a lower burden of genes that increase a person's chances of being overweight and not because they are morally superior, as some people like to suggest," says Professor Farooqi. "It's easy to rush to judgement and criticise people for their weight, but the science shows that things are far more complex. We have far less control over our weight than we might wish to think."

Three out of four people (74%) in the STILTS cohort had a family history of being thin and healthy and the team found some genetic changes that were significantly more common in thin people, which they say may allow them to pinpoint new genes and biological mechanisms that help people stay thin.

"We already know that people can be thin for different reasons" says Professor Farooqi. "Some people are just not that interested in food whereas others can eat what they like, but never put on weight. If we can find the genes that prevent them from putting on weight, we may be able to target those genes to find new weight loss strategies and help people who do not have this advantage."